Analysis of nuclear 3,3',5-triiodothyronine receptor in the brown adipose tissue (BAT) of the postnatal lamb.

Postnatal thermogenesis in sheep is associated with increased sympathoadrenal activities, a T3 surge and an enhanced brown adipose tissue (BAT) type II 5'-monodeiodinating (5'-MDI) activity. The latter peaks 3-4 days after birth and is known to be important in generating intracellular T3 for nuclear receptor binding. In order to further investigate the mechanism(s) responsible for neonatal thermogenesis, thyroid hormone nuclear receptor (T3NR) binding characteristics were quantified in lamb BAT from newborn (NB) to 30d of postnatal age. Maximal binding capacities (MBC, mean +/- SEM fmoles T3/mg DNA) in BAT showed a decrease as studied by ANOVA during the first 11 days (NB to 1d, 148 +/- 24 [N = 5, p < 0.01, cf. 3-5d group]; 3-5 d, 61 +/- 5.5 [N = 5]; 10-11d, 72 +/- 9.1 [N = 4]). Afterwards, MBC increased at 30d (196 +/- 32, N = 4, p less than 0.01, cf. 3-5d group). BAT T3NR binding affinities (10(9) M-1) were comparable in all age groups studied (NB-1d, 2.8 +/- 0.3; 3-5d, 3.4 +/- 0.3; 10-11d, 4.0 +/- 1.1; 30d, 2.4 +/- 0.4). The data suggest that the postnatal surge in T3 and type II 5'-MDI is accompanied with a concurrent decrease in MBC of BAT T3NR. The latter may represent a down-regulation of T3NR presumably in an attempt to regulate the overall effect of thyroid hormone in neonatal thermogenesis.


Effect of insulin and adrenaline on the 59Fe transferrin uptake of lactating mouse mammary gland cells.

The results of insulin action (0.4 IU per mouse) are demonstrated in intact animals only. This action leads to a higher uptake of 59Fe. rabbit transferrin of isolated cells from lactating mouse mammary gland. It is suggested that most inactive transferrin receptors in the cell membrane are incorporated by the hormone action or some new receptors are synthesized. On the contrary, adrenaline in a dose 0.5 micrograms per animal demonstrated an opposite effect--a lower uptake of 59Fe. human transferrin from lactating mouse mammary gland. This is probably due to a redistribution of some part (about 28%) of the iron. Instead of flowing to the mammary gland it flows towards other organs for overcoming the stress situation. An alternative explanation could be the inhibition of endogenous insulin secretion by adrenaline. From our data it follows that insulin and adrenaline have an antagonistic effect on regulation of Fe transport in lactating mouse mammary gland.


Differential effects of body weight, hyperinsulinemia and oral glucose load on serum C-peptide/insulin molar ratio.

Serum C-peptide immunoreactivity (CPR)/immunoreactive insulin (IRI) molar ratio was determined in 136 subjects without renal, hepatic and thyroid disorders, at fasting, and during the initial period of 75 g-oral glucose tolerance test. The subjects were divided into 4 groups based on their body weight and age; Group A, young (< 55 years) and normal body weight (body mass index [BMI, kg/m2] < or = 25) subjects; Group B, young and overweight (BMI > 25) subjects; Group C, aged (> or = 55 years) and normal body weight (BMI < or = 25) subjects; Group D, aged and overweight subjects. Fasting CPR/IRI ratio and absolute CPR level negatively correlated in Groups B and D but not in A and C. After oral glucose load with elevation of insulin, CPR/IRI ratio invariably declined in all groups and significant negative correlation between CPR/IRI and CPR was found in Groups A, B and D but not in C. Slope of the regression lines obtained for correlation between CPR/IRI ratio and CPR were significantly steeper at fasting compared to the post-stimulation phase. CPR/IRI ratio is affected by hyperinsulinemia and oral glucose load but not by obesity alone. Assuming that CPR/IRI ratio reflects hepatic extraction of insulin, the insulin clearance at fasting is progressively reduced with increasing insulin secretion in overweight subjects: failure to detect such phenomenon in normal body weight subjects may be due to a narrower CPR range in this population. Insulin metabolism at fasting and during glucose stimulation is likely to be regulated by distinct factors.


Acute thyroid dysfunction (thyroiditis) after therapy with interleukin-2.

Interleukin-2 (IL-2) is frequently incorporated in antineoplastic therapy: While the effect of interferon on the thyroid has been extensively studied the impact of other cytokines on thyroid function is less well understood. We monitored the thyroid function in six patients who received IL-2 in combination with tumor necrosis factor-alpha (TNF) or alpha-Interferon (alpha IFN). Hyperthyroxinemia with suppressed TSH developed within the first four weeks of IL-2 administration; during this phase, there was no technetium or iodine uptake by the thyroid gland. During the following few weeks, serum thyroxine decreased and serum TSH rose, consistent with the development of primary hypothyroidism; during this phase, thyroidal isotope incorporation was normal. All hypothyroid patients received thyroxine replacement therapy upon documentation of hypothyroidism; in several cases thyroxine was successfully discontinued after 2-3 months. None of the patients had detectable antithyroidal antibodies and none experienced thyroid-related pain, although two patients developed thyroid enlargement. We conclude that IL-2 administration is associated with the development of transient, subacute, painless thyroiditis. The frequency and severity of this complication requires further elucidation through systematic, prospective study.


Serum procalcitonin as an index of inhalation injury in burns.

The molecular heterogeneity of serum immunoreactive calcitonin (iCT) was analyzed from a prospective study of 41 burn patients. Using different region-specific anticalcitonin antisera, the ratio of mid-region-recognizing to carboxyl terminal-region-recognizing iCT was found to increase acutely in those who subsequently died. The highest ratios occurred in those who died early of respiratory complications. Sephadex chromatography and reversed-phase HPLC demonstrated that the serum iCT circulated predominantly in the large molecular mass prohormone form (16 kDa). In comparison, iCT of normal human lung and of normal thyroid was shown to consist primarily of smaller monomeric mass forms. Furthermore, in 12 normal volunteers who were evaluated with a calcium-pentagastrin infusion, the ratio of iCT levels did not differ from the baseline ratio despite a 50% increase in serum iCT. These results suggest that in burns, the inhalational injury-associated hypercalcitonemia is characterized by a preferential release of procalcitonin; a form of constitutive secretion. The measurement of serum procalcitonin levels would appear to be a useful prognostic indicator of the severity of inhalational injury occurring in burn patients.


A correlative study on serum cholylglycine levels in hepatobiliary disease.

The serum cholylglycine (CG), alanine aminotransferase (ALT) and total bilirubin levels were studied in 210 patients with hepatobiliary disease and in 70 healthy subjects. Serum CG concentrations in all the hepatobiliary diseases were found to be significantly higher than those of their controls. Patients with abnormal increases in ALT and bilirubin levels also showed raised CG concentrations; however, some patients with normal ALT and bilirubin levels, still had markedly elevated CG values. Patients with hepatic cirrhosis had high serum CG levels, followed, in descending order, by chronic active hepatitis and chronic persistent hepatitis. In the cholecystitis and cholelithiasis cases, their CG levels were significantly higher than those of the controls but lower than the values in hepatic disease patients; however, more cholecystitis cases had abnormally high serum bilirubin levels than CG. The results also show that serum CG concentrations vary in the different hepatobiliary diseases, and that serial CG measurements are more sensitive than measuring ALT and bilirubin levels in the diagnosis of hepatic diseases. Serum CG can be used as an index for evaluating the activity of chronic hepatitis; it can also be employed as a diagnostic tool in cholecystitis and cholelithiasis.


A role for thyroid hormone in the induction of ovulation and corpus luteum function.

We have previously demonstrated that thyroid hormone synergizes with follicle-stimulating hormone (FSH) to exert stimulatory effects on granulosa cell differentiation and function, suggesting that it plays a physiological role in amplifying FSH-mediated differentiation of granulosa cells. The adequate differentiation of these cells, followed by normal follicle development, is indispensable for ovulation and subsequent corpus luteum formation. Thus, in the present studies, the clinical implications of thyroid hormone in the induction of ovulation and corpus luteum function were investigated. Serum levels of total 3,5,3'-triiodothyronine (T3) and total thyroxine (T4) as well as free T3 and T4 were significantly lower in patients with weight loss amenorrhea compared to normal cycling women. Although no ovulation was induced by clomiphene therapy when the serum T3 levels were less than 80 ng/dl, the rate of ovulation induced by clomiphene increased in parallel with the augmentation of serum T3 levels. This suggests that an adequate circulating level of thyroid hormone is one of the factors responsible for successful induction of ovulation by clomiphene citrate. Furthermore, the short luteal phase and insufficient progesterone secretion observed in patients with subclinical hypothyroxinemia were not improved by clomiphene therapy alone, but were improved markedly by combined treatment with thyroid hormone replacement and clomiphene citrate. These data imply that concomitant clomiphene treatment with thyroid hormone replacement therapy is of a great value not only for ovulation induction, but also for the treatment of luteal-phase defect in patients with subclinical hypothyroxinemia.


Possible involvement of lipoxygenase products in human corpora lutea.

