Hair zinc and dietary zinc intake during pregnancy and puerperium.

A longitudinal study of hair zinc concentration was carried out in 36 pregnant women at 12 and 36 weeks of gestation and 40 days postpartum. A progressive decrease in hair zinc concentration was noted through pregnancy; the decline between 12 and 36 weeks of gestation was statistically significant (P < 0.005) remaining without significant changes in the postpartum. Nutrient intakes were calculated from 3-day weighed food records at the same periods and at 20 weeks of gestation. Zinc, energy and protein intakes decreased during pregnancy. Mean zinc intake at 20 and 36 weeks of gestation was about 66% of the recommended dietary allowance (RDA) (9.8 and 10 mg, respectively) and about 52% of the RDA in the postpartum (9.8 mg). Although hair zinc levels do decline in pregnancy and zinc intake was lower than RDA, the study revealed that zinc nutriture was adequate for normal growth and development of fetus.


Cytogenetic analysis of spontaneous abortions with direct analysis of chorionic villi.

A total of 224 cases of spontaneous abortions were studied by analysing chromosomes directly from chorionic villi. Abnormal karyotypes were found in 51.3% of the investigated cases. Among the chromosome abnormalities the most frequent were the trisomies (55.7%), followed by polyploidy (23.5%), monosomy X (15.6%) and structural anomalies (5.2%). The rapid and relatively simple method is suitable for studying the causes of spontaneous abortions, and this information may be helpful also for genetic counselling.


[Respective weight of genotypes DQA1 and DQB1 associated with insulin-dependent diabetes in French children].

Genetic susceptibility alleles have been identified at the DQ HLA region. The aim of the present study was to confirm the value of these markers, and to evaluate the respective weight in the risk of the different alleles at the DQA1 and DQB1 levels, identified by restriction mapping after polymerase chain reaction on exon 2. A significant enrichment in DQB1 alleles encoding for an aminoacid different from Aspartic acid at position 57 (NA) was observed in diabetic (n = 213) in comparison to control (n = 93) children (94% vs 52%; p < 10(-8)). Not all the given NA/NA allelic combinations were equally and positively associated to the disease. Homozygous "Ala/Ala" combinations carried the highest relative risk (OR = 12.3; p < 10(-8)), and among them, the *0201/*0302 genotype was more positively associated to type 1 diabetes (OR = 66; p < 10(-8)). A significant enrichment in DQA1 alleles encoding for Arginine at position 52 in diabetic children was also observed (82% vs 40%; p < 10(-8)). The *0301/*0501 (Arg/Arg) genotype was significantly associated to Type 1 diabetes (OR = 16.2; p < 10(-4)). The highest risk was carried by the whole genotype, a result which could be expected from the known linkage desequilibrium between HLA-DQA1 and DQB1, DRB1 loci. The frequency of Ala DQB1 alleles was low in the background non-at-risk population, although the incidence of the disease is low in our country.


The reliability, acceptability and applications of basal body temperature (BBT) records in the diagnosis and treatment of infertility.

The possibilities and limitations of basal body temperature (BBT) records as an adjunct in the management of infertility were re-evaluated. To assess its accuracy as an index of ovulation, 172 charts were analyzed by three different physicians. While the average true positive rate was 90%, the false negative rate was only 2%. The remaining graphs (8%) were classified as non-interpretable, probably reflecting measurement problems. Retrospective assessment of 210 biphasic records showed the thermal nadir to occur within 1 day of the urinary luteinizing hormone (LH) surge in 75% of the cases, and in 90% when 2 days where considered. This confirms BBT as a relatively accurate guide for retrospective identification of the periovulatory period. Moreover, results of a study conducted to investigate how patients experienced daily recording of BBT graphs suggest that the method is well accepted by a high proportion of women. From all these it appears that there are many indications where BBT graphs can still be applied. Development of new electronic devices may further improve the reliability, acceptability and applications of the BBT records in the fertility investigation.


Similarity of HLA-DQ profiles in adult-onset type 1 insulin-dependent diabetic patients with and without extra-pancreatic auto-immune disease.

Some insulin-dependent diabetic patients present with auto-immune diseases involving extra pancreatic tissues (type 1b diabetes mellitus). The genetic specificity of this syndrome, as opposed to insulin dependent diabetes mellitus (IDDM) free of such associations (Type 1a IDDM) is not clearly established. We have analyzed the HLA-DQB1 and DQA1, loci, after PCR amplification of genomic DNA, in 44 Type 1b IDDM patients, 78 Type 1a IDDM patients and 105 control subjects. No essential difference in HLA-DQ profiles appeared between Type 1b and Type 1a IDDM patients. Both diabetic groups displayed a significant enrichment in DQB1 alleles negative for aspartate at position 57 (Type 1b: 83%; Type 1a: 89%; controls 48%; p < 0.001 vs both patient groups) and in DQB1 Asp 57 negative homozygosity: 71% of Type 1b; 80% of Type 1a; 25% of controls (p < 0.01). This enrichment in DQB1 Asp 57 negative alleles was accounted for by DQB1* 0201 in the Type 1b group, and by DQB1 % 0201 and 0302 in the Type 1a patients. Conversely, alleles DQB1* 0602 and 0301 (DQB1 Asp 57 positive) were protective. Both diabetic groups also displayed a significant enrichment in DQA1 alleles positives for arginine at position 52 (65% of Type 1b; 76% of Type 1a; 50% of control subjects; p < 0.01 and 0.001, respectively, vs controls), and in DQA1 Arg 52 positive homozygotes (48% of Type 1b, 58% of Type 1a, 22% of control subjects; p < 0.01). All differences between diabetic groups and the control group were more pronounced in the case of Type 1a than of Type 1b patients. The HLA-DQ genes shared by Type 1a and Type 1b patients must therefore be closely associated with islet autoimmunity. Genetic differences between Type 1a and Type 1b syndromes, if any, must be investigated in other MHC and non-MHC regions of the genome.


Paradoxical ovarian stimulations in the use of LHRH analogs.

In the case of in vitro fertilization, LHRH analogs are used to induce an hypophysary blockage, before the phase of stimulation, via administration of exogenous gonadotropin. During in vitro fertilization attempts using LHRH analogs, the blockage is controlled after 14 days of treatment through measurement of the plasmatic estradiol and pelvic ultra-sonography. In this retrospective study, which concerned 1075 in vitro fertilization cycles, a paradoxical ovarian stimulation with LHRH analogs was observed in 93 cases (8.7%), with high estradiol levels and follicular growth (detected by ultra-sonography), in spite of low FSH and LH levels. In 4 cases, a follicular puncture was performed, which allowed to collect oocytes from which embryos were obtained, thus confirming the observed follicular growth and maturation. The most probable hypothesis explaining this phenomenon seems to be a direct ovarian stimulation, effectuated in vivo by LHRH analogs. This stimulation is only observed in certain patients, and apparently more frequently, with certain LHRH analogs, probably through a variation in the expression of ovarian LHRH receptors.


The unicornuate uterus: clinical implications.

The unicornuate uterus is associated with a poor reproductive outcome and many gynecological problems. We collected data from 45 women with a unicornuate uterus. We found a high abortion rate of 22% in the first trimester and 16% in the second trimester. Premature labor occurred in 18%. The prevalence of infertility and endometriosis in women with a unicornuate uterus was comparable to women without the anomaly.


Early stage cervical cancer: aborted versus completed radical hysterectomy.

In a retrospective study, the treatment results of patients with stage IB and IIA cervical cancer were evaluated. In 26 patients radical hysterectomy was discontinued after intra-operative finding of positive lymph nodes. These patients received radiotherapy. In 57 patients lymph nodes were negative, and radical hysterectomy was completed. Of these, 13 patients received adjuvant radiotherapy because of positive surgical margins or parametrial involvement, and 44 patients received no adjuvant therapy. Five-year survival was 61% in patients with positive pelvic lymph nodes and 88% in patients with negative pelvic lymph nodes, comparable with the results mentioned in the literature. The complication rate did not differ from similar other reports. This management shows treatment results comparable with other reports with minimal morbidity.


Beneficial effects on serum lipoproteins by 17 beta-oestradiol-dydrogesterone therapy in postmenopausal women; a prospective study.

To study the possible changes of reproductive hormones, sex hormone binding globulin, serum lipids and lipoproteins, lipoprotein (a) included, coagulation and glucose in postmenopausal women treated with 17 beta-oestradiol and cyclic dydrogesterone for 14 days per 28 days treatment cycle. Open longitudinal prospective study. Twelve 28 days treatment cycles. Gynaecological department of university hospital. 27 healthy postmenopausal women. After treatment for six cycles serum concentrations of FSH and LH decreased significantly with 43.0% and 24.4%, respectively. Serum concentrations of 17 beta-oestradiol and oestrone increased significantly with 302% and 792%, respectively, and SHBG increased as well with 111% (P < 0.01). Serum total cholesterol decreased with 9.0% (P < 0.01). Serum VLDL-cholesterol did not change significantly. Serum LDL-cholesterol decreased with 16.3% (P < 0.01) and HDL-cholesterol increased with 8.0% (P < 0.01). This was accompanied with similar significant changes in the apolipoproteins: apolipoprotein A-I rose with 14.4% and apolipoprotein B decreased with 6.0%. Serum triglycerides and VLDL-triglycerides increased significantly with 14.4% and 17.9%, respectively. Lipoprotein (a) decreased with 17.5% (P < 0.01). These results more or less sustained at cycle 12 of treatment. Serum concentrations of antithrombin III and glucose did not change. Fibrinogen decreased slightly but significantly below the initial value. This combination replacement therapy gives beneficial changes in lipid-metabolism, indicating a reduced risk of developing coronary heart disease without unfavourably changing coagulation and glucose metabolism. The expected beneficial changes with oestradiol alone are not counteracted by the intermittent addition of dydrogesterone. Therefore this oestrogen/progestagen scheme can, indeed, be recommended for use in HRT.


Ultrasound diagnosis of interstitial pregnancy.

A case of interstitial pregnancy is reported. The diagnosis was made by ultrasound examination in an asymptomatic patient at risk for ectopic pregnancy following cornual anastomosis. Characteristic sonographic signs are discussed, with a review of the literature.


Vulvar pseudolymphoma.