The present study was undertaken to determine the ability of cultured luteal cells from human corpora lutea to secrete progesterone (P4) and prostaglandins (PGs), and to assess the effects of the products of the lipoxygenase pathway on luteal P4 production. Luteal cells responded to human chorionic gonadotropin (hCG) with a significant increase (2- to 7-fold) in P4 production. Arachidonic acid significantly stimulated PGE2 synthesis by luteal cells in a dose-dependent manner. Both basal PGE2 production and the responsiveness to arachidonic acid were maintained for 8 days. In contrast, both PGF2 alpha and 6-keto-PGF1 alpha production abruptly declined as the culture proceeded. However, the addition of hCG did not further stimulate the accumulation of the 3 PGs assayed. In the subsequent experiment, 5-hydroxyeicosatetraenoic acid (5-HETE) and the reaction products of soybean lipoxidase of arachidonic acid (AA-LIP) were utilized for evaluating the involvement of the lipoxygenase pathway in luteolysis. The addition of 5-HETE dose-dependently inhibited P4 production by the cultured luteal cells. Although treatment with either arachidonic acid or lipoxidase alone had no effect on P4 production, AA-LIP significantly reduced P4 production in the presence or absence of hCG. These results suggest that the products of the lipoxygenase as well as of the cyclo-oxygenase pathway may be important in regulating the life span and function of human corpora lutea.


Modulation of progesterone secretion by androgens in porcine granulosa cell cultures.

The influence of testosterone, androstenedione and dihydrotestosterone (DHT) on the progesterone (P4) production by cultured porcine granulosa cells was studied in the presence or absence of gonadotropins. Porcine granulosa cells from large follicles (6-12 mm in diameter) were incubated for 2 days with 5% CO2 in air with testosterone, androstenedione and DHT (10(-12), 10(-10), 10(-8) and 10(-6) M) in the presence or absence of luteinizing hormone (LH, 10 ng/ml) or follicle-stimulating hormone (FSH, 30 ng/ml). P4 and pregnenolone (P5) in conditioned culture media were quantified by their specific RIAs. In the absence of gonadotropins, P4 in media with androgens were not significantly different from controls. In the presence of LH, the addition of testosterone (10(-10), 10(-8) M), androstenedione (10(-8) M) and DHT (10(-8) M) caused a significant 1.3- to 2.3-fold increase in P4 over that caused by LH alone. In contrast, in the presence of FSH, testosterone (10(-12), 10(-10) M), androstenedione (10(-12)-10(-6) M) and DHT (10(-6) M) reduced the levels of P4 by 22% to 41%. The addition of androgens with LH caused a significant increase in P5, while P5 decreased in the presence of FSH. P4/P5 ratios remained unchanged in the presence of both LH and FSH. These data suggest that the P4 production by cultured porcine granulosa cells is modulated in a paracrine or an autocrine fashion by androgens in the presence of gonadotropins, and that androgens may exert their actions partly by altering the activity of cholesterol side chain cleavage enzymes.


Sporadic appearance of luteal-phase defect in prospective assessment.

We studied the sporadic appearance of luteal-phase defect in the prospective assessment of consecutive cycles. Basal body temperature (BBT) was recorded in 36 women (20-35 years of age) for at least 3 consecutive cycles (total of 194 cycles). These BBT records were analyzed for pattern and luteal-phase length (LPL). Furthermore, the relationship was investigated between the BBT and luteal function in terms of serum hormonal levels and endometrial dating in the luteal phase. The length of the transitional period from the hypothermic to the hyperthermic phase was also studied in relation to luteal function in 59 women (21-33 years of age). The results were as follows: (1) Different BBT patterns and LPLs in consecutive cycles occurred in 36 and 67% of the observed cycles, respectively. (2) Cycles with abnormal steroid levels and endometrial dating were observed sporadically. (3) The length of the transitional period appeared useful for prospective evaluation of luteal function. These findings suggest that the conditions of the luteal function do not appear in every cycle of each woman. Therefore, assessing the function of one cycle seems of little use in predicting the function of the next or future cycles.


Association of immunoreactive-inhibin levels with luteal function.

To evaluate immunoreactive (IR) inhibin as a marker of corpus luteal function, 134 women with natural ovulatory cycles were studied. Serum IR-inhibin levels during the luteal phase were significantly lower in women with low progesterone (P4) levels (less than 10 ng/ml). Endometrial dating correlated more with serum P4 than IR-inhibin levels. All 14 conceiving cycles showed serum P4 levels greater than or equal to 10 ng/ml and IR-inhibin levels greater than or equal to 3.67 IU/ml during the midluteal phase. Furthermore, IR-inhibin levels in the early follicular phase seemed to be associated with lowered P4 levels in the ensuing luteal phase. These results suggest that IR inhibin may be closely related to corpus luteum function.


Analysis of clinical backgrounds and pathogenesis of luteal-phase defect.

To elucidate the clinical background of the luteal-phase defect (LPD), 201 LPD cycles were studied in 753 infertile women. One hundred and twenty-one cases (62.2%) of LPD showed transient hyperprolactinemia. In transient hyperprolactinemia, there was a significant inverse correlation between serum prolactin (PRL) 30 min after the 500-micrograms intravenous loading of thyrotropin-releasing hormone TRH (PRL30) and progesterone (P4) in the luteal phase (r = -0.67, p less than 0.005). Mature follicles (diameter greater than 20 mm as determined by ultrasonography) were observed in 74 cases (61.2% of the transient hyperprolactinemia cases). On the contrary, in 25 (12.4%) of the 121 LPD cases who showed the hyper-luteinizing hormone (LH) syndrome (LH/FSH ratio greater than 1), only 9 (36%) had mature follicles. Of the remaining 55 cases who showed neither transient hyperprolactinemia nor the hyper-LH syndrome, 27 cases (49.1%) had mature follicles. Five of these patients indicated a significantly higher LH pulse amplitude despite depressed P4 secretion in the luteal phase. From these results, it was concluded that the most common cause of LPD was transient hyperprolactinemia. The second cause of LPD was suspected to be disturbed follicle development due to the inappropriate ratio of LH/FSH in the hyper-LH syndrome. Another cause was speculated to be the primary failure of a response from the corpus luteum to LH. Treatments based on the conclusions mentioned above resulted in a 48.3% pregnancy success rate.


Hysteroscopic assessment of midsecretory-phase endometrium, with special reference to the luteal-phase defect.

To investigate the functional aspects of secretory-phase endometrium, hysteroscopy was performed in 61 patients for in vitro fertilization-embryo transfer (IVF-ET), and 50 women for infertility evaluation. All women had normal ovulatory cycles. The hysteroscopic assessment of secretory-phase endometrium was made by characterizing the glandular openings (GO) and vasculature. The assessments were classified as 'good': characterized by ring-type GO and well-developed vessels; and 'poor': characterized by dot and/or punctate-type GO and fine vasculature. In the 30 patients classified 'good' prior to the IVF cycle, there was a higher pregnancy rate (40%) than in 'poor' ones (13%). Thirty of 50 infertile women were classified 'good', and their average age was lower than that of the remaining 20 in the 'poor' group. Preovulatory estradiol was significantly higher in the 'good' than in the 'poor' group. From an analysis of 20 patients with a 'poor' assessment, it was demonstrated that the maturation of secretory-phase endometrium was affected by a failure of folliculogenesis, progesterone secretion, endometrial growth and menstrual shedding.


Clinical importance of endometrial histology and progesterone level assessment in luteal-phase defect.

In order to clarify the relationship between endometrial histology and progesterone (P4), plasma P4 and estradiol levels in the luteal phase were measured in 126 cases of unexplained infertility. Endometrial biopsies were performed in the midluteal period of menstrual cycles. Forty-three of the 126 cases showed retarded endometrium. Of these 43 cases, 23 exhibited three different types of abnormal P4 secretion. Type A showed low P4 levels throughout the luteal period. Type B showed low P4 levels only in the early luteal period. Type C showed normal P4 levels in the early luteal period followed by a prompt decline. These findings indicated that P4 determination during the early, mid- and late luteal phases is necessary to assess P4 secretion. However, 20 of the 43 cases had normal P4 levels through the entire luteal phase, demonstrating an insufficient response of the endometrium to P4. Consequently, histological examination of the endometrium is required to investigate the luteal phase defect.


Influence of progesterone/estradiol ratio on luteal function for achieving pregnancy in gonadotropin therapy.

The purpose of this study was to evaluate the influence of the relationship between plasma progesterone (P4) and estradiol (E2) levels in the luteal phase for achieving pregnancy in human menopausal gonadotropin (hMG)-human chorionic gonadotropin (hCG)-treated cycles. Plasma P4 and E2 levels were determined in 93 hMG-hCG-treated cycles (23 pregnant and 70 nonpregnant) of 46 patients during 3 periods of the luteal phase, using radioimmunoassay. In addition, 88 spontaneous ovulatory cycles and 100 clomiphene-treated cycles were also studied in the same manner. In hMG-hCG-treated cycles in the early luteal phase, the P4/E2 ratio in pregnant cycles was significantly higher than that in nonpregnant cycles. There was no significant difference between the P4/E2 ratios of the luteal phase of hMG-hCG-treated pregnant-group, clomiphene-treated and spontaneous ovulatory cycles. In nonpregnant cycles, however, the P4/E2 ratio in hMG-hCG-treated cycles was significantly lower than that in clomiphene-treated or spontaneous ovulatory cycles. These results suggest that in hMG-hCG-treated cycles, the P4/E2 ratio may be a more reliable index of luteal function for achieving pregnancy than P4 levels alone.


Factors promoting embryo implantation in in vitro fertilization and embryo transfer.

The low implantation rate after embryo transfer (ET) is the most important problem to be solved in in vitro fertilization and embryo transfer (IVF-ET). Various factors which may affect embryo implantation in the endometrium have been examined. In this study, the influence of the timing of luteinization on the establishment of pregnancy was investigated. Follicle stimulation was performed by luteinizing hormone-releasing hormone agonist, human menopausal gonadotropin and human chorionic gonadotropin (hCG). hCG was injected on the day when the mean diameter of two follicles exceeded 16 mm, and 36 h after the injection the oocyte was retrieved. Progesterone (P4) supplement was started on the day of ovum retrieval (50 mg), followed by 30 mg for 14 days. The patients were divided into three groups: (1) the pregnant patients (n = 20: group Pre); (2) the nonpregnant patients without bleeding during P4 injection (n = 35; group N), and (3) the nonpregnant patients with bleeding during P4 injection (n = 30; group B). The number of follicles that developed, endometrial thickness, the day of operation, the number of oocytes harvested, the number of good quality oocytes, the number of oocytes fertilized, the number of embryos transferred, estradiol (E2) and P4 levels, and the E2/P4 ratio were examined. The endometrial thickness of group Pre (10.9 +/- 0.6 mm; mean +/- SEM) on the day of hCG injection was significantly (p less than 0.05) greater than that of groups N (9.0 +/- 0.4 mm) and B (9.2 +/- 0.3 mm).(ABSTRACT TRUNCATED AT 250 WORDS)


Further observations on serial serum immunoreactive inhibin levels in the luteal phase and early gestation after ovarian stimulation for in vitro fertilization and embryo transfer.

Serum immunoreactive inhibin of the luteal phase was measured by radioimmunoassay in 71 patients in vitro fertilization and embryo transfer (IVF-ET). The correlation between the pregnancy outcome and the serial inhibin pattern from the luteal phase to early gestation was studied. In nonconception cycles (n = 35), serum inhibin concentration rose and reached a peak level around 5 or 6 days after oocyte pick-up (OPU), then fell to the level of the early follicular phase. In conception cycles (n = 22), serum inhibin levels rose again 10-15 days after OPU. Serum inhibin levels were significantly higher from 10 days after OPU in multiple pregnancy (n = 5) than in single pregnancy (n = 17). In viable single pregnancy (n = 17), serum inhibin levels were significantly higher than in non-viable pregnancy (n = 14) from 15 days after OPU. Serum inhibin levels in early gestation correlated well with the pregnancy outcome of IVF-ET. These data suggest that inhibin is an important factor for the diagnosis of pregnancy outcome.


Role of corpus luteum function in embryo implantation.

The present study was undertaken to evaluate the role of corpus luteum function in the implantation process of cryopreserved embryos. Six patients with tubal infertility were studied, with a total of 27 fresh embryos being replaced following controlled ovarian hyperstimulation and in vitro fertilization. These embryo transfers failed to produce pregnancy. From the patients, 22 supernumerary embryos were cryopreserved and 10 viable frozen-thawed embryos were transferred in a subsequent natural cycle, resulting in 2 pregnancies. In 1 of the pregnancies, the serum concentrations of estradiol (E2) and progesterone (P4) in the midluteal phase were 29 pg/ml and 5.6 ng/ml, respectively. These values were considered to be below the physiological range. These data suggest that a pregnancy can be achieved in spite of low circulating E2 and P4 levels during the luteal phase, which are generally indicative of the luteal phase defect.


Day-night rhythm disturbance, pineal function and human disease.

Depression, mania and probably starvation all induce changes in pineal function. At present it is unknown what secondary effects on the endocrine and other systems are produced by these changes. Studies in rats have established an entraining effect of melatonin on locomotor activity and a feedback effect on the pineal itself. Studies of jet-lag and of sleep dysregulation in a blind subject established that melatonin treatment has a synchronizing effect in these conditions. Further investigations will be necessary to establish whether melatonin reduction in depression and other disorders leads secondarily to dysregulation of other circadian rhythms.


Gonadotropin regulation, oestrogens and the immune system.

Several transmitters and neuropeptides participate in the regulation of gonadotropins. At the hypothalamic level, control of gonadotropin releasing hormone (GnRH) involves noradrenaline, GABA, glutamate, angiotensin II, neuropeptide Y, neurotensin, and 5-hydroxytryptamine as well as interleukins 1 and 2. Ovarian steroids can interfere with gonadotropin regulation by either direct effects on GnRH release or by increasing the sensitivity of anterior pituitary cells to GnRH, thus potentiating the release of pituitary hormones. These interactions involve discrete actions on second messenger systems; similar processes also account for brain and endocrine effects on immune cells.


Neurohypophyseal peptides and psychopathology.

The study of neurohypophyseal peptides in various neuropsychiatric disorders is of interest because the hypothalamo-posterior pituitary axis is directly influenced by modifications of central neurotransmitter metabolism involved in behaviour control. Moreover, the main neurohypophyseal peptides, namely vasopressin and oxytocin, are themselves capable of modifying behaviour. In this paper the author discusses current understanding of the anatomy and physiology of the main central vasopressinergic and oxytocinergic pathways, followed by a description of the principal actions of exogenously administered vasopressin and oxytocin on human behaviour. Finally, modification of endogenous neurohypophyseal function encountered in different pathological states are described.


Genetic disorders of adrenal hormone synthesis.

Steroid 21-hydroxylase is the enzyme involved in 90-95% of cases of congenital adrenal hyperplasia (CAH). The general feature of CAH, which results from an enzymatic block at any stage in the synthesis of cortisol, is increased serum adrenocorticotropin and thus stimulated adrenal synthesis of steroids proximal to the block. All enzyme defects causing CAH are autosomal recessive traits. The early steps in cortisol synthesis are common to adrenal and gonadal steroid pathways, thus CAH caused by dysfunction of the enzymes supporting these steps is also characterized by insufficient production of gonadal hormones, causing impaired genital development in the genetic male. The absence of or severe reduction of steroid 21-hydroxylase activity also causes prenatal hypersecretion of androgens by the adrenal cortex, which results in external genital ambiguity in genetic females. This paper discusses the classical and nonclassical forms of CAH, their aetiology, diagnosis and treatment, and also describes recent advances in prenatal diagnosis and treatment which avoids the need for corrective genital plastic surgery in infancy.


Adrenal disorders and polycystic ovary syndrome.

Adrenal hyperandrogenism is a common feature of polycystic ovary syndrome (PCO). It is controversial whether the noncongenital adrenal hyperplasia disorders represent some sort of primary defect within the adrenal gland or are secondary to the effects of the abnormal hormonal milieu on adrenal enzyme activity, either the high androgen or luteinizing hormone levels. Adrenal androgens, both directly and by their aromatization to oestrogens, can cause the clinical and biochemical syndrome of PCO.


Evaluation of young women with congenital adrenal hyperplasia: a pilot study.

To evaluate the outcome of medical and surgical treatment of 10 young women with congenital adrenal hyperplasia (CAH), final height, weight, body proportions and body hair growth as well as aspect and functionality of the external genitalia were assessed. The final height was below-2 SD of the target height in 55%, though the body proportions were in the normal range. Only 3 patients were menstruating regularly. Scores for 'hormonal' body hair growth were in a higher range. Gynaecological examination revealed that in 5 out of 9 patients, the genitalia were functionally acceptable. This pilot study stresses that from birth into adulthood of female patients with CAH there is a need for a combined therapeutic approach by a paediatric endocrinologist, a surgeon and a psychologist. This will improve the physical and psychosocial well-being of these patients.


Congenital anorchia: natural history and treatment.

This paper discusses the definition, pathogenesis, diagnosis and treatment of congenital anorchia. It concludes that preparations containing esters of testosterone are preferable to synthetic derivatives for long-term treatment as they are metabolized in the same way as endogenous testosterone. In addition, it appears that recommended doses for replacement therapy are lower than previously suggested. An ideal formulation of testosterone for use in androgen replacement therapy is not currently available.


Physical and mental development of adolescent males with Klinefelter syndrome.

Of 25,000 Danish schoolboys, aged 15-16 years, 16 were found to have previously undiagnosed Klinefelter's syndrome. Comparison of these boys with normal controls indicated that on average these subjects had increased height, reduced weight, impaired hearing, slightly lowered intelligence, poor school performance, increased incidence of psychological consultation and lowered sexual activity compared with their peers.


Hypogonadotropic hypogonadism; the genetic defect. A hypothesis based on human and animal prototypes.

X-linked hypogonadotropic hypogonadism (HH) in humans may involve the genes responsible for the development and migration of GnRH neurons from the olfactory placode to the hypothalamus. The evidence for this includes the lack of hyperprolactinaemia in cases of X-linked HH, the associated abnormalities in the context of contiguous gene syndromes involving Xp deletions, and pertinent anatomical findings. The genetic defect in human HH appears, therefore, to be different from that found in the hpg mouse model.


Clinical data regarding the growth of diabetic children.

Many authors have reported retarded growth in children with diabetes, though this has been a somewhat variable finding. However, with the newer treatment regimens for diabetes the problem of reduced growth rates has largely been solved.


Insulin and growth factors adaptation to normal puberty.

Insulin and IGF-1 production were measured throughout childhood and puberty and into adult life. Basal insulin and IGF-1 secretion increased during puberty, falling back to prepubertal levels in adulthood. However, fasting glucose levels remained constant, implying an increase in tissue resistance to insulin coinciding with puberty.


The GH-transgenic mouse as an experimental model for growth research: clinical and pathological studies.

The objectives and the methodology of mammalian gene transfer are discussed and findings in growth hormone (GH) transgenic mice are reported to illustrate the potential offered by genetically designed animal models for investigations in various areas of biomedical research. Transgenic mice expressing hybrid genes composed of either human or bovine GH coding sequences fused to the mouse metallothionein I promoter show high serum levels of heterologous GH, increased growth rates and final adult size, decreased life expectancy and a variety of pathological changes.


Growth hormone gene regulation by trans-acting factors.