We report a 31-year-old patient with longstanding complaints of vulvar itching and painful intercourse treated with many antimycotic drugs. On examination a small tumor, clinically not differentiable from a malignant lymphoma, on and near the clitoris was found. After excision biopsy the lesion proved to be a pseudolymphoma. Six months after excision of this rare vulvar tumor the patient was completely free of complaints. Although pseudolymphomas are small benign tumors they may case diagnostic problems and major complaints. To our knowledge this very rare disorder has not been reported in the gynecological literature until now.


Post-menopausal cyclic eruptions: autoimmune progesterone dermatitis.

Two cases of autoimmune progesterone dermatitis (AIPD) are reported. The patients developed a recurrent eruption, primarily on the extremities after receiving oral oestrogen/progesterone replacement for the treatment of climacteric symptoms. The diagnosis was confirmed in one of the cases who had intradermal progesterone injection producing an early positive reaction. One case required transient prednisolone therapy and both eventually resolved completely. Aetiological postulates are discussed.


Doppler velocimetry of the umbilical artery in pregnancies complicated by insulin-dependent diabetes mellitus.

The purpose of this study was to investigate vascular resistance by Doppler ultrasound in the umbilical artery of insulin-dependent diabetics longitudinally over the course of pregnancy. Special interest was put on the effects of glycemic control and maternal vascular disease on the flow velocity waveform (FVW) and the predictive value of Doppler flow measurements with regard to perinatal morbidity. Using a duplex-pulsed wave scanner, the resistance-index (PR index) in the umbilical artery was calculated. The mean value of a 24-h blood glucose profile and the concentration of glycosylated hemoglobin (HBA1C) were used as parameters of metabolic control. 53 pregnant diabetic women were examined longitudinally during the course of pregnancy on average on three occasions (range: 1-7) between 17 weeks of gestation and delivery at 37.7 +/- 1.3 (mean +/- SD) weeks. To test the predictive value of Doppler flow velocimetry with regard to perinatal morbidity the results were compared to the FVWs measured in the umbilical arteries of 30 non-diabetic women with normal fetal outcome. Vascular resistance in the umbilical artery of the diabetics declined significantly during the course of pregnancy, with a mean PR index of 0.729 (SD 0.051) at 17 weeks and 0.603 (SD 0.083) at the end of pregnancy (P < 0.002). The majority of PR indices were within the range reported for normal pregnancy and measured in the non-diabetic women. Regression analysis showed no significant correlation between vascular resistance and mean blood glucose level (r = 0.1325) or concentration of HBA1C (r = -0.0519). Maternal vascular disease had no effect on umbilical FVWs.(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibition of binding of bacteria to amniochorionic membranes by amniotic fluid.

The immunological composition of amniotic fluids is shown to be of such a lower order of activity that its role in fetal protection may be limited. Also, amniotic fluids were found not to have classical antibiotic activity. Amniotic fluids (25/31), however, were found to inhibit, by 27.5% to 88.2%, three target bacteria from binding to discs of amniochorionic membranes. This inhibition is also demonstrable with the monosaccharides alpha-D(+)-fucose, D(+)-galactose, alpha-D-glucose, alpha-D-lactose and bovine serum albumin-lactose conjugate, whereas other glycoconjugates enhanced bacterial binding. This demonstrates that the test bacteria bind to the amniochorionic membranes using bacterial lectins. In intraamniotic infection bacterial lectins may be complexed by amniotic fluid glycoconjugates which prevent the bacteria from binding to the amniochorionic membranes. This would explain asymptomatic infection and in the absence or reduced levels of the glycoconjugates the bacteria would bind to the amniochorionic membranes giving rise to symptomatic infection.


Calbindin-D9k gene expression during pregnancy and lactation in the rat.

Calbindin-D9k (CaBP-9k) is a calcium binding protein expressed in mammalian intestine, uterus and placenta. It is believed to be involved in transepithelial calcium transport in intestine and placenta and regulation of cytosolic calcium concentration in uterus. CaBP-9k mRNA levels were measured by Northern blot analysis in maternal duodenum, uterus, placenta and fetal/neonatal duodenum during pregnancy and lactation. In maternal duodenum a maximal increase occurred at day 15 of lactation (2.3-fold) and 20 days post-lactation levels decrease to 30.3% of non-pregnant controls. In non-pregnant uterus a 10-fold variation of CaBP-9k mRNA levels was observed between individual animals despite a uniform expression of beta-actin. During pregnancy high CaBP-9k expression is found, averaging about 20% of duodenal levels, which abruptly drops below detection during early lactation. At late lactation CaBP-9k mRNA levels are again subject to great variation ranging from no expression to maximal levels found in the non-pregnant uterus. Placental CaBP-9k is maximally expressed at the end of pregnancy (day 20) reaching about 2.5% of duodenal levels. Fetal intestinal CaBP-9k mRNA was detectable in 20 micrograms total RNA at day 18 of pregnancy and rose sharply in early lactation reaching about 50% of adult duodenal levels at day 20 lactation. The profound changes of uterine CaBP-9k mRNA in non-pregnant (cycling), pregnant, and lactating rats indicate a rapid hormonal regulation of gene expression, most likely involving 17 beta-estradiol.


Rat oocytes induced to mature by epidermal growth factor are successfully fertilized.

Epidermal growth factor (EGF), which is a known mitogen, can also induce resumption of meiosis in the rat oocyte. The present study was designed in an attempt to elucidate whether oocytes, induced to mature by EGF in a follicle-enclosed oocyte culture, are fertilizable and can further develop into two-cell embryos. For further clarification of the effect of EGF on steroidogenesis in the ovarian follicle, progesterone concentrations were determined by radioimmunoassay. We found that oocytes matured by EGF (100 ng/ml) were successfully fertilized. Even though their rate of fertilization was relatively lower as compared to that of oocytes stimulated by luteinizing hormone (LH) both in vitro and in vivo (61%, 79%, and 83% respectively), once fertilized they exhibit an equal potential for further development (EGF: 48%, LH: 45%). On the other hand, EGF-induced progesterone production was very poor. These findings strongly support the idea that both mitogenesis and meiogenesis can be mediated by common signals. The results further suggest that progesterone production and oocyte maturation, in the rat, are independent events.


Interaction of the 90-kDa heat shock protein with native and in vitro translated androgen receptor and receptor fragments.

Androgen receptor (AR) from rat ventral prostate and AR synthesized in vitro by translation in rabbit reticulocyte lysate of AR mRNA, transcribed from a pGEM-4Z DNA template were compared by gel permeation chromatography and by sucrose gradient ultracentrifugation. Under non-activating conditions the AR from rat prostate migrated as an 8-9 S complex of approx. 300 kDa. The addition of chicken antibodies against HSP90 shifted this complex to the void volume of the column or to the bottom of the ultracentrifugation gradient. Under activating conditions, on the other hand, the AR migrated as a 110 kDa, 5.2 S protein and was no longer displaced by HSP90 antibodies. Under all these conditions, the behaviour of in vitro synthesized AR was very similar to that of AR from rat prostate. By selective use of restriction enzymes on the template of transcription AR mutants could be prepared from which an increasing part was deleted at their carboxy terminal end. The interaction with HSP90 was conserved for AR1-758 missing the last 145 amino acids, but was lost in AR1-703. Furthermore, a large internal deletion (ARd41-469) of the major part of the amino terminal half of the AR did not result in the loss of HSP90 binding. These results indicate that a specific subregion (amino acids 704-758) of the carboxy terminal half of the AR is required for the interaction with HSP90.


Identification of a transcriptional enhancer upstream from the bovine thyroglobulin gene.

The DNA sequences corresponding to a DNaseI-hypersensitive region identified previously in bovine thyroglobulin gene chromatin (Hansen et al. (1988) Eur. J. Biochem. 178, 387-393) exhibited the properties of a transcriptional enhancer in a transient assay in primary cultured dog thyrocytes, but did not so in transfected HeLa cells. By contrast to the thyroglobulin proximal promoter, the enhancer element did not require cyclic AMP stimulation of the thyrocytes to be active. Using a bi-directional deletion approach, the minimal region displaying enhancer activity has been localized between positions -1906 and -1744 relative to the thyroglobulin gene transcription start. DNA-footprinting experiments revealed the presence of several binding sites for the thyroid-specific transcription factor TTF-1 within the enhancer sequence.


Evidence for basic fibroblast growth factor receptors in cultured immature Leydig cells.

Previous studies have shown that basic fibroblast growth factor (bFGF) can modulate basal and luteinizing hormone/human chorionic gonadotropin (LH/hCG)-stimulated Leydig cell functions. It has not been ascertained whether these actions are due to direct or indirect effects on Leydig cells. To resolve this question, a multi-step procedure was used to isolate highly-purified Leydig cells from immature rats. 125I-bFGF binding studies were performed on cultured cells. Scatchard analysis of the data indicated a single binding site with an apparent Kd of 82 pM and a binding capacity of approximately 2800 sites per cell. Both bFGF and acidic FGF similarly were effective in displacing 125I-bFGF, suggesting that the receptor binds both bFGF and aFGF. However, neither hCG, follicle-stimulating hormone (FSH), insulin, insulin-like growth factor-1 (IGF-1), prolactin, platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) were effective competitors. When binding studies were conducted on cultured testicular interstitial cellular fractions that are normally discarded during Leydig cell purification, bFGF receptors were identified in these fractions. These results demonstrate that bFGF can have direct effects on Leydig cells through specific receptors; however, because other interstitial cell type(s) also have bFGF receptors, they stress the importance of using highly purified cells when evaluating bFGF actions on Leydig cells.


Biphasic effects of exogenous ganglioside GM3 on follicle-stimulating hormone-dependent expression of luteinizing hormone receptor in cultured granulosa cells.

The major ganglioside NeuAc alpha 2-->3Gal beta 1-->4Glc beta 1-->1Cer (GM3) present in cultured rat granulosa cells was examined for potential function in the expression of luteinizing hormone (LH) receptor on the cell surface in response to follicle-stimulating hormone (FSH). Synthesis of GM3 was stimulated concentration-dependently by FSH, and the stimulation was enhanced synergistically by insulin, as revealed by metabolic labeling of glycosphingolipids with [3H]galactose. When granulosa cells were cultured in the media containing GM3 (0.2-20 microM), biphasic changes in FSH-dependent expression of LH receptor were observed, as measured by the binding of 125I-deglycosylated human choriogonadotropin to the intact cells. Exogenous GM3 suppressed expression of LH receptor in the cells treated with a low dose of FSH (20 ng/ml), which was characterized by a low GM3 level, to 30% of control at 10 microM, with a half-maximal inhibitory concentration of 8 microM. In contrast, in the cells treated with a high dose of FSH (100 ng/ml) and insulin, which was characterized by a high GM3 level, expression of LH receptor was enhanced by exogenous GM3, to 148% of control at 10 microM, with a half-maximal effective concentration of 2 microM. Exogenous GM3 produced concomitant changes in the levels of extracellular cAMP. These effects of exogenous GM3 were not accompanied by changes in granulosa cell proliferation. Exogenous GM3 also modulated the LH receptor expression by the synergistic action of 12-O-tetradecanoylphorbol 13-acetate with insulin, with no significant changes in cellular DNA contents, suggesting that exogenous GM3 does not modulate directly the action of FSH at its receptor sites.(ABSTRACT TRUNCATED AT 250 WORDS)


The murine luteinizing hormone and follicle-stimulating hormone receptor genes: transcription initiation sites, putative promoter sequences and promoter activity.