The promoter sequence of the growth hormone (GH) gene binds the ubiquitous factors nuclear factor 1, activator protein-2, upstream stimulatory factor and Sp1. A pituitary-specific factor known as growth hormone factor 1 or Pit-1 also binds to the promoter sequence. This factor is responsible for somatotroph-specific expression of GH. It is also involved in the effect of GH-releasing hormone and in the ontogeny of the anterior pituitary.


Biological rhythms in reproductive processes.

Biological rhythms play an important role in the regulation of many different physiological systems, including the reproductive system. The 24-hour clock system plays a role in regulating the production, release, synthesis and action of reproductive hormones and in the timing of critical events in the ovarian cycle. Research into the importance of biological rhythms on human reproduction is just beginning, future work is likely to reveal new and unexpected ways in which these rhythms affect human reproduction.


Perinatal development of day-night rhythms in humans.

Evidence suggests that the suprachiasmatic nuclei function as a circadian pacemaker in humans. The development of the circadian timing systems may be similar to that described in rodents and nonhuman primates. Awareness of circadian rhythmicity during development should improve infant care and increase the understanding of several disease states.


Hepatitis C virus infection in medical personnel after needlestick accident.

Hepatitis C virus infections in medical personnel after needlestick accidents have been documented generally by detection of seroconversion to a hepatitis C virus nonstructural region antigen, c100-3 (a marker of infection). We tested for hepatitis C virus core-derived antibodies and genomic RNA in addition to c100-3 antibody in 159 cases of needlestick exposure that did not involve patients positive for HBsAg. Of these we found 68 cases with index patients positive for both hepatitis C virus RNA and antibodies and members negative for antibodies to HCV core or c100-3 before the needlestick accidents. Seven of these medical personnel became infected with hepatitis C virus after the accidents. Their hepatitis was generally subclinical or self-limited and transient, except for one patient in whom liver enzyme elevation persisted along with the antibodies. In our study, the risk of hepatitis C virus transmission from a single needlestick accident with hepatitis C virus RNA-positive blood was 10%, considerably higher than the 4% estimated in a previous study. We found that donor blood with antibody to an hepatitis C virus core-derived peptide with enzyme-linked immunosorbent assay optical densities greater than 2.0 carried a significant risk of transmitting hepatitis C virus to needlestick victims. No hepatitis C virus seroconversions occurred in medical personnel exposed to hepatitis C virus antibody-negative or hepatitis C virus RNA-negative blood; however, one such exposure resulted in a very mild non-A, non-B, non-C hepatitis.


Therapy for chronic hepatitis B with lymphoblastoid interferon-alpha and levamisole.

About one third of patients with chronic hepatitis B show a sustained response when treated with interferon-alpha. Combining interferon-alpha with immunomodulators might be a way to increase response rate. The aim of this study was to compare the efficacy of lymphoblastoid interferon-alpha given alone with its efficacy when combined with levamisole in chronic hepatitis B. Forty-five patients with HBeAg-positive chronic hepatitis were randomly selected (with stratification for ALT levels) to receive a 6-mo course of combination therapy with lymphoblastoid interferon-alpha (5 million units/m2 three times per week) and levamisole (150 mg three times per week) or lymphoblastoid interferon at the same dose regimen and a matching placebo. Final evaluation 18 mo after randomization revealed a loss of both HBeAg and hepatitis B virus DNA with ALT normalization in 38% of patients treated with interferon-alpha alone and in 10% of patients receiving combination therapy. The higher response rate observed in patients treated with interferon-alpha alone was maintained after stratification for basal ALT levels (i.e., higher [45% vs. 10%] or lower [31% vs. 9%] than three times the upper normal value). The length of time to sustained HBeAg clearance was significantly (p < 0.05) shorter in patients receiving monotherapy than in patients receiving combination therapy. Blinded histological assessment revealed improvement in 44% of patients treated with interferon-alpha alone compared with improvement in 6% of patients receiving combination therapy. These results indicate that levamisole has no additive effects when combined with interferon-alpha in the treatment of HBeAg-positive chronic hepatitis.


Expression and localization of the small and large delta antigens during the replication cycle of hepatitis D virus.

To study the expression and localization of delta antigen during the replication cycle of hepatitis D virus, we cotransfected HuH-7 hepatoma cells with a hepatitis B virus expression plasmid and plasmids expressing the small or large delta antigen or the entire HDV genome. The transfected cells and culture medium were analyzed on double immunofluorescence staining for delta antigen and HBsAg, on Western blotting and on Northern-blot hybridization from 4 hr to 9 days after transfection. In cells transfected with the expression plasmid carrying the small delta antigen open reading frame, only the small delta antigen was expressed; it was localized in the nucleolus and was not released into the medium during the culture period. In cells transfected with the large delta antigen expression plasmid, the large delta antigen expressed was localized in the nucleolus at the initial stage; this was followed by relocalization in nucleoplasm. Finally, large delta antigen was released in HBsAg-enveloped particles within 1 day of transfection. In cells cotransfected with hepatitis B virus and hepatitis D virus expression plasmids, the small delta antigen was expressed 4 hr after transfection, whereas the large form was expressed 3 days after transfection. Expression of the large delta antigen coincided with the localization changes from nucleolar to mixed stage and, finally, to nucleoplasm and release of the hepatitis D virus particles. The large delta antigen appears to play a key role in relocalization of the delta antigen and packaging of the hepatitis D virus virions.(ABSTRACT TRUNCATED AT 250 WORDS)


Emergency liver transplantation for fulminant liver failure in infants and children.

We report our results with orthotopic liver transplantation in children with fulminant liver failure. Thirty-five children with fulminant liver failure were evaluated for liver transplantation. The main causes of liver failure were viral hepatitis (54.2%), drug-induced liver injury (14.2%) and Wilson's disease (11.4%). Children were considered as candidates for liver transplantation only if hepatic encephalopathy was associated with a decrease in the level of factor V to below 25%. Seven children (20%) did not meet this criterion and recovered spontaneously. Six children (17.1%) had contraindications for liver transplantation and died. In three of these six children, contraindications included irreversible brain damage at the time of admission. Twenty-two children (62.8%) met the criteria for liver transplantation and were placed on the emergency transplant list. Three of them died awaiting grafts. Nineteen children underwent liver transplantation; 13 of them (68.4%) are alive without sequelae, after 6 mo to 4 yr of follow-up, at this writing. Four of the children who died after surgery had severe encephalopathy on admission that did not improve after liver transplantation. In conclusion, emergency liver transplantation appears to be an effective treatment for children with fulminant liver failure. Nevertheless, irreversible brain damage developed in 10 patients, and they died before or after surgery. We postulate that many of these deaths could have been avoided if children had been transferred to a liver transplantation facility and had undergone transplantation earlier. We emphasize that children with acute liver failure should be transferred to a center that performs liver transplantation before the development of hepatic encephalopathy.


Human cholecystitis is associated with increased gallbladder prostaglandin I2 and prostaglandin E2 synthesis.

Microsomal prostanoid synthesis was compared in normal gallbladders removed during organ donation and inflamed gallbladders removed at cholecystectomy. Normal human gallbladder microsomes demonstrated low rates of conversion of [14C]arachidonic acid to total labeled prostanoids, which increased during 1 to 30 min of incubation. Normal human gallbladder microsomes converted labeled substrate to all primary prostaglandins without demonstration of a major product. Inflamed human gallbladder microsomes increased the rate of conversion of [14C]arachidonic acid to total labeled prostanoids two or three times over the levels demonstrated by normal gallbladder microsomes at all times of incubation (p < 0.01). The main prostanoids synthesized by the inflamed human gallbladder microsomes were prostaglandin E2 and 6-keto-prostaglandin F1 alpha, which were increased four times over the levels demonstrated by normal gallbladder microsomes (p < 0.01). These data showed that inflammation of the human gallbladder was associated with increased synthesis of gallbladder 6-keto-prostaglandin F1 alpha and prostaglandin E2.


Octreotide inhibits the meal-induced increases in the portal venous pressure of cirrhotic patients with portal hypertension: a double-blind, placebo-controlled study.

The aim of this study was to determine the effects of the long-acting somatostatin analog, octreotide, on portal venous pressure and collateral blood flow in cirrhotic patients with portal hypertension during fasting and postprandial states. In a double-blind, placebo-controlled study, we investigated the effects of octreotide on the hepatic venous pressures and azygos blood flow of 21 patients before and after a standard liquid meal containing 40 gm of protein in 250 ml. Octreotide significantly reduced azygos blood flow from a mean of 499 +/- 65 ml/min to a mean of 355 +/- 47 ml/min (p < 0.01), but it had no effect on the hepatic venous pressure gradient. The hepatic venous pressure gradient of patients in the placebo group increased significantly, from a fasting mean of 16.4 +/- 1.6 mm Hg to a mean of 20.0 +/- 1.7 mm Hg 30 min after the meal (p < 0.01). In a second protocol hepatic venous pressures were measured in 20 patients at 30-min intervals for 2 hr after ingestion of the mixed meal. Again the placebo group showed a significant increase in the hepatic venous pressure gradient 30 min after the meal (20.4 +/- 1.5 mm Hg vs. 18.2 +/- 1.2 mm Hg; p < 0.05), but the group receiving octreotide showed no significant changes during the 2 hr of observation. We conclude that octreotide significantly reduces azygos blood flow, with little effect on portal venous pressure, and that it appears to inhibit postprandial increases in portal pressure in cirrhotic patients with portal hypertension.


Characterization of sodium-dependent amino acid transport activity during liver regeneration.

Liver regeneration occurs after removal of or damage to a portion of the liver; it leads to restoration of the original liver mass. The activities of three sodium-dependent amino acid transporters--system A, system N and system ASC--were determined during a 5-day period of liver regeneration in the rat. Seventy-percent hepatectomy or laparotomy was performed in pairs of rats; these rats' livers were removed at different time points after surgery. Transport activity was determined through measurement of the Na(+)-dependent uptake of tritiated amino acids by isolated hepatic plasma membrane vesicles. System A activity, as measured by the Na(+)-dependent uptake of 2-aminoisobutyric acid, is increased in the regenerating liver 2 to 24 hr after surgery compared with that of controls. Kinetic analysis of 2-(methylamino)isobutyric acid uptake showed a 100% increase in the maximum velocity of system A transport in the hepatectomized animals with no change in the Michaelis constant, suggesting an increase in the number of system A transport proteins in the plasma membrane of regenerating liver. During liver regeneration, no changes were noted in the transport activities of system N and system ASC as measured by the uptake of glutamine and cysteine, respectively, in the presence of 2-(methylamino)isobutyric acid. Our work suggests that system A performs a unique role in the secondary active transport of its substrate neutral amino acids to meet the metabolic demands of regenerating liver.


The incidence of portal vein thrombosis at liver transplantation.

The incidence of portal vein thrombosis was examined in 885 patients who received orthotopic liver transplantations for various end-stage liver diseases between 1989 and 1990. The thrombosis was classified into four grades. Grade 1 was thrombosis of intrahepatic portal vein branches, grade 2 was thrombosis of the right or left portal branch or at the bifurcation, grade 3 was partial obstruction of the portal vein trunk, and grade 4 was complete obstruction of the portal vein trunk. Among the 849 patients without previous portosystemic shunt, 14 patients (1.6%) had grade 1, 27 patients (3.2%) had grade 2, 27 patients (3.2%) had grade 3 and 49 patients (5.8%) had grade 4 portal vein thrombosis. The incidence of portal vein thrombosis was highest (34.8%) in the patients with hepatic malignancy in the cirrhotic liver, followed by those with Budd-Chiari syndrome (22.2%) and postnecrotic cirrhosis of various causes (15.7%). The patients with encephalopathy, ascites, variceal bleeding, previous splenectomy and small liver had significantly higher incidences of portal vein thrombosis than the others. The total incidence of portal vein thrombosis among the 36 patients with previous portosystemic shunt was 38.9%, which was significantly higher than that (13.8%) of those without shunt.


Failure of simple biochemical indexes to reliably differentiate fulminant Wilson's disease from other causes of fulminant liver failure.

Serum, urine and tissue biochemical findings were studied in 21 cases of fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in fulminant Wilson's disease were significantly different from those found in other cases of fulminant liver failure, but differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in fulminant Wilson's disease than in other categories of fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non-Wilsonian fulminant liver failure would erroneously be assigned a diagnosis of fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase-to-bilirubin ratio (< 0.57) in any category of fulminant liver failure suggested a significantly worse prognosis than in cases with higher ratios (chi 2, Yates' corrected = 5.37, p = 0.02). In the Wilson's disease group, serum and hepatic copper and ceruloplasmin concentrations were normal in 4/21, 2/15 and 2/19, respectively, whereas urinary copper level was elevated in 18/18 and was the most valuable test in diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Sequential appearance of intestinal mucosal cell types in the right and caudate liver lobes of furan-treated rats.

Furan rapidly induces in rat liver a unique, lobe-specific pattern of development of intestinal metaplasia and associated cholangiofibrosis. To establish early cell-precursor relationships in the genesis of this cholangiofibrosis, a time-course study was conducted in which young adult male Fisher 344 rats received furan by gavage at a daily dose of 45 mg/kg body wt over a 32-day treatment period. An analysis of individual liver lobes obtained at different time points from these animals during furan treatment revealed the following sequence of histopathological changes, which were located mainly in the right and, to a lesser extent, the caudate liver lobes: day 1, severe hepatonecrosis in zone 3 extending into zone 2 of the liver acini; days 3 to 5, presence of a diffuse inflammatory cell infiltrate in hepatonecrotic areas, which gradually resolved; day 7, prominent bile ductule hyperplasia in tissue sections exhibiting marked loss of normal liver parenchyma; day 9, continued replacement of injured liver by hyperplastic bile ductule tissue, which now contained occasional metaplastic glandular structures composed of columnar basophilic epithelial cells; days 12 to 16, increasing cell diversity in the developing metaplastic glands, with the sequential appearance of goblet cells, Paneth cells and serotonin-positive neuroendocrine cells; and day 32, typical cholangiofibrosis defined by hyperplastic bile ductule-type structures in association with an increased number of metaplastic intestinal glands and progressively more dense fibrotic stroma. Interestingly, at 16 and 32 days the cellular composition of the newly formed metaplastic intestinal glands in liver closely resembled that of the crypts of Lieberkühn in the normal adult rat small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)


Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo.

Hepatocyte growth factor, a potent mitogen for mature hepatocytes in vitro, seems to function as a hepatotrophic factor for liver regeneration. We examined the mitogenic effect of hepatocyte growth factor on mouse liver in vivo. The labeling index of hepatocytes was markedly increased when recombinant human hepatocyte growth factor was injected intravenously into mice subjected to 30% hepatectomy (control, 1.7% +/- 0.1%; 1 microgram hepatocyte growth factor, 6.4% +/- 1.3%; 5 micrograms hepatocyte growth factor, 18.3% +/- 0.2%) and into mice administered carbon tetrachloride (control, 12.7% +/- 1.0%; 1 microgram hepatocyte growth factor, 26.3% +/- 2.8%) or alpha-naphthylisothiocyanate (control, 0.4% +/- 0.1%; 1 microgram hepatocyte growth factor, 3.8% +/- 1.1%; 5 micrograms hepatocyte growth factor, 14.2% +/- 2.0%). In addition, weights of the remnant livers in mice given hepatocyte growth factor 60 hr after 30% hepatectomy were significantly greater than those of untreated control mice (control, 0.93 +/- 0.04 gm; 5 micrograms hepatocyte growth factor, 1.06 +/- 0.04 gm). Hepatocyte growth factor prevented any marked increase in the serum levels of liver enzymes and bilirubin when it was administered to mice also treated with alpha-naphthylisothiocyanate (control: ALT, 394 +/- 278 IU/L; lactate dehydrogenase, 2,644 +/- 1,109 IU/L; bilirubin, 9.6 +/- 2.6 mg/dl; and 5 micrograms hepatocyte growth factor: ALT, 135 +/- 7.9 IU/L; lactate dehydrogenase, 1,672 +/- 626 IU/L; bilirubin, 1.0 +/- 0.8 mg/dl). Our findings show that intravenously injected hepatocyte growth factor stimulates the growth of hepatocytes in mouse liver and protects the integrity of hepatocytes in vivo against hepatitis caused by hepatotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)


Inflammation and platelet-activating factor production during hepatic ischemia/reperfusion.

The role of platelet-activating factor as a potential mediator of hepatic inflammatory injury associated with liver ischemia/reperfusion was investigated using a partial no-flow model in rats in vivo. Platelet-activating factor levels of livers from sham-operated rats and from animals experiencing hepatic reperfusion for less than 6 hr were very low. They were observed to increase significantly after 12 hr of reperfusion and reached peak levels after a 24-hr reperfusion period, a time when maximal hepatic injury and inflammation occurred. Treatment of experimental rats with WEB2170, a platelet-activating factor receptor antagonist, attenuated the hepatic injury and inflammation, as evidenced by decreases in plasma ALT and in hepatocyte necrosis and neutrophil infiltration. Both inactivation of Kupffer cells with gadolinium chloride and inhibition of the formation of reactive oxygen species with allopurinol reduced platelet-activating factor production in the liver, whereas induction of neutropenia had no effect, suggesting that interaction of Kupffer cells with oxygen-derived free radicals may be a plausible mechanism for hepatic platelet-activating factor accumulation. It is concluded that platelet-activating factor contributes to the inflammatory consequences of ischemia/reperfusion underlying late-phase hepatic injury.


Differential expression of hepatocyte growth factor, transforming growth factor-alpha and transforming growth factor-beta 1 messenger RNAs in two experimental models of liver cell proliferation.

Hepatocyte growth factor, a potent hepatocyte mitogen in vitro, appears to trigger hepatocyte regeneration after partial hepatectomy and after acute liver cell necrosis. Transforming growth factor-alpha and transforming growth factor-beta 1 may also be involved in the control of liver regeneration. In this study we assessed possible roles of hepatocyte growth factor, transforming growth factor-alpha and transforming growth factor-beta 1 on liver cell proliferation in vivo, using a model of choline deficiency that is associated with liver cell necrosis and a model of a hypolipidemic agent (4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyethyl) acetamide) without liver necrosis. Male F344 rats were fed a choline-deficient diet or 0.16% 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyethyl) acetamide diet for 6 and 4 wk, respectively. Rats were killed periodically, and the expression of hepatocyte growth factor messenger RNA in the liver, lung and kidney was determined by Northern-blot analysis. The levels of transforming growth factor-alpha and transforming growth factor-beta 1 messenger RNAs in the liver were also determined. Feeding a choline-deficient diet for 1 to 6 wk led to gradual increases in the levels of hepatocyte growth factor, transforming growth factor-alpha and transforming growth factor-beta 1 messenger RNAs in the liver. Feeding a 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyethyl) acetamide diet for 3 days and 2 wk induced marked enhancement of liver cell proliferation as judged by hepatocyte 5-bromo-2-deoxyuridine incorporation.(ABSTRACT TRUNCATED AT 250 WORDS)


Identification and partial characterization of a hepatocyte-derived factor promoting proliferation of cultured fat-storing cells (parasinusoidal lipocytes).