The putative promoter regions of the murine follicle-stimulating hormone (FSH) and luteinizing hormone (LH) receptor genes were isolated and used to map transcription initiation sites for both genes. For the FSH receptor gene, a major transcription initiation site was found 534 nucleotides upstream, and for the LH receptor gene 310 nucleotides upstream of the corresponding translation initiation codons. In addition, several alternative minor transcription initiation sites were observed for both genes. The nucleotide sequences of the promoter regions revealed no canonical promoter elements, such as TATA and CCAAT consensus sites 5' of the main transcriptional start sites. The isolated promoter segments for both receptor genes showed low functional activity as verified in transient expression studies in immature rat granulosa cells using the luciferase coding region as the reporter for promoter activity. Both promoter elements seem to be still under tissue specific control, since neither LH receptor nor FSH receptor promoter activity was detectable in another cell line (CHO) investigated.


Differential regulation of anterior pituitary prodynorphin and gonadotropin-subunit gene expression by steroid hormones.

Prodynorphin is expressed by neurons of the hypothalamus and gonadotrophs of the anterior pituitary gland (AP) and plays a role in the negative feedback regulation of the reproductive neuroendocrine axis. The present study examined whether gonadal steroid hormones are capable of modulating pituitary prodynorphin expression in immature, female rats. Steroids were administered via subcutaneous Silastic implants and rats were killed at 29 days of age. Northern blot analysis was used to measure AP prodynorphin, luteinizing hormone-beta (LH beta), follicle-stimulating hormone-beta (FSH beta), and common alpha-subunit mRNA levels (normalized to 18S ribosomal RNA). Treatment groups (n = 5-6) consisted of control (CNT; empty implants), estradiol (E2; 4 days), E2 + progesterone (E2 + P4; 8 days and 4 days, respectively), and dihydrotestosterone (DHT; 4 days). Pituitary prodynorphin mRNA was significantly suppressed in only the DHT-treated animals (26 +/- 10% of CNT, p < 0.01). LH beta mRNA was suppressed by all steroid treatments (p < 0.01), FSH beta was lower in only the E2 group, and alpha-subunit was reduced in both the E2 + P4 and DHT groups (p < 0.01). Serum LH was suppressed by all steroid treatments but FSH was reduced in only the E2 and E2 + P4 groups (p < 0.01). Treatment of prepubescent rats with continuous high levels of gonadal steroids is known to severely reduce endogenous hypothalamic gonadotropin releasing hormone (GnRH) release and this is supported by our observation of reduced gonadotropin-subunit gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)


Ontogeny of apomorphine-induced stereotypy and its D1 and D2 receptor mediation in rats depleted of dopamine as neonates.

The ontogeny of apomorphine-induced stereotypy in rats treated with 6-OHDA (100 micrograms) or its vehicle on postnatal Day 3 was determined on Days 6, 21, or 60-90. Stereotypic sniffing and mouthing behavior were produced by apomorphine in control and DA-depleted animals as early as Day 6. Animals depleted of DA as neonates exhibited supersensitivity to these behavioral effects from Day 6 into adulthood. The relative contributions of D1 and D2 receptor activation to apomorphine-induced behaviors were determined by measuring the ability of specific D1 or D2 antagonists to block these effects in adults. Blockade of D1 receptors with SCH 23390 or D2 receptors with clebopride suppressed apomorphine-induced stereotypy in both vehicle- and 6-OHDA-treated rats. However, adults depleted of DA as neonates were less sensitive to the DA antagonists than were control rats. These results demonstrate that apomorphine-induced stereotypy is present as early as postnatal Day 6. Rats depleted of DA as neonates continue to exhibit these behaviors, even at lower doses of apomorphine than were necessary in control animals. Finally, coactivation of D1 and D2 receptors appears necessary for apomorphine-induced stereotypy in both groups of rats.


Thermogenesis during ultrasonic vocalization by rat pups isolated in a warm environment: a thermographic analysis.

Ultrasonic vocalizations, emitted by rat pups when separated from their mother, littermates, and home cage, have been used as a measure of isolation distress. Recently, we demonstrated that cold exposure is the primary component of isolation that induces the vocalization. We were unable, however, to suppress all ultrasound production when transferring pups to a thermoneutral (35 degrees C) environment. Using an infrared thermography system that allows us to estimate noninvasively heat production by brown adipose tissue, we found that pups transferred from the home nest to a 35 degree C test chamber exhibited sizable levels of heat production while they were vocalizing. Moreover, both heat production and ultrasound emission decreased over the 15-min test. Next, we used extreme care to minimize thermal, and therefore respiratory, stimulation of pups before, during, and after the transfer procedure. We found that such precautions prevented both heat production and ultrasound emission following transfer. These results indicate that infant rats' thermal sensitivities are far greater than previously suspected.


Ultrasonic vocalization by rat pups during recovery from deep hypothermia.

Vocalization in the ultrasonic range (USV) has been reported to occur in young rodents in response to isolation, novelty, handling, and cold. Heretofore these calls have been known to occur only in alert, attentive, or emotionally aroused animals. These studies describe the emission of USV by comatose 9- to 10-day-old rat pups during recovery from deep hypothermia. Calling began at 15-18 degrees C core temperature while pups were virtually unresponsive to stimulation. Experimental results describe the patterns of call production in relation to respiration, cardiac function, colonic temperature, and brown adipose tissue thermogenesis. These vocalizations were 32-42 kHz in frequency, reached peak rates of 50/min at 23 degrees C, and were eliminated by laryngeal denervation, thus resembling isolation-induced vocalizations. However, contact with their dams failed to reduce call rates until pups had warmed above 25 degrees C. Newborn and weanling pups also emitted USV in deep hypothermia, but no USV were observed in pups recovering from general anesthesia. The possible functions and evolution of this behavior are discussed.


Prenatal stress exposure alters postnatal behavioral expression under conditions of novelty challenge in rhesus monkey infants.

This prospective study investigated whether mild maternal stress during pregnancy could alter the behavioral and affective responses in rhesus monkey infants in a complex, novel environment. Twenty-four rhesus monkey infants were tested on three occasions at 6 months of age in a novel environment. Twelve infants were derived from mothers exposed to a daily 10-min mild stressor from Day 90 to Day 145 postconception, while 12 were derived from mothers undisturbed during pregnancy. Prenatally stressed infants demonstrated more disturbance behavior, and lower levels of gross motor/exploratory behavior. Moreover, half of the prenatally stressed infants showed an abnormal response, falling asleep, while none of the control infants displayed this behavior. Males exhibited more clinging to surrogates, while females spent more time in gross motor/exploratory behaviors, with prenatally stressed males tending to spend the least time in gross motor/exploratory activity.


Protective effect of human pancreatic secretory trypsin inhibitor on cerulein-induced acute pancreatitis in rats.

We examined the protective effect of human pancreatic secretory trypsin inhibitor (PSTI), a specific trypsin inhibitor secreted from pancreatic acinar cells into the pancreatic duct, on cerulein-induced acute pancreatitis in conscious rats. The protective effect of human PSTI-RS, an analogue of PSTI with Arg-44 to Ser substitution which has a longer half-life in vitro, was also examined. Intraperitoneal administration of a pharmacological dose of cerulein to conscious rats induced acute pancreatitis, characterized by light microscopy as cellular disorganization of the acini and interstitial edema. Intravenous infusion of human PSTI (10, 50 or 250 micrograms/rat/h) into rats with cerulein-induced acute pancreatitis decreased their pancreatic wet weight and plasma amylase concentration. It also caused a dose-dependent decrease in vacuoles in acinar cells and interstitial edema. Human PSTI-RS, which has a longer half-life in vivo, was more effective than native PSTI at the same dose rate (10 micrograms/rat/h) in reducing pancreatitis. These results suggest that human PSTI may have a beneficial effect on acute pancreatitis.


Gallbladder emptying in patients with primary achalasia.

Being more evident that primary achalasia is not confined to the esophagus and that it may involve other organs in the digestive tract, gallbladder emptying was ultrasonographically evaluated in 10 patients affected with primary achalasia and in 10 controls. An intravenous cerulein infusion was used to induce gallbladder contraction. Eight out of 10 achalasic patients had a lower gallbladder emptying, and 6 out of 10 had a markedly delayed gallbladder emptying compared with the controls. Achalasic patients, taken as a whole, showed a significantly lower and delayed mean gallbladder emptying when compared with the controls. Such a finding confirms the possible extra-esophageal extension of primary achalasia. In this study, the hypothesis of impaired cholinergic gallbladder innervation in primary achalasia is discussed.


E2 prostaglandins modulate cell proliferation in the small intestinal epithelium of the rat.

Groups of Sprague-Dawley rats were administered 1 mg/kg indomethacin subcutaneously, indomethacin subcutaneously plus 200 micrograms/kg oral 15-R-15 methyl-prostaglandin E2 (MePGE2) or oral MePGE2 twice daily for 10 days. The animals were treated with antibiotics to prevent mortality. Two control groups were used: control 1 was given placebo and control 2 was treated with antibiotics. All rats were killed 4 h after injection of a metaphase blocker, and the proliferative activity of the distal small intestine was examined in histological sections by means of the cumulative mitotic index (MI). A reduction in the number of villous cells was observed in the rats given antibiotics (p < 0.05 vs. control 1). The small intestinal villi of the rats treated with indomethacin had fewer cells than those of both control groups (p < 0.05) whereas the crypts contained more cells (p < 0.05) and had a higher MI than those of the controls (p < 0.05 vs. controls 1 and 2). These changes were reverted by the prostaglandin analogue. The number of cells of the small intestinal crypts and the cumulative MI in the rats who received indomethacin and the prostaglandin analogue were similar to controls, and they were significantly lower than the values observed in the animals treated with indomethacin (p < 0.05). The animals treated with the prostaglandin analogue and placebo developed a marked hyperplasia of the small intestinal villi (p < 0.05 vs. both control groups), but the atrophy of the villi induced by indomethacin was not prevented by simultaneous administration of the analogue.(ABSTRACT TRUNCATED AT 250 WORDS)


Life events and daily stress in duodenal ulcer disease. A prospective study of patients with active disease and in remission.

Life events and daily stress were assessed in patients with duodenal ulcer, active or in remission, and in matched disease and normal controls. The mean positive life event scores were significantly lower in duodenal ulcer patients than in disease and healthy controls, and lower in patients with active ulcer than in those in remission. The positive scores and total life change scores decreased significantly after 6 months in the control groups and showed no significant variation in the duodenal ulcer group after 6 months. We conclude that the perception of life events, especially positive ones, is associated with duodenal ulcer.


pH-dependent secretion of gastrin in duodenal ulcer disease: effect of suppressing Helicobacter pylori.

Patients with duodenal ulcers and Helicobacter pylori infection have elevated plasma gastrin concentrations which fall after suppression of the organism. This may be due to H. pylori elevating the pH of the antral mucous layer, therefore preventing luminal acid from inhibiting gastrin release. To test this idea, we measured the plasma gastrin concentrations under basal conditions and in response to 4% peptone when the gastric lumen was maintained at pH 2.5 and at pH 5.5 by gastric perfusion. We studied 11 duodenal ulcer patients before and after suppression of H. pylori. Gastrin concentrations were significantly higher before suppression of H. pylori than after treatment in all three states; basal gastrin (pmol/l) fell from 9.2 (3.7-23, median and range) to 5.1 (1.7-15) after treatment; from 11.3 (3.8-29) to 5.9 (5.7-6.1) at pH 2.5 and from 15.2 (3.9-32) to 7.15 (6.1-14) at pH 5.5. The ratio of peptone-stimulated gastrin at pH 2.5/pH 5.5 was similar before (0.8; 0.5-1.7) and after (0.8; 0.5-1.1) suppression of H. pylori. These results indicate that infection with H. pylori increases basal and peptone-stimulated plasma gastrin concentrations, and that this response is independent of luminal pH.


Sexual dysfunction amongst women with Crohn's disease: a hidden problem.

The sexual problems of 50 women with Crohn's disease, of whom 45 had a stable relationship, were investigated by structured interview and compared with age-matched controls. Twenty-four percent patients had either infrequent or no intercourse compared with 4% of controls (chi 2 = 8.3, p < 0.005). However, amongst patients and controls who were sexually active, the frequency of intercourse was similar. Reasons for sexual inactivity included abdominal pain (24%), diarrhoea (20%) and fear of faecal incontinence (14%). Dyspareunia was common in patients (chi 2 = 6.5, p < 0.01) and this was irrespective of the site of disease (large vs. small bowel chi 2 = 0.85, NS). Women with perianal disease and fistulae were more likely to have dyspareunia than women with neither (chi 2 = 4.2, p < 0.05), although this was not so for less extensive involvement with only perianal disease (chi 2 = 2.8, NS) or fistulae (chi 2 = 0.8, NS). Vaginal candidiasis was more common in patients (chi 2 = 5.8, p < 0.02), and on occasions this may have contributed to dyspareunia. Women with Crohn's disease experience sexual problems much more than healthy controls and they need support, sympathetic investigation and management.


The integrated response of the cardiovascular system to food.

To obtain information about the integrated response of the cardiovascular system to food, cardiac output and regional blood flow (superior mesenteric artery, renal artery and calf blood flow) were measured in 14 normal young healthy subjects after an overnight fast and following a standard 800-kcal meal. Results were compared with 8 subjects who remained fasted throughout the study. Cardiac output increased from a mean (SEM) fasting value of 4.8 (0.3) l/min to a peak after 30 min of 6.1 (0.5) l/min (p < 0.001). Superior mesenteric blood flow increased from a fasting value of 463 (45) to a peak of 854 (110) ml/min also after 30 min (p < 0.001). These changes were accompanied by a significant fall in both systemic vascular resistance and superior mesenteric vascular resistance (p < 0.001). Only at the 15-min postprandial measurements was there a significant relationship between the increase in cardiac output and superior mesenteric artery blood flow (r = 0.62, p = 0.02). Calf blood flow increased and vascular resistance fell postprandially (p < 0.05), but there was little change in right renal artery blood flow. There was an insignificant fall in renal vascular resistance. Heart rate increased from a resting value of 65 (3) to a peak of 77 (4) beats/min after 15 and 30 min (p < 0.001), diastolic blood pressure fell postprandially with little change in systolic blood pressure. These results suggest that in healthy young subjects the increase in gut blood flow is met by an increase in cardiac output, with little evidence of redirection from other vascular beds. The early postprandial increase in superior mesenteric blood flow may account for the increase in cardiac output, although the magnitude of the change is much greater for cardiac output than superior mesenteric artery blood flow.


Medical therapy of Ménétrier's disease with omeprazole.

Medical therapy of Ménétrier's disease is often unsatisfactory and may lead to surgical treatment. Two cases, previously unresponsive to H2 antagonists, are presented showing a marked response to omeprazole.


Irritable bowel syndrome: can the patient's response to colonoscopy help with diagnosis?

The irritable bowel syndrome (IBS) is a common disorder estimated to affect up to 20% of adult Caucasians, with only a small percentage requiring investigation. This prospective study was performed to substantiate the impression that patients with IBS experience more pain during endoscopic examination of the colon than do patients with other conditions. Patients with IBS were observed to experience significantly more pain during colonoscopy than did patients without IBS (median observed pain scores 46 and 9, respectively), p < 0.001. The intensity of the pain perceived during examination was significantly higher for patients with IBS than for those without IBS (median 52.5 and 23.5, respectively), p < 0.001. Within the groups, there was no significant difference between flexible sigmoidoscopy and colonoscopy in observed or perceived pain. 64% of the patients with IBS said that the pain experienced at colonoscopy was identical to their presenting pain. This study supports the hypothesis of a lower colonic pain threshold with colonic hyperalgesia in patients with IBS. We have found that hypersensitivity to the endoscopic examination of the colon is a useful clinical adjunct in the diagnosis of the IBS in those selected to undergo colonoscopy.


Lack of effect of synthetic human gastric inhibitory polypeptide and glucagon-like peptide 1 [7-36 amide] infused at near-physiological concentrations on pentagastrin-stimulated gastric acid secretion in normal human subjects.

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 [7-36 amide] (GLP-1) are glucose-dependent insulinotropic gut hormones. Under experimental conditions, both have been shown to reduce stimulated gastric acid secretion. To study their individual and combined effects on pentagastrin-stimulated (0.1 micrograms/kg/h from -90 to 120 min) gastric volume, acid and chloride output, on separate occasions, synthetic human GIP (1 pmol/kg/min) and/or GLP-1 [7-36 amide] (0.3 pmol/kg/min) or placebo (0.9% NaCl with 1% albumin) were infused intravenously (from -30 to 120 min) in 9 healthy volunteers. At 0 min, a glucose infusion was started that mimicked the glycemic profile after an oral glucose load of 50 g/400 ml and allowed for the glucose-dependent insulinotropic action of GIP and GLP-1 [7-36 amide]. Pentagastrin stimulated acid output significantly, but neither GIP nor GLP-1 [7-36 amide] either alone or in combination, reduced pentagastrin-stimulated gastric acid secretion. The circulating concentrations of GIP and GLP-1 [7-36 amide] obtained at steady state during exogenous administration of synthetic peptides were similar to or higher than those reached after oral glucose (endogenous secretion). In conclusion, (penta)gastrin-stimulated gastric acid secretion is not inhibited by physiological circulating concentrations of GIP or GLP-1 [7-36 amide]. Therefore, the insulinotropic action of these intestinal hormones is physiologically more important than their possible role as enterogastrone.


Increased concentrations of synovial-type phospholipase A2 in serum and pulmonary and renal complications in acute pancreatitis.

The most important fatal complications of acute pancreatitis are respiratory dysfunction and anuria. Phospholipase A2 has been postulated to be associated with pathologies of various diseases, such as acute pancreatitis, septic shock and multiple injuries. We have recently developed immunoassays for the measurement of pancreatic and nonpancreatic synovial-type phospholipase A2. The present prospective study on 35 consecutive patients with acute pancreatitis indicated that the concentration of synovial-type phospholipase A2, the catalytic activity of phospholipase A2 and the concentration of C-reactive protein in serum were significantly higher in those patients suffering from acute pancreatitis who needed respirator treatment than in those who managed with spontaneous breathing, while there was no difference between these groups in the concentration of pancreatic phospholipase A2. The only significant difference between patients whose highest creatinine concentration rose up to 140 mumol/l and those whose highest creatinine concentration remained below this cutoff value was in their synovial-type phospholipase A2 values. The increased concentration of nonpancreatic synovial-type phospholipase A2 in serum was associated with pulmonary and renal complications. These results emphasize the role of synovial-type phospholipase A2 in the pathophysiology of acute pancreatitis.


The mammalian anti-alpha-smooth muscle actin monoclonal antibody recognizes an alpha-actin-like protein in planaria (Dugesia lugubris s.l.).

The presence of an alpha-smooth muscle (alpha-sm) actin-like protein in planaria (Dugesia lugubris s.l.) is reported. The protein shows a 42 kDa molecular weight determined by sodium dodecyl sulphate polyacrylamide gel electrophoresis and is specifically recognized by the mammalian anti alpha-sm actin monoclonal antibody. When a planarian is induced to regenerate by head amputation, the immunostaining of the alpha-sm actin-like molecule becomes important in the area of growing blastema, reaching a maximum between 70-120 hours after injury. Conventional electron microscopy at the 4-day-regeneration stage shows that blastema-forming cells are a homogeneous population whose morphological features resemble those of migrating mesenchyme-like cells; only the myoblasts show a recognizable phenotype. The immunocytochemical localization of alpha-sm actin-like molecule by immunoperoxidase (light microscopy) and immunogold stains (electron microscopy) was carried out on both intact and injured worms. The antigen was localized mainly at the basal portion of the epidermal cells and in the undifferentiated mesenchyme-like cells. Myoblasts, but not differentiated myofibers, were also labelled by this antibody. The results indicate that in the lower Eumetazoan planarians, as well as in vertebrates, the alpha-sm actin can be considered to be a marker for myoid differentiation. The suggestion that alpha-sm actin can be used as a marker for mesenchyme-like cells in vertebrates and in invertebrates is also discussed.