The molecular and cellular mechanisms of activation of fat-storing cells (Ito cells or parasinusoidal lipocytes), a prerequisite of the fibrogenic response of injured liver, were studied by analysis in vitro of some aspects of the intercellular communication between parenchymal liver cells and fat-storing cells. Conditioned medium harvested from early serum-free monolayer cultures of hepatocytes isolated from normal rat liver stimulated strongly, reproducibly and dose-dependently the proliferation of nonconfluent fat-storing cells maintained under serum-reduced conditions. During exposure of fat-storing cells for 48 hr to the conditioned medium, the incorporation of [3H]thymidine into DNA was stimulated four to six times over control values, the DNA content per culture well was elevated by 40% above control values and the immunocytochemical detection of bromodeoxyuridine-labeled cell nuclei was increased from 13% stained nuclei in controls to 70% stained nuclei in treated fat-storing cells. The mitogenic effects of hepatocyte-conditioned medium were similar to or even higher than those of 10% fetal calf serum. No mitoinhibitory activity could be detected in the hepatocyte-conditioned medium when arginase, as a potential inhibitor, was excluded. Rat skin fibroblasts could not be stimulated under conditions where the proliferation activity of fat-storing cells was greatly enhanced. The occurrence of the mitogenic activity in the medium is not dependent on de novo synthesis or secretion because the media of hepatocytes cultured under anoxic conditions in the presence of cycloheximide, brefeldin A or ethylenediaminetetraacetate were highly active in promoting fat-storing cell proliferation, although hepatocyte viability was greatly reduced under some of these conditions. A significant positive correlation (r = 0.95, p < 0.01) was found between lactate dehydrogenase activity and the mitogenic potency of the conditioned medium. The proliferation factor for fat-storing cells could also be demonstrated in the lysate of freshly isolated hepatocytes from normal liver. The stimulatory activity in the medium was partially enriched by a combination of gel permeation and anion exchange fast protein liquid chromatography and characterized as a protein with an apparent molecular weight of about 60 kD that is heat and pH sensitive but insensitive to reducing agents. It does not bind to immobilized heparin; nor does soluble heparin or proteinase inhibitor affect the mitogenic activity of the factor.(ABSTRACT TRUNCATED AT 400 WORDS)


Effect on the canine Eck fistula liver of intraportal TGF-beta alone or with hepatic growth factors.

Transforming growth factor-beta canceled the hepatocyte proliferation caused by transforming growth factor-alpha when the two substances were mixed and administered through a disconnected central portal vein branch after creation of an Eck fistula. In contrast, transforming growth factor-beta had no antidotal action on the stimulatory effects of insulin or full test doses of insulinlike factor-2, hepatocyte growth factor, epidermal growth factor or triiodothymanine. A minor antidotal effect on hepatic stimulatory substance activity could be detected, but only with hepatic stimulatory substance was given in doses smaller than those known to cause maximum stimulatory response. These results suggest a highly specific pharmacological and physiological interaction between transforming growth factor-alpha and transforming growth factor-beta in the modulation of liver growth control.


Rapid donor liver nutritional enhancement in a large animal model.

Organ donors are typically subject to acute hyponutrition that might affect postpreservation liver function. Livers from nutritionally supplemented rats function better after preservation than livers from fasted rats. We have developed a method to glycogenate the liver of large animals in the temporal context of a human donor liver operation and have studied the fate of glycogen stores during preservation. Starved anesthetized pigs were infused with a hexose solution (glucose, fructose or galactose) by way of the superior mesenteric vein for 3 hr. Regular porcine insulin was infused to maintain a hyperglycemic hyperinsulinemic arterial glucose clamp at 12 to 16 mmol/L. Liver biopsy specimens and blood samples were taken before infusion and hourly. At 3 hr the liver was excised, stored for 24 hr at 1 degrees C in University of Wisconsin solution and biopsied. It was then placed at 20 degrees C for 1 hr to simulate the reimplantation stage of transplantation. Glycogen and nucleotide levels were measured, and results were corrected for starch in the University of Wisconsin solution. A 20% glucose infusion produced rapid hepatic glycogenation without side effects. Greater glycogenation was obtained with 20% fructose but at the cost of lactic acidosis and a fall in pH. A combination of 15% glucose and 5% fructose produced intermediary glycogenation without significant side effects. Galactose (20%) was less efficient than glucose alone. The addition of alanine and glutamine (20 mmol/L) did not significantly improve glycogenation. Metabolism of glycogen at 1 degree C did occur. Glycogen content fell 0.15% +/- 0.05% dry weight liver per hour during cold preservation and 5.49% +/- 2.15% per hour during ischemic rewarming.(ABSTRACT TRUNCATED AT 250 WORDS)


Selection and timing of liver transplantation in primary biliary cirrhosis and primary sclerosing cholangitis.

In summary, we answer the three questions we have previously posed: (a) Can liver transplantation prolong survival? Evolving data from several centers indicate that liver transplantation indeed prolongs survival in patients with PBC and PSC as compared with estimated survival using disease-specific risk scores based on the natural history of PBC and PSC. (b) Can we optimize timing of liver transplantation? Although many factors enter into the timing of liver transplantation, including when the patient is actually referred for liver transplantation and the individual desires of the patient to pursue liver transplantation, evidence is growing that having patients with chronic liver diseases like PBC and PSC undergo transplantation a little earlier in the course of the disease rather than waiting until the patients have experienced life-threatening complications or are on life-support measures can indeed improve early postliver transplant survival. In patients with PBC and PSC, the survival risk score, which reflects disease severity, can serve as an objective measurement to assess and evaluate the effect of liver disease severity on transplant outcome. Indeed, a number of studies have strongly suggested that optimal timing of liver transplantation may indeed be important to improve outcome, decrease morbidity and decrease cost. (c) Does the present allocation system in the United States allow for optimal use of our scarce donor organ resource?(ABSTRACT TRUNCATED AT 250 WORDS)


Classification of amok in DSM-IV.

Culture-bound syndromes have been described worldwide in many individuals and, for certain syndromes, in epidemic proportion, yet these disorders have been classified as rare and exotic conditions warranting minimal attention. Development of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders and the tenth edition of the International Classification of Diseases offers an opportunity for providing a more sophisticated classification of these phenomena. The authors examine amok, a syndrome first described in Malaysia that consists of homicidal frenzy preceded by a state of brooding and ending with somnolence and amnesia. They discuss the concept of and criteria for a culture-specific disorder and propose that amok be classified as a culture-specific explosive behavioral disorder in DSM-IV.


An estimation of the impact of OBRA-87 on nursing home care in the United States.

The Omnibus Budget Reconciliation Act of 1987 (OBRA-87) established criteria for Medicare- or Medicaid-certified nursing homes to use in admitting or retaining mentally ill patients. In effect, the law created five dispositional categories for residents or potential residents of nursing homes. Using data from the 1985 National Nursing Home Survey conducted by the National Center for Health Statistics, the authors estimate what proportion of nursing home residents would fall into each of the categories. They suggest that the initial impact of the law will be to shift costs from federal programs to the states. Nursing homes will be expected to provide more mental health services. In the absence of other services, the regulations have a high potential for creating homelessness and continuing a pattern of failure to adequately serve patients with serious mental illness.


Clinical factors associated with better quality of life in a seriously mentally ill population.

Improving the quality of life of persons with chronic mental illness is becoming an important treatment goal. In this study, 101 former acute care psychiatric inpatients with serious mental illness who were living in Mississippi communities were interviewed using portions of Lehman's Quality of Life Interview. A particular focus was whether clinical characteristics, such as medication compliance and social skills, that could be changed by interventions were associated with patients' ratings of their quality of life. Self-reports of better quality of life were associated with fewer depressive symptoms, fewer medication side effects, and better family interactions. Results indicate that clinical interventions to improve quality of life in this population should include family psychoeducational programs and better detection, evaluation, and treatment of both depressive symptoms and side effects of medication.


Case management, quality of life, and satisfaction with services of long-term psychiatric patients.

Two scales developed in Great Britain, the QOL Profile and the General Satisfaction Questionnaire, were used to examine the relationship between type of case management services and quality of life and satisfaction with treatment of 68 long-term psychiatric patients in Colorado. Factor analysis identified three types of case management activities that tended to occur together: assertive outreach (direct help, out-of-office visits, and monitoring), brokerage (referral to other agencies), and counseling and assessment. Monitoring was the only variable positively associated with quality of life for all patients; brokerage was the only variable negatively associated with acceptability of services. The number of case management contacts was negatively associated with treatment satisfaction.


Patient outcome after transfer within a psychiatric hospital.

Patients' satisfaction with the process and outcome of transfer between units of a private psychiatric hospital and the immediate impact of the transfer were examined through chart reviews (59 patients) and interviews (29 of the 59 patients). Results suggested that most patients were satisfied with the transfer and were not adversely affected by it. Satisfaction was positively correlated with briefer hospitalization, feeling better (less anxious or depressed) after transfer, and being informed ahead of time about the program on the new unit. The adversely affected patients had fewer previous hospitalizations at the current facility, were transferred sooner after admission, and had briefer current stays. No relationship was found between adverse effects and dissatisfaction. Patients suggested that better communication, more information about the new unit, and more advance notice would be helpful.


Treatment-resistant chronic mental illness: is it Asperger's syndrome?

In some cases of treatment-resistant chronic mental illness, it may be useful to reconsider the primary diagnosis. Patients with Asperger's syndrome, a rare pervasive developmental disorder, have characteristics such as eccentricities, emotional lability, anxiety, poor social functioning, repetitive behavior, and fixed habits that can mimic symptoms of other illnesses, including schizophrenia spectrum illness, bipolar disorder, anxiety disorders, and obsessive-compulsive disorder. Their disorganizing anxiety in response to stress, which may be accompanied by increased oddness of speech, can easily be misinterpreted as psychosis. The author describes features of Asperger's syndrome, discusses differential diagnosis, and presents care examples. A habilitative treatment plan that concentrates on modifying the patient's eccentricities into strengths and carefully tailors the work and living situation may be effective with some patients.