Identification of plakoglobin in oocytes and early embryos of Xenopus laevis: maternal expression of a gene encoding a junctional plaque protein.

We have isolated a cDNA encoding the junctional plaque protein plakoglobin of Xenopus laevis and determined its amino acid sequence. Comparisons with sequences of related proteins of the same and other species revealed that in Xenopus plakoglobin and beta-catenin are two different proteins, encoded by separate genes, that both genes are expressed in embryogenesis, and that the amphibian plakoglobin is more closely related to the human plakoglobin than to beta-catenin of the same species. Using this cDNA as a probe, we also show that plakoglobin mRNA is produced and stored in Xenopus oocytes and eggs. We discuss the possibility that the maternal pool of this junctional protein contributes to the junctional structures connecting the oocyte with the follicle epithelium and to the rapid formation of desmosomes and other plaque-bearing junctions in pregastrulation embryogenesis.


Time dependency of 1,25(OH)2D3 induction of calbindin mRNA and calbindin expression in chick enterocytes during their differentiation along the crypt-villus axis.

Quantitative methods of in situ hybridization and immunocytochemistry have been used to measure 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) induction of calbindin mRNA and calbindin protein expressed in jejunal enterocytes at all points along the crypt-villus axis over a 24 h period. Small amounts of calbindin mRNA detected in vitamin D3 deficient (D-deficient) chick intestine increased rapidly to maximal values 8 h after hormone injection. The magnitude of this response was inversely related to age of enterocyte measured separately by injecting tritiated thymidine into D-deficient and 1,25(OH)2D3-injected birds. Enterocytes of all ages expressed small amounts of calbindin 3 h after hormone injection. This amount of calbindin then increased up to 24 h after hormone injection. Maximal calbindin expression took place in basal villus enterocytes. Later decrease in the ability of upper villus enterocytes to express calbindin was associated with a similar fall in calbindin mRNA expression. Previously it was suggested that inefficient translation to calbindin mRNA might take place in basal villus enterocytes 48 h after vitamin D injection. Present work using 1,25 (OH)2D3 shows that calbindin expression takes place at a constant rate during this early stage of enterocyte development. Secondary events limiting higher rates of calbindin synthesis in upper crypt and basal villus enterocytes remain to be identified.


The chromatin structure of the mouse beta-2-microglobulin locus.

Within the promoter regions of both major histocompatibility complex (MHC) class I genes and the beta 2-microglobulin (beta 2m) gene, there are a number of common regulatory elements suggesting co-ordinate control. However, there is also evidence to suggest that beta 2m and class I are differentially regulated, indicating that these genes may have distinct regulatory elements. We sought to explore this question by analysing DNase I hypersensitive (DH) sites flanking the beta 2m gene. Five DH sites have been found within the vicinity of the beta 2m gene. One of these sites (DH1) located within the promoter region, correlates with the transcriptional activity of beta 2m since it is weak in embryonal (beta 2m negative) cell lines. The remaining DH sites (2-5) are located downstream of the beta 2m gene. The most proximal downstream site, (DH2) located 5.5 kb from the last exon, was observed only in embryonal cell lines, indicating possible involvement in the downregulation of beta 2m. Furthermore, this site is markedly diminished in differentiated F9 cells. Possible roles for the remaining sites are discussed, in particular relationship to a second transcriptional unit identified in the vicinity. In addition, a similar analysis reveals a cluster of DH sites located downstream from the last exon of the human beta 2m gene.


Ontogenesis of the murine hepatic extracellular matrix: an immunohistochemical study.

To define the role of the extracellular matrix (ECM) in hepatogenesis, we examined the temporal and spatial deposition of fibronectin, laminin and collagen types I and IV in 12.5-21.5 day fetal and 1, 7 and 14 day postnatal rat livers. In early fetal liver, discontinuous deposits of the four ECM components studied were present in the perisinusoidal space, with laminin being the most prevalent. All basement membrane zones contained collagen type IV and laminin, including those of the capsule (mesothelial), portal vein radicles and bile ductules. Fibronectin had a distribution similar to that of collagen type IV early in gestation. However, at later gestational dates, fibronectin distribution in the portal triads approached that of collagen type I, being present in the interstitial connective tissues; whereas, collagen type IV and laminin were restricted to vascular and biliary basement membrane zones in those regions. The cytoplasm of some sinusoidal lining cells and hepatocytes reacted with antibodies to extracellular matrix components. By electron microscopy the immunoreactive material was localized in the endoplasmic reticulum, indicating the ability of these cells to synthesize these ECM proteins. Biliary ductular cells had prominent intracytoplasmic staining for laminin and collagen type IV from day 19.5 gestation until 7 days of postnatal life, but lacked demonstrable fibronectin or collagen type I. These results demonstrate that by 12.5 days of gestation the rat liver anlage has deposited a complex extracellular matrix in the perisinusoidal space. The prevalence of laminin in the developing hepatic lobules suggests a possible role for this glycoprotein in hepatic morphogenesis. In view of the intimate association of the hepatic lobular extracellular matrix with the developing vasculature, we hypothesize that laminin provides a scaffold of the developing liver, but once the ontogenesis is complete, intrahepatic perisinusoidal laminin expression is suppressed.


Cytoplasmic events in human meiotic arrest as revealed by immunolabelling of spermatocyte proacrosin.

Proacrosin appears in the Golgi complex as early as the mid-pachytene stage and immediately thereafter initiates partition to be equally distributed in spermatids. The anti-proacrosin monoclonal antibody 4D4 (mAb 4D4) was used as a marker of these cytoplasmic events in ten men exhibiting spermatogenesis arrest in three specific stages: (i) leptotene/zygotene spermatocyte I with impaired chromosome pairing (six cases), (ii) early pachytene I (one case) and (iii) metaphase/anaphase I (three cases). Prophase arrest stages were identified on testis sections stained by silver nitrate. MAb 4D4 labelling revealed two types of leptotene/zygotene arrest depending on whether proacrosin was expressed or not. The data obtained enabled us to distinguish between: (i) nuclear blockages due to chromosome and/or nuclear matrix anomalies, when cytoplasmic events were either inhibited or not inhibited, and (ii) nuclear anomalies due to microtubular disturbances. In this latter case, cytokinesis was impaired as early as the prophase I, thus indicating a relationship between the Golgi partitioning and the microtubule network. Data show that meiotic arrest investigations, by means of an appropriate marker of the cytoplasmic events, provide valuable information on spermatogenic developmental processes.


Reducing the number of rabbits in the low-volume eye test.

Although the Draize eye irritation test has provided important and useful information for eye safety assessments, considerable effort has been directed toward refining the assay procedure, reducing the number of animals used, and replacing this assay with alternative methods. The low-volume eye test (LVET) is a refinement of the Draize eye irritation test that uses 1/10 the volume of test substance placed directly on the cornea. The level and duration of eye irritation in the LVET are less than those in the Draize procedure, which means that it is a less stressful test. Furthermore, LVETs are more predictive of human response. Statistical studies have been conducted to determine the effects of reducing the number of animals used in the Draize test. These results suggested that a three-animal test would provide essentially the same information as the six-animal test. A similar analysis has not been performed on results from the LVET. Accordingly, the present study was undertaken to evaluate previously existing LVET data to determine if the number of animals used in a LVET can be decreased as has been shown for the Draize test. The results of the analysis are consistent with the findings of earlier evaluations of classical Draize data. Three-animal subsets from 119 six-animal LVETs provided the correct classification greater than 92% of the time for three different classification schemes. Furthermore, the discrepancies between the three-animal subsets and the six-animal maximum average score tended to be smaller than those observed for the Draize test.(ABSTRACT TRUNCATED AT 250 WORDS)


Adduction of hemoglobin and albumin in vivo by metabolites of trichloroethylene, trichloroacetate, and dichloroacetate in rats and mice.

Adducts to macromolecules from trichloroethylene formed by in vivo and in vitro metabolism have been reported by many investigators. We examined the in vivo adduction of the blood proteins hemoglobin (Hb) and albumin in rats and mice dosed orally with [14C]trichloroethylene ([14C]TRI) to explore the development of a protein adduct biomarker of TRI exposure. We also examined the adduction of these two proteins from doses of [14C]trichloroacetate (TCA) and [14C]dichloroacetate (DCA), two metabolites of TRI. Association of label with albumin peaked at 4-8 hr in the rat (2480 nmol eq TRI/mg protein) and 2-4 hr in the mouse (1580 nmol eq TRI/mg protein). The decay was exponential with a half-life consistent with that of rat or mouse albumin (approx 24 hr). The time course of label with Hb was characterized by an early plateau at 8 hr in rat (28 nmol eq TRI/mg protein), 4 hr in mouse (7 nmol eq TRI/mg protein), and followed by a slow steady increase, peaking at 120 hr (54 nmol eq TRI/mg protein, rat; 38 nmol eq TRI/mg protein, mouse). This apparent binding was linear with dose in the rat, but was convex in the mouse albumin (mouse Hb label was below detection at low dose). We also found that a portion of the irreversibly associated label, referred to by previous investigators as "binding," could be accounted for as metabolic incorporation of label into glycine and serine.(ABSTRACT TRUNCATED AT 250 WORDS)


The action of chelating agents in experimental uranium intoxication in mice: variations with structure and time of administration.

The determination of the relative abilities of 11 chelating agents to enhance the urinary and fecal excretion of uranium when administered 10 min after uranyl acetate dihydrate (UAD) in mice showed that the most effective of these were Tiron, desferrioxamine, and 1,2-dimethyl-3-hydroxypyrid-4-one. An increase in the interval between UAD administration and that of the chelating agent drastically reduces the net mobilization of the uranium by the chelating agents examined. When given shortly after UAD, Tiron produced the greatest reduction in renal and bone levels of uranium. None of the chelating agents were able to affect the bone levels of uranium when administered 24 hr or more after the administration of the UAD.


Pulmonary toxicity of inhaled polypropylene fibers in rats.

This study was initiated to assess the pulmonary toxicity of a polyolefin fiber composed of polypropylene in male Fischer 344 rats after 90 days of inhalation exposure. To increase fiber respirability in the rodent, polypropylene fibers were size-selected before aerosolization to have a geometric mean diameter of 1.6 microns (46% < 1 micron) and a geometric mean length of 30.3 microns. Three groups of animals were exposed in nose-only inhalation chambers, 6 hr/day, 5 days/week, for 90 days to 15, 30, or 60 mg/m3 of polypropylene, or filtered air (negative control). Microscopic examination of the polypropylene fiber-exposed lungs revealed that, at all time points examined in the study, there was a dose-dependent increase in pulmonary macrophages. These minimal or mild increases in cellularity appeared to be reversible, especially at the lower doses 30 days post exposure. No fibrosis was observed in any of the groups. A strong correlation was found between the external exposure concentration, the time of exposure, and the lung fiber burden. The number of partially degraded (segmented) fibers within the lung increased with the exposure concentration and period of exposure, as well as with the period of recovery after termination of exposure at 90 days. Fibers were recovered from exposed lungs using a hypochlorite digestion technique.


The effect of exposure pattern on the accumulation of particles and the response of the lung to inhaled particles.

We hypothesized that a rapid rate of delivery of particles to the lung would overwhelm the normal clearance mechanisms of the lung and result in a higher lung burden of particles and a greater inflammatory response than a slower rate of particle delivery. F344/N rats were exposed over a 12-week period to the same weekly concentration times time product of carbon black (CB) particles, but at three different exposure rates: 3.5 mg/m3, 16 hr/day, 7 days/week; 13 mg/m3, 6 hr/day, 5 days/week; or 98 mg/m3, 4 hr/day, 1 day/week. The intermediate exposure rate was chosen to mimic an occupational work week and to give an 8-hr, time-weighted average exposure equal to the threshold limit value (TLV) for nuisance dusts of the American College of Governmental Industrial Hygienists (10 mg/m3). Pure CB has a lower TLV, 3.5 mg/m3, than nuisance dusts, but this is based on avoidance of excessive dirtiness in the workplace, not on the toxicity of CB. Lung burdens of CB were measured after 3, 6, 9, and 12 weeks of exposure and at 4, 8, 12, 16, and 24 weeks after the exposure ended. The inflammatory response was quantified by analysis of bronchoalveolar lavage fluid (BALF) after 6 and 12 weeks of exposure and at 1, 12, and 24 weeks after exposure. The histopathology of the lung was evaluated at the end of the exposure and at 24 weeks after the exposure. Acquired lung burdens were between 3 and 4 mg/lung at the end of the exposure.(ABSTRACT TRUNCATED AT 250 WORDS)


Quantitation of paraquat in biological samples by radioimmunoassay using a monoclonal antibody.

We have developed a sensitive and specific radioimmunoassay for the quantitative determination of paraquat in plasma, urine, and bronchoalveolar lavage fluid using a monoclonal antibody. The synthesis of the iodinated paraquat tracer is novel and less complicated than a previously reported method. Regardless of the type of biological sample analyzed, the sensitivity of the assay was 0.46 ng/ml in a 200-microliters aliquot. The results correlated well with those of another assay performed in a separate laboratory. Paraquat concentrations were determined in plasma and in urine of a dog over several days after the intravenous administration of 7.48 mg paraquat cation/kg and in bronchoalveolar lavage fluid obtained 34 hr after the 2-hr infusion was discontinued. Concentrations of paraquat measured ranged from 14.1 to 0.03 micrograms/ml in plasma and 2034 to 0.36 micrograms/ml in urine. Concentrations of paraquat in plasma obtained at various times after the ingestion of paraquat by three patients ranged from 51.0 to 0.010 micrograms/ml.


Neuropathologic findings in young male rats in a subchronic oral toxicity study using triethyl lead.

This study was undertaken to ascertain the neuropathologic effects of low level exposure of triethyl lead (3EL) to young male rats. Groups of 20 male Sprague-Dawley weanling rats were given 3EL at 0, 0.05, 0.10, 0.20, 0.50, and 1.00 mg/kg body wt for 91 days, 5 days/week by oral gavage. Lead acetate (PbHOAC) was given at 200 mg/kg body wt/day as a positive control. Animals (five or six) were perfused with glutaraldehyde following barbiturate anesthesia at the termination of the experiment. These animals and the remaining members of the group received a thorough gross and microscopic postmortem examination. Sections of the central, peripheral, and autonomic nervous systems were examined and lesions scored. No lesions were noted in the brain, but randomly distributed light microscopic changes of spinal cord Wallerian degeneration were noted to increase in a dose responsive manner (rho = 0.48; p < 0.01), with 3EL administration. Ultrastructural examination of selected sections of the lumbosacral nerves, revealed lesions characterized by reduced neurofilaments and neurotubules, and irregular lamellated axoplasmic dense bodies in all animals receiving lead. Organolead was only detected in animals receiving 3EL, but lead cations were detected in all lead-treated animals. The brain lead levels of 1.00 mg/kg/day and 200 mg Pb acetate positive control animals were equivalent. As distinctive ultrastructural lesions were seen in all rats treated with 3EL, we suggest that the no observed adverse effect level (NOAEL) for 3EL be lowered to less than 0.05 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)


Relative bioavailability of lead from mining waste soil in rats.

The purposes of this study were to determine the extent of absorption of lead (Pb) in mining waste soil from Butte, Montana, and to investigate the effect of mining waste soil dose (g soil/day) on tissue lead concentrations. Young, 7- to 8-week-old male and female Sprague-Dawley rats (5/sex/group) were given mining waste soil that contained 810 or 3908 ppm lead mixed in a purified diet (AIN-76) at four different dose levels (0.2, 0.5, 2, and 5% dietary soil) for 30 consecutive days. Standard groups included untreated controls and dosed feed soluble lead acetate groups (1, 10, 25, 100, and 250 micrograms Pb/g feed). The test soil dose levels bracketed a pica child's soil exposure level and the lead acetate concentrations bracketed the test soil dose levels of lead. Liver, blood, and femur were analyzed for total lead concentration using graphite furnace atomic absorption spectroscopy. Clinical signs, body weight, food consumption, and liver weights for test soil and standard groups were similar to control. Tissue lead concentrations from test soil animals were significantly lower than the tissue concentrations for the lead acetate group. Relative percentage bioavailability values, based on lead acetate as the standard, were independent of the two different test soils, dose levels, and sex and were only slightly dependent on the tissue (blood > bone, liver). Mean relative percentage bioavailability values of lead in the Butte mining waste soil were 20% based on the blood data, 9% based on the bone data, and 8% based on the liver data. The results of this study will provide the information needed to determine the significance of lead exposure from Butte soils in assessing human health risks as part of the Superfund Remedial Investigation/Feasibility Study process.


Gonadal effects of fetal exposure to the azo dye congo red in mice: infertility in female but not male offspring.

The present study describes the relationship between gonadal agenesis and fertility in male and female mice exposed in utero to the diazo dye Congo red (CR). Maternal CR treatment inhibited testicular and ovarian function in the offspring after oral administration of 1 or 0.5 g/kg/day on Gestational Days 8-12. The testes of male offspring from CR-exposed dams were small in size and contained hypospermatogenic seminiferous tubules. However, despite the fact that testis weight was reduced by more than 70% in some males, they displayed normal levels of fertility when mated to untreated females for over 10 months. In contrast, female offspring from CR-exposed dams produced only about half as many litters and pups as the control pairs did under long-term mating conditions. Histological examination of the ovaries revealed that subfertility was correlated with ovarian atrophy. Females lacking maturing follicles were considerably less productive (1.3 litters and 11.5 pups) than treated females with histologically normal ovaries (7.1 litters and 78.1 pups). In summary, prenatal exposure to the dye CR affects the gonads of both male and female offspring, but only the female offspring display reduced fertility.


Toxicity and carcinogenicity studies of quercetin, a natural component of foods.

Quercetin is a naturally occurring chemical found in our daily diet in fruits and vegetables. Toxicity and carcinogenicity studies of quercetin were conducted in male and female F344/N rats, under conditions which allowed comparison to results of approximately 400 previously tested chemicals. The chemical was administered in the feed for 2-years at concentrations of 0, 1000, 10,000, or 40,000 ppm, and the estimated dose delivered was approximately 40-1900 mg/kg/day. There were no treatment-related effects on survival and no treatment-related clinical signs of toxicity. The high-dose groups had reduced body weight gain in comparison to controls during the last half of the study. At interim evaluations at 6 and 15 months, treatment-related toxic lesions were not observed, but at 2 years toxic and neoplastic lesions were seen in the kidney of male rats, including increased severity of chronic nephropathy, hyperplasia, and neoplasia of the renal tubular epithelium. Under the conditions of these 2-year studies quercetin showed carcinogenic activity in the kidney of the male rat, causing primarily benign tumors of the renal tubular epithelium. Quercetin did not cause tumors at other sites. Quercetin is a genotoxic chemical, but the neoplastic response observed in the kidney may be due in part to a combination of nongenotoxic and genotoxic events.


Examination of the local lymph node assay for use in contact sensitization risk assessment.

The purpose of this study was to evaluate the utility of the murine local lymph node assay (LLNA) for contact sensitization risk assessment. Cellular proliferative activity in draining lymph nodes was determined for individual animals on Day 5 following four daily epicutaneous applications of the test chemical to the ears. Seventeen chemicals were tested, covering a range of materials including preservatives, drug actives, and perfume raw materials. The assay was found to be useful for identifying strong, moderate, and some weak sensitizers as defined by other testing methods (guinea pig, human). For evaluating the antigen specificity of the LLNA proliferative response, an in vitro blastogenesis assay was used. Dendritic cells (DC) isolated from lymph nodes of mice treated 24 hr earlier with trinitrochlorobenzene (TNCB) were capable of in vitro stimulation of lymphocytes from TNCB-sensitized mice, but not lymphocytes from mice sensitized to the preservative mixture of 5-chloro-2-methylisothiazolinone plus 2-methylisothiazolinone (MCI/MI). Conversely, DC from mice treated 24 hr earlier with MCI/MI were capable of stimulating lymphocytes from MCI/MI-sensitized mice, but were unable to stimulate lymphocytes from TNCB-sensitized mice, demonstrating the specificity of the response. The results of these studies support the use of the murine LLNA for both investigative and predictive contact sensitization testing. The LLNA offers the advantages of requiring less time for completion, incorporating an objective endpoint, requiring approximately half the number of animals, and being less costly than most currently employed guinea pig test methods. In addition, we believe the murine LLNA is a useful test to incorporate into a scheme for contact sensitization risk assessment.(ABSTRACT TRUNCATED AT 250 WORDS)


Alkoxyresorufin metabolism in white-footed mice at relevant environmental concentrations of Aroclor 1254.