Classification and characteristics of Army stress casualties during Operation Desert Storm.

During the Persian Gulf War, the U.S. Army provided mental health care to soldiers using a model that emphasized the identification and management of factors associated with combat stress. Nonpathological labels, such as combat stress reaction, a non-hospital-based care delivery system, and simple interventions were used to promote return to duty. The authors describe such services provided to the U.S. Army 7th Corps. A total of 158 patients were treated; 72 percent were men. Seventy percent were from the junior ranks. Thirteen soldiers were treated for axis I disorders, four for axis II disorders, and 118 for stress reactions. Ninety-nine percent of the soldiers treated were returned to effective duty after a brief intervention.


Clinical presentation of PTSD in World War II combat veterans.

Clinicians have increasingly recognized posttraumatic stress disorder (PTSD) among Vietnam veterans, but the disorder may be easily overlooked among World War II combat veterans. The authors review recent studies of PTSD in older veterans and describe five cases that illustrate the diverse clinical presentations of PTSD in this population. Symptoms included anxiety, cognitive and somatic complaints, depression, alcohol dependence, and amnestic periods. Despite the varied presentations, a fairly consistent patient profile emerged. Patients avoided reminders of war, showed an exaggerated startle response, and experienced restless sleep and chronic anxiety. Factors associated with exacerbations of symptoms were retirement and reminders of war experiences. Although past studies have emphasized resuppression of the trauma, the authors encourage a flexible approach to treatment, including exploratory techniques.


Cultural influences in psychotherapy with refugee survivors of torture and trauma.

A selective review of the literature describing treatment of refugee survivors of torture and trauma revealed that approaches to psychotherapy used in treating South American patients differed from those used in treating Indochinese patients. South American patients were receptive to psychodynamic psychotherapeutic approaches that focused on detailed recollection of past trauma. Indochinese patients responded to a broader-based rehabilitation approach that could include psychotropic medication, supportive psychotherapy, and assistance in meeting practical needs. The authors suggest that many of the differences in treatment of the two groups may be attributed to cultural factors, with South American patients reflecting an affinity for the Western philosophical assumptions in which psychodynamic therapy is rooted and Indochinese patients reflecting a cultural background that values responsibility to the group, deference to authority, and restrained modes of emotional expression.


Social issues in the management of released hostages.

Mental health clinicians have assumed a more important role in the release of individuals held hostage by international terrorists. The author uses his experiences during three hostage releases in the late 1980s--the Achille Lauro incident, the hijacking of Pan Am Flight 73 in Karachi, Pakistan, and the release of a single hostage from Beirut--to illustrate important factors in managing victims. He describes an intervention model that emphasizes the importance of creating a healing social environment immediately after release. Such an environment encourages strong cohesiveness within the victim group, isolates the victims from external groups, promotes abreaction, and provides an opportunity for rest and replenishment. Interventions are made to restore a sense of power to the victims and to reduce their feelings of isolation and helplessness and of being dominated by the terrorists.


Interpersonal psychotherapy of depressed HIV-positive outpatients.

In an open pilot study, 23 depressed adults infected with human immunodeficiency virus were treated using interpersonal therapy. Twenty subjects recovered from depression after a mean of 16 sessions. The authors discuss six aspects of interpersonal therapy that make it useful with depressed HIV-infected persons: psychoeducation about the sick role; a here-and-now framework; formulation of problems from an interpersonal perspective; exploration of options for changing dysfunctional behavior patterns; identification of focused interpersonal problem areas (grief, role transition, interpersonal disputes, and interpersonal deficits); and the confidence therapists gain from a systematic approach to problem formulation and treatment. Results suggest that mental health professionals should consider interpersonal therapy as a treatment for depressed HIV-positive patients.


A group approach to psychosocial issues faced by HIV-positive women.

Women now constitute the fastest-growing population of persons with AIDS in the U.S. The psychosocial problems of women with AIDS and HIV infection are underrecognized, and economic, personal, and social resources to meet their needs are often inadequate. The authors describe development of a group for HIV-infected women and discuss issues raised by group members. HIV-infected women often feel isolated and experience stigma and shame. Their roles as caregivers and as wives and mothers are often changed or lost, and they experience anxiety and confusion about options for sexual activity. They sometimes fear transmitting HIV to family members through non-sexual contact. Physicians may discount their symptoms and may need to be educated about gynecological problems associated with HIV. Other issues involve coping with being both ill and a mother, disclosing information to children about the illness, and loss of reproductive choice.


Involvement in productive activities and satisfaction with living situation among severely mentally disabled adults.

Eighty-three adults with severe mental disabilities participated in a study examining effects on life satisfaction of having nothing to do, receipt of a housing subsidy, and enrollment in an intensive case management program. The clients were divided into four groups receiving subsidized housing and intensive case management, subsidized housing and nonintensive case management, intensive case management and nonsubsidized housing, and nonintensive case management and nonsubsidized housing. Initially and at ten months, clients reported how much time they spent with nothing to do and their level of satisfaction with supported-living arrangements. A significant association was found between time spent with nothing to do and both satisfaction and change in satisfaction and between having a housing subsidy and satisfaction. Results suggest that getting clients involved in activities of their own choosing would result in much greater increases in satisfaction.


A report on the "worst" state hospital recidivists in the U.S.

A total of 196 nonspecialty state hospitals in the U.S. each identified one patient--referred to as the hospital's "worst" recidivist--admitted to the hospital in 1987 who had the most lifetime admissions to that hospital. Persons admitted for mental retardation or substance abuse detoxification were excluded. The mean age of the recidivists was 42.2 years; their mean age at first admission was 24.7. The number of admissions per patient ranged from five to 121, with a mean of 31. Compared with the national population of state hospital admissions, significantly larger proportions of recidivists had diagnoses of schizophrenia, bipolar disorder, and personality disorder. More research is needed to determine actual community tenure of patients who receive revolving-door care and whether alternative approaches would be more effective.


A clozapine treatment program for patients living in the community.

Clozapine treatment for schizophrenic patients living in the community requires strategies to ensure safe use of the medication and to foster patients' emerging social and living skills. The authors describe a clozapine treatment program in a community mental health center that includes a weekly clozapine support group meeting followed by drawing of blood for monitoring of side effects. Case managers and other program staff remind patients to take clozapine as prescribed and help them comply with hematological monitoring requirements, manage side effects, deal with the emotional aspects of improvement, and benefit from emerging capabilities. About 75 percent of the center's patients who have been offered clozapine have decided to take the medication, and almost all patients in the clozapine treatment program have experienced significant symptom relief and functional development with manageable side effects.


Length of time spent in seclusion and restraint by patients at 82 VA medical centers.

Analysis of data from 82 Veterans Affairs medical centers showed that during a one-year period in 1987-88, VA psychiatric inpatients spent about 240,000 hours in seclusion or restraint, with about half of that time in mechanical restraints. The median length of time patients in each medical center spent in seclusion and restraint was used to classify centers as having "higher" or "usual" rates of use of those techniques. In the 20 centers classified as higher users, patients spent two to three times longer in seclusion and restraint per incident than patients in the 62 centers classified as usual users. Time spent by patients in seclusion and restraint in centers with usual rates of use was consistent with reports from other U.S. studies. The longer time in seclusion and restraint per incident in higher-user centers may be due to characteristics of the medical center or of the patient population.


Do-not-resuscitate orders for depressed psychiatric inpatients.

Many patients, especially those who are elderly and who have chronic medical illnesses, choose to forgo cardiopulmonary resuscitation (CPR) in case of cardiac arrest. The right of mentally competent patients to refuse CPR is supported by ethicists, the courts, and medical associations. Psychiatrists are increasingly presented with dilemmas about resuscitation preferences of elderly psychiatric inpatients whose decision-making capacity may be impaired because of mental illness such as depression. The authors discuss justifications for patients' refusing resuscitation, the role of advance directives in communicating patients' preferences, and the use of do-not-resuscitate orders for depressed psychiatric inpatients. Survival rates after CPR among elderly patients with chronic medical illnesses are low. Patients and their families need accurate information about the risks and benefits of CPR and about the consequences of refusing the procedure.


Improving psychiatric environments through minimal architectural change.

Minimal architectural changes in a treatment environment can lead to significant improvements in how the setting functions, with positive effects for staff, patients, and families. When a mental health center located in an antiquated hospital in Jerusalem added five additional entrances, the change improved accessibility, increased the sense of freedom, and helped define the identity of the units. Other therapeutic effects were obtained from minimal modifications in a day hospital unit, including brightening paint and changing lighting, reopening a separate stairway for use by patients not enrolled in the day unit, and defining separate living, dining, and personal-expression areas within the common room. The authors note that cooperation between the disciplines of architecture and psychiatry is essential and that the idea of change as a continuous process should be incorporated into an organization's culture.


Countertransference and clinical choices in public-sector treatment of a patient and her family.

Clinical decision making in the treatment of families of individuals with prolonged mental illness can be affected by countertransference that is stimulated by the context of treatment as well as by the family being treated. For clinicians, psychoeducation, the current intervention of choice for such families, can serve defensive functions that are motivated by counter-transference; a case example illustrates how such defenses led a clinician to avoid deeper therapeutic work. The authors believe that clinicians must strive to understand their motivations for whatever clinical decisions they make; to facilitate this awareness, intensive psychotherapy should be required as an adjunct to training.


Hospitals cope with America's new 'family value'.