Recent investigations have detected polychlorinated biphenyl (PCB) body burdens in wild white-footed mice (Peromyscus leucopus) captured at hazardous waste sites. Insufficient information is currently available to interpret the toxicological significance of these body burdens. In an effort to provide this information, we investigated hepatic changes and PCB body burdens in white-footed mice following a 21-day dietary exposure to a PCB mixture, Aroclor 1254. Dietary concentrations tested were 0, 2.5, 25, 50, and 100 mg Aroclor 1254/kg diet (reported as ppm). Liver weights were significantly increased at all concentrations except 2.5 ppm. Ethoxyresorufin O-dealkylase (EROD) activity, an aryl hydrocarbon hydroxylase-type substrate, was significantly increased at all PCB concentrations, but the dose-response tended to plateau above 25 ppm. Pentoxyresorufin O-dealkylase (PROD) activity, a putative phenobarbital-type substrate, was significantly increased in a dose-dependent manner at 25 ppm PCB and above, with no plateau response. Pentobarbital sleep time was significantly decreased at 25 ppm, but not at 2.5 ppm. Results indicate white-footed mice undergo a mixed-type induction pattern following exposure to Aroclor 1254, with EROD the most sensitive indicator of PCB exposure. This investigation identified a no observed effect concentration for liver weights and PROD activity at 2.5 ppm in the diet which is equivalent to a body burden of 2.0 mg Aroclor 1254/kg wet wt of mice; the no observed effect concentration for EROD is below these levels. These results support the use of EROD, PROD, and liver weight as biomarkers of PCB exposure in field-captured rodents.


Neurobehavioral effects from acute exposures to methyl isobutyl ketone and methyl ethyl ketone.

Subjects were tested for neurobehavioral performance in an environmental chamber to detect the presence of subclinical central nervous system effects from 4-hr exposures to methyl isobutyl ketone (MIBK) at 100 ppm, methyl ethyl ketone (MEK) at 200 ppm, MIBK at 50 ppm with MEK at 100 ppm, or a placebo (i.e., a 5-min presentation of 25 ppm MEK-MIBK at each exposure period outset). Subjects were 68 males and 75 females recruited from local universities; ages ranged from 18 to 32 years. Ethanol by ingestion (95%-0.84 ml/kg) was used as a positive control. Five psychomotor tests (choice reaction time [CRT], simple reaction time [SRT], visual vigilance, dual task [auditory tone discrimination and tracking], memory scanning), one sensorimotor test (postural sway), and a test of mood (profile of mood states) were used to measure neurobehavioral effects. Additionally, chemical measurements (blood and breath) and reports of sensory and irritant effects were measured. The chemical exposures produced statistically significant performance effects on only 4 of 32 measures (% correct responses-visual vigilance, movement time-CRT, SRT, % incorrect responses-dual task). These effects, however, were not substantial and could not be attributed directly to the chemical exposures. Alcohol ingestion, however, produced significant decrements on every performance test except memory scanning and mood. An interaction occurred between gender and alcohol ingestion, such that more statistically significant performance decrements were found for females than for males. Significant odor sensations and irritant effects were reported by the subjects during the chemical exposures. The MEK results agree with earlier MEK experiments at comparable exposure conditions, and the MIBK results are consistent with a recent Swedish study that used MIBK exposures and showed no significant behavioral performance decrements from single MIBK exposures at 50 ppm with 50 W exercise. Additionally, the MIBK-MEK combination exposure showed no evidence of any interaction effects on either the behavioral or chemical measurements. The principal effects resulting from exposures to MEK and MIBK at the durations and concentrations used in the study are limited to sensory and irritant effects.


Behavioral development following daily episodes of mother-infant separation in the rat.

Use of dermal or inhalation routes of maternal exposure during the postnatal period in rodent developmental neurotoxicity evaluations would be most practical if dams could be separated from their pups during the exposure period. However, this procedure raises questions concerning the effects of mother-infant separation itself on neurotoxicity endpoints. In the present study, Sprague-Dawley rat pups were either maternally deprived in warm incubators for 6 hr each day (7:00 AM-1:00 PM) or left with their dams (control), from Postnatal Day 4-20 (PND4-20), and were tested on a range of endpoints commonly used in developmental neurotoxicology. These included motor activity (PND13, 17, 19, 21, 29, 60), olfactory learning (PND18) and retention (PND25), T-maze delayed alternation (PND23, 24), acoustic startle response (PND23, 62), and auditory thresholds (PND62). None of the behavioral measures were affected by daily separation. Apparently, interrupting the mother-infant interaction for 6 hr/day has little or no effect by itself on behavioral development, as assessed by these measures.


Diagnosis, antibiotic treatment and outcome of acute tonsillitis: report of a WHO Regional Office for Europe study in 17 European countries.

The diagnostic and prescribing habits of general practitioners from 17 European countries for 4094 patients with acute tonsillitis were assessed, and differences in outcome were identified. At least 10 general practitioners from each country filled in a questionnaire for each episode of acute tonsillitis treated during a three month period, November 1989-May 1990. Differences in days of fever and illness were tested by one-way analysis of variance. Bacteriological tests were rarely used for diagnosis in East Germany, Poland and the Netherlands, while a high percentage (70-96%) occurred in Turkey, Romania, Israel, Yugoslavia, Finland and Greece. Group A beta-haemolytic streptococci (40 per cent) and a negative test result (43 per cent) were the most common results. Ninety per cent or more patients were treated with an antibiotic. Oral penicillin was especially prescribed in the northern countries of Europe and parenteral penicillin in southern Europe. For almost all countries the mean number of days with fever was between 2 or 3 days. The mean number of days with illness differed greatly (F = 62.12; P = 0.0000). Turkey had the lowest mean (2.56), while Poland had the highest mean (8.23).


Fever in general practice. I. Frequency and diagnoses.

Although fever is a common symptom, few studies have broadly addressed this as a clinical problem in general practice. The aims of this study were to determine the frequency of fever among general practice patients in two rural municipalities in Norway, the diagnoses (according to ICHPPC-2-def.) of conditions causing fever, and the receptionist's role in the management of these problems. All the general practitioners and their receptionists within the study area participated. During 4 weeks throughout 1988 all individuals attending their general practitioner had their body temperature measured with an electronic thermometer (orally > or = 7 years, rectally < 7 years). Fever was defined as an oral body temperature > or = 37.5 degrees C (rectally > or = 38.0 degrees C in those < 7 years). All telephone applications, including telephone encounters for fever, were recorded. Fever was detected in 80 (5%) of a total of 1610 direct encounters: 36% of those below 7 years of age (n = 70) were febrile. One-third of the total encounters for fever were telephone encounters (n = 36), of which 30% were managed by the receptionists. A wide range of diagnoses were made, most of which were associated with infectious diseases. The distribution of the diagnoses of primary care patients with fever is different from those admitted to hospital for fever of unknown origin. General practitioners and their receptionists should consider fever a diagnostic challenge, especially when the patient is handled over the telephone.


Pregnant women's ailments and psychosocial conditions.

Pregnant women's ailments may cause anxiety and reduce the quality of life. Sixty-five pregnant women were followed prospectively in antenatal care in general practice, and spontaneously reported ailments not associated with serious pregnancy complications were registered prospectively. The vast majority of pregnant women spontaneously reported one or more ailments. A higher number of ailments was reported by women with psychosocial problems and heavy physical work. Abdominal pain was more often reported by women assessed as having psychosocial problems. Based on background knowledge, clinical observations and a somewhat extended history on the psychosocial situation, it is possible to identify a subgroup of women who experience a more than 50% increase in the frequency of such ailments. Reporting of a high number of ailments in antenatal care may provide the clinician with important clues regarding need for psychosocial support.


Striking balances: detachment or empathy in the management of Parkinson's disease?

This paper, based on in-depth interviews with a group of 18 GPs, was part of a wider study of what GPs and patients thought about communication between them in the case of Parkinson's disease. Four areas where GPs experienced anxiety and uncertainty in responding to their Parkinson's disease patients were examined: that of sustaining care over time; accepting that patients cannot be cured; managing the task of 'just being there' with patients; and responding to patients with communication impairments. Such uncertainties have to be managed if doctors are to accomplish their work lives. The paper goes on to examine how GPs struck balances for themselves between detachment and empathy to keep uncertainty at bay, enabling some GPs to be responsive to patients' needs and others less so. An understanding of these difficulties and strategies has important implications for doctor-patient communication. Some suggestions for change are discussed.


Cataract, functioning and co-morbidity: a cross-sectional study in family practice.

Cataract is a slowly developing eye disease, the prevalence of which rises with age. Although patients often adapt to the diminished visual acuity accompanying the development of cataracts, their functional health may be impaired by poor vision. An index for visual functioning was derived from the literature. As older people often have additional chronic diseases, vision, visual functioning index and chronic co-morbidity were measured. Functional health was measured with different validated instruments. Eighty cataract patients participated in this study and were visited at home. Results showed statistically significant correlations between vision and co-morbidity on the one hand and visual functioning and functional health on the other. As in most participants vision was only slightly impaired, these results might even be more pronounced in patients with mature cataract. We conclude that indications for cataract surgery might not only be derived from visual acuity, but also from visual functioning and functional health.


The effects of treatment of urinary incontinence in general practice.

A total of 110 women who had reported urinary incontinence to their general practitioners were randomly assigned to a treatment or control group. Treatment consisted of pelvic floor exercises in the case of stress incontinence and bladder training in the case of urge incontinence. The results were measured after 3 and 12 months by a research assistant on the basis of a constructed severity scale, an incontinence diary, and a comparison by the patients themselves of their previous and current conditions. After 3 months the control group were given the same treatment. After a further 3 and 12 months, they were assessed in exactly the same way as the treatment group. After 3 months about 60% of the patients were either dry or only mildly incontinent; the mean number of wet episodes had gone down from 20 to 7, and 74% of the women felt improved or cured. These results were later corroborated by the control group. After 12 months this successful outcome was improved slightly further. It may be concluded that the majority of women with incontinence can be successfully treated by the general practitioner. The effect of this treatment continues after one year.


Morbidity from childhood to adulthood. The medical life history of 103 patients.

The aim of the study was to investigate the relationship between presented morbidity in consecutive periods of time in the first 35 years of life. Data were collected in a large rural general practice from 1946 to 1990 and covered 103 persons born between 1946 and 1959 in a general practice in the east of The Netherlands. Morbidity scores were calculated for all registered diagnoses in 5-year periods. Morbidity was allocated to three degrees of seriousness, to all atopic disorders, and to eight important diagnosis groups. There were strong correlations between consecutive time periods for all but serious morbidity. The same pattern was found between 0-4 years of age and consecutive periods till the age of 20-25. After this age no significant correlations could be established. Atopic disorders were inter-related in the first 20 years of life. Strong correlations were also found for eczema and lower respiratory tract infections in the first 20 years, while strong correlations were found for accidents and nervous complaints between the ages of 20 and 35. We conclude that causes of morbidity presented in general practice in childhood and adulthood are strongly inter-related over consecutive 5-year periods.


Eliciting patients' views of the cause of their problem: a practical strategy for GPs.

One thousand consecutive consultations with one general practitioner were studied to determine the value of seeking the patients' ideas about the cause of their condition. The diagnosis was an issue in 543 of the consultations. A total of 150 patients spontaneously volunteered a clear cause. When the remainder were asked to express their ideas about cause, 266 were able to do so. There were no significant age or sex differences between those who were able to express a cause compared with those who were unable to. The most common ideas expressed were infection, injury, anxiety and allergy. Thirty per cent of ideas were valuable to the doctor in reaching a deeper understanding of the patient's concerns over the condition and 20% helped determine the most likely cause of the condition. There were no significant differences in the value to the doctor between the causes spontaneously volunteered and those given as a result of questioning. The most valuable ideas to the doctor were cancer, anxiety, age, occupation, and heart disease. This study suggests that in the half of general practitioner consultations in which diagnosis is an issue, it is worthwhile seeking the patients' ideas as to cause of their condition.


Women's undefined disorders--a challenge for clinical communication.

Patients presenting illness without disease are common in general practice. A clinical communicative method was developed in order to clarify women's 'undefined' disorders. Outcomes from this approach registered from 122 audiotaped consultations were qualitatively analysed, in order to explore potential conditions and premises constituting the phenomena labelled as undefined. Knowledge produced by female patients was applied for transformation of the undefined nature of the problem into various levels of medical understanding. Gender-specific illness-promotive mechanisms were identified, as well as certain communicative dilemmas distorting symptom presentation into undefinedness. Relevant medical management was also suggested.


Patient satisfaction in primary health care. A comparative study of two modes of treatment for hypertension.

The object of this study was to compare patients' experiences of two different treatments of hypertension (one mainly non-pharmacological and one pharmacological) and study the degree of patient satisfaction and experiences of treatment in general. The 165 patients in the non-pharmacological group participated in a two-year-long study of non-pharmacological treatment of hypertension (NPTH) at eight health centres in mid-Sweden. In addition to regular visits to the same doctor at the health centre, patients received monthly check-ups by a nurse at the health centre and participated in information programmes and group activities. The NPTH patients also used cuffs for home measurements of blood pressure. The 85 patients in the control group were recruited from two health centres and received traditional, pharmacological treatments of hypertension. The hypothesis was that the patients in the NPTH group would experience satisfaction with the treatment and perceive the treatment in general as more positive than those in the control group. The 250 patients have answered a postal inquiry with structured and open questions concerning the treatment. The results show that the patients in the NPTH group throughout this study have experienced higher satisfaction with the treatment and had a more positive attitude towards the treatment than the controls. The content and design of the treatment obviously had a positive influence on patient satisfaction.


Patient-centredness: is it applicable outside the West? Its measurement and effect on outcomes.

Patient-centredness has been shown to be associated with improved patient outcomes in the West. The objectives of this study were: (i) to further test a specific method for measuring patient-centredness that had previously demonstrated validity and reliability, and (ii) to test the effectiveness of a patient-centred approach amongst poor, non-Western people in South Africa. Patient-centredness was measured in terms of the practitioner's facilitation of the patient's reasons for coming, including symptoms, thoughts, feelings, and expectations. The study involved nurse practitioners and medical doctors in three primary care settings with patients from eight language groups. The method for measuring patient-centredness was found to be valid, reliable (inter-rater correlations, rs = 0.95, 0.88, and 0.87), sensitive, and practical, being inexpensive, time efficient, suitable for consultations involving interpreters, and not requiring transcripts. The score for the first 2 minutes of the consultation correlated highly with the score for the entire consultation (rs = 0.92), which could make the method useful on a large scale. Patient-centredness itself, was also time effective, applicable to cross-cultural consultations involving interpreters, and was associated with patients feeling understood (P = 0.03), patient-practitioner agreement (P = 0.049), symptom resolution (P = 0.01), and concern resolution (P = 0.006). This study supports the effectiveness of patient-centred interviewing in a non-Western setting as well as this method of assessing it.


Differences between patient and physician perceptions of predicted compliance.

One approach to improving patient compliance is for physicians to adapt their behaviour to fit patients' psychological characteristics. Previous university-based research has suggested that physician adaptation to patients' locus of control interferes with patient-physician congruence on expected compliance, but not with congruence on satisfaction with their relationship. This study was conducted in a community practice to clarify the relationship between the physician's adaptation to locus of control and likelihood of and commitment to compliance, and satisfaction with the doctor-patient match. One physician saw 148 patients with a variety of illnesses after they had completed the Health Locus of Control (HLC) questionnaire. The physician altered how he spoke with a patient based on whether the patient scored internally or externally on the HLC. After the encounter, both patient and physician rated the patient's likelihood of and commitment to complying with each of the three recommendations. The physician and each patient also rated their satisfaction with the match between them. Patients' ratings of commitment, likelihood, and satisfaction were significantly higher than those of the physician. Unlike earlier results, there were strong correlations between the patients' and physician's estimates of compliance (commitment and likelihood). Just as with the previous study, there was no correlation between the levels of physician and patient satisfaction with their match. This study indicates that physician adaptation to patients' locus of control does not interfere with compliance outcomes of doctor-patient encounters. Whether such adaptation will improve compliance outcomes is yet to be determined.


Medical students' perceptions of an undergraduate general practice preceptorship.

A survey was undertaken to evaluate an undergraduate general practice preceptorship by means of an open-ended six-item questionnaire given to students at the end of their general practice attachment. The aim of the survey was to evaluate the preceptorship as a learning experience and to examine ways in which the preceptorship might be improved. Questionnaires from two medical student years (1985 and 1990) were examined retrospectively. Of 398 potential responders, 386 (97%) had completed questionnaires. Students expressed a very high level of satisfaction with the attachment and this was expressed most often in terms of the personal interest shown by the general practitioner, the variety of clinical problems encountered, and the experience gained in managing common clinical problems. Areas of the attachment which students felt could be improved were: involvement in the consultation, the time constraints on teaching and the teaching of practical skills. The paper discusses possible improvements which could be made to preceptorship programmes on the basis of these findings.


International primary care classifications: the effect of fifteen years of evolution.

To better understand the development of primary care classifications over the past 15 years, 10 primary care databases have been retrospectively analysed using the structure of the International Classification of Primary Care (ICPC) as the basis. All datasets were based on routine data collection using different classification systems by several family physicians during all encounters with their patients over considerable periods of time, in most cases one year. The prevalences or the rates of the available diagnostic--and reason for encounter--classes were distributed over four frequencies. With a few exceptions the distribution of diagnostic labels referring to common diseases is surprisingly similar. The use of ICPC however results in a quantum leap in the use of symptom and complaint diagnoses. Because of this shift primary care physicians now have available a classification with 400 diagnostic classes used with a prevalence of > or = 1/1000 patient-years or per 1000 visiting patients per year. The classification of reasons for encounter allows the physician to identify over 300 reasons for encounter used > or = 1/1000 patient years or per 1000 visiting patients per year. Family physicians have been successful in the development of new primary care classifications. Rag bag rubrics which are the result of the structure of ICPC are used relatively often and deserve more attention from primary care taxonomers.


The conversion between ICPC and ICD-10. Requirements for a family of classification systems in the next decade.

The International Classification of Primary Care (ICPC) was developed to order medical concepts into classes that have been chosen for their relevance for family medicine. Family physicians use this to label the most prevalent conditions in their practice as well as their patients' symptoms and complaints. At the same time they do not want to be divorced from the needs of the medical community at large as these are reflected in the most recent medical nomenclature: the Tenth Revision of the International Classification of Diseases (ICD-10). A full conversion between all classes in the first and seventh component of ICPC (n = 646) with those of ICD-10 (n = 1983), with the exception of the chapter on external causes, has been prepared. It was concluded that ICD-10 at the three-digit level cannot function as a core classification for an international primary care system. Of the three-digit ICD-10 rubrics only 120 are compatible on a one to one basis with an ICPC rubric. A total of 114 three-digit ICD-10 rubrics have to be broken open into four-digit rubrics to allow at least one compatible conversion to one or more ICPC rubrics. On this basis only 25% of the diagnostic classes in ICPC can be converted to a single three- or four-digit ICD-10 rubric without lumping. The rest of ICD-10, either on the three- or on the four-digit level, has to be grouped into combinations of classes (lumping) to allow compatible conversion to the remaining rubrics of ICPC. Even though ICD-10 cannot serve as a core classification for primary care, a technical conversion between ICPC and ICD-10 is practically always possible which allows primary care physicians to implement ICD-10 as a contemporary nomenclature within the classification structure of ICPC.


Minimum basic data set in general practice: definitions and coding.

A minimum basic data set (MBDS) was designed and used in general practice. The most important purpose and need for establishing such a data set is to assist in the provision of patient care. MBDS is designed to meet common needs for many general practitioners. Minimum means that individual programmes or the GP are free to collect as much additional data as they may wish. The MBDS includes two kinds of data: permanent and dynamic/encounter items. Permanent items are: patient data (identification, problem list, chronic treatments, source of payment) and GP data (professional characteristics). Dynamic/encounter items are: date, place, reasons for encounter, problems, process and prior encounter status.


Computerization of general practices and quality control. Blood glucose regulation in type 2 diabetics investigated in the Registration Network family practices.

The extent to which computerized medical administration facilitates quality control was studied using as an example the quality of blood glucose regulation in diabetics supervised by general practitioners in 11 computerized practices. Systematic use of the general practice computer rapidly provided an unequivocal answer that 37% of such patients were not regulated in accordance with the guidelines for type 2 diabetes mellitus of the Dutch College of General Practitioners. The extra workload for the participating general practitioners was minimal. Automated recording of problem lists, as applied in the general practices belonging to the Registration Network, facilitates access to data on chronic diseases and risk factors for purposes of research, quality control and quality assessment.