It's not a new problem, but the attention it's getting is growing every day. Domestic violence, or family violence, a concept that encompasses child abuse, partner abuse, and elder abuse, is being understood more and more as a trauma to the nation's families. Very often it's hospitals, particularly hospital emergency departments, that are the first community organization that the abused person sees for examination or treatment. The question is, are hospitals prepared? In a comprehensive look at the problem and some possible approaches to solving it, Hospitals senior correspondent Frank Sabatino talks to the experts in every area touching on this complex, tragic societal issue.


Vendors worry: will health reform place technology on trial?

The outcome of the reform debate will have an enormous impact on the health care vendor community as well as on providers. With arguments swirling about regarding such issues as technology costs, vendors offer their views of reform.


Tax-exempt challenges continue.

National attention to the tax-exempt status issue is not as acute as it has been in the last few years, but the challenges are continuing in a number of states. Hospital administrators and legal experts in Pennsylvania, the nation's flashpoint state on the issue, discuss what's going on and why.


Employment of full-time staff outpaces part-time growth.

Data from the AHA's Hospital Panel Survey show faster growth in hospitals' full-time staffs than in their part-time staffs in the first six months of the year. And slower labor cost growth was offset by fast non-labor cost growth.


Surveying customer needs, not satisfaction, is crucial to CQI.

Experts say that understanding the differences between customer needs and customer satisfaction is crucial to hospitals' success in quality management. And hospitals on the leading edge are applying that theory to their programs.


Observers see Clinton moving quickly on health care reform.

The 1992 presidential election was about a lot of things, from the economy to taxes to education. Health care reform played a major role in the public policy debate, and the different approaches taken by the candidates on that issue helped define them. A look at the result and what it may mean for the health care field.


12 cost-cutting measures. Hospitals use creative ideas to gain control of expenses.

With operating costs ever rising and reimbursements ever tightening, hospitals are looking for ways to cut costs at every turn. The good news is that there are a lot of innovative, imaginative approaches being tried in every area of hospital operations--approaches that don't require massive financial investment, organizational restructuring, or teams of outside consultants. The examples we've found through talking with hospitals across the country are a fair sample of the types of opportunities out there. They range across the entire hospital, from the laboratory to the pharmacy to nursing to waste management to the medical staff to the operating suite. In other words, something for everyone.


1991 data: low interest rates cut both ways for hospitals.

Low interest rates proved to be a mixed blessing for hospitals in 1991, as many capitalized on plummeting interest rates by refinancing existing debt. And though lower rates caused investment income to shrink, one CEO notes that, because most hospitals have higher debt loads than investment income, the situation has proven to be a net positive for that majority.


Ambulatory care strategic plans outline hospitals' new priorities.

With more and more of hospitals' clinical services shifting to the outpatient sector, the issue of whether to have a separate strategic plan for ambulatory care is growing more prominent. Hospitals that have such plans cite many advantages.


Economic forces drive collaboration push.

Over 60 percent of CEOs surveyed say their hospital will belong to a regional, integrated health system by 1995. The question, they say, is not whether integration will happen, but how.


Studies of cardiovascular disease and cause-specific mortality trends in Japanese-American men living in Hawaii and risk factor comparisons with other Japanese populations in the Pacific region: a review.

The Honolulu Heart Program (HHP) is a long-term prospective epidemiologic study of cardiovascular disease (CVD) in male descendants of Japanese migrants to Hawaii. The article is a review of data from recent and past HHP studies relevant to the Seventeenth Pacific Science Congress symposium "Changes in Disease Patterns in the Western Pacific and Southeast Asia." The Ni-Hon-San Study, which compared CVD rates and risk factors in Japanese men living in Japan, Hawaii (HHP), and California, showed that coronary heart disease (CHD) and stroke mortality rates in Hawaii were intermediate between rates in Japan and California. Gradients in CVD risk factors were similar to the gradients in disease rates. From 1966 to 1984 trends in incidence rates for CHD, stroke, and cause-specific mortality were compared for the 8006 participants and 3130 non-participants in the HHP. CHD and stroke rates declined by about 40% for the total HHP cohort. There was a larger decline for CHD mortality (over 60%) in the nonparticipants. There was also a much greater decline in total mortality and cancer mortality rates in the nonparticipants. The results of the reviewed studies show that the subjects, although sharing a common ethnic background, experience different rates of disease when living in diverse geographic and cultural locales. This finding supports evidence that environmental and behavioral factors influence chronic disease rates and provides a basis for intervention and prevention. The finding that nonparticipants in epidemiologic studies can show different incidence trends suggests that caution should be used in interpreting trends limited only to participants.


Temporal changes and rural-urban differences in cardiovascular disease risk factors and mortality in China.

We summarize several studies, from the last 10 years, of temporal changes and rural-urban differences in the risk factors of cardiovascular disease (CVD) in China to indicate the influences of economic modernization. Two national blood pressure surveys have shown that the prevalence of hypertension increased from 5.1% to 7.7% between 1958-1959 and 1979-1980. Throughout China hypertension is more prevalent in urban areas than in rural areas. Within the Shanghai region body mass index, blood pressure, and total serum cholesterol were higher in urban districts than in rural areas. Rural-urban differences in lipid levels were also found in the Beijing and Guangzhou regions. A related four-year followup study showed that total serum cholesterol and triglycerides increased markedly in both urban and rural areas of Guangzhou. In Shanghai part-time farmers who worked in factories had a higher age-adjusted prevalence of definite hypertension than farmers who worked full-time in the fields (5.0% versus 2.3%). In a prospective study in Wuhan a new productivity-based salary system was associated with increased serum cholesterol and blood pressure. Age-adjusted CVD mortality increased from 1973 to 1982 in a rapidly industrializing county in the Shanghai metropolitan region. The results from several studies indicate that China is undergoing the expected increase in modernization-related CVD risk factors and mortality, especially in urban metropolitan regions.


Causes and consequences of increase in child survival rates: ethnoepidemiology among the Hmong of Thailand.

The Hmong "hill tribe" minority in Thailand has much higher exposure to factors usually associated with risk of child mortality (high fertility, low status of women, low education, less use of modern medical care for births, exposure to warfare, economic and physical disruption, and poor hygienic conditions) than the rural ethnic Thai population. Nonetheless, infant mortality has declined from over 120 per 1000 to under 50 per 1000 live births among both these populations in the past 30 years. The reason for the rapid increase in child survival among the Hmong appears to be better access to and more use of modern curative and preventive medical care associated with road construction rather than major changes in social or hygienic conditions. Conventional wisdom suggests that high fertility is both a cause and a consequence of high infant and child mortality and that parents will not reduce fertility until they see that mortality has declined. Most Hmong parents recognize the decline in child mortality and attribute it to better access to modern medical care. Most Hmong parents also say that, if they were starting to have children now, they would want to have fewer children. Fear of child death is infrequently mentioned as a motive for having more children, and the perceived decline in child mortality is rarely mentioned as a reason for reduced fertility. Most Hmong parents explain their desired family size in terms of economic conditions rather than perceived risk of child mortality. Results of this study suggest that fertility and child mortality can vary independently of one another and that major reductions in child mortality can be accomplished without waiting for major social changes (e.g., improved education or status of women) or major reductions in fertility.


Human T-cell lymphotropic virus type I infection and disease in the Pacific basin.

Human T-cell lymphotropic virus type I (HTLV-I), the cause of adult T-cell leukemia/lymphoma (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is widespread in the Pacific basin. Modes of virus transmission include blood transfusion (and intravenous drug use), breast milk, and sexual intercourse. High prevalences of HTLV-I infection and disease occur among the inhabitants of southwestern Japan and among first- and second-generation (issei and nisei) Japanese-Americans in the Hawaiian Islands. Other Pacific populations with high prevalences of HTLV-I infection include several remote groups in West New Guinea, Papua New Guinea, the Solomon Islands, and Vanuatu, which have had no contact with Japanese or Africans. By contrast, Micronesian and Polynesian populations, even those with prolonged contact with Japanese, exhibit low prevalences or no evidence of HTLV-I infection. Low prevalences of infection are also found in Australia, except among some aboriginal populations. Changing patterns of HTLV-I infection and disease are no better exemplified than in Japan, where striking reductions in transfusion-acquired infection and subsequent development of HAM/TSP have followed the institution of nationwide screening of blood donors for HTLV-I infection. Furthermore, virus transmission from mother to infant by means of infected breast milk has been markedly curtailed in HTLV-I-hyperendemic regions in Japan by interrupting the practice of breast feeding by HTLV-I-infected mothers. The next frontier of HTLV-I research is in Melanesia, where highly divergent sequence variants of HTLV-I have been discovered.


Genetic disease patterns in Japan: a review.

Comprehensive genetic studies in which the genetic structure of a population is considered against the background of ecological factors, including environmental and social variables, often supply valuable information for the solution of a number of problems in human biology, including reproductive compensation and inbreeding depression. In the first section of this paper we consider the incidence of genetic diseases in Japan in reference to other populations. Some of the genetic disorders found elsewhere do not occur or are of lower frequencies in Japan. On the other hand, a number of genetic diseases occur at higher than usual frequencies, leading to an incidence of genetic disease of the order of about 1 per 100 in newborn Japanese. We next review the studies of consanguinity in Japan and report evidence of very high levels, ranging from 8.6% to 58.0%, for villages during the early part of the twentieth century. The rates are declining rapidly for the country but, because of traditional social values, inbreeding rates remain significant in many small villages. In the final section we consider the probable trends in the frequency of inbreeding on a worldwide basis and point out that frequencies of certain genetic diseases are likely to remain high and even increase in some societies because of various socially prescribed mating patterns.


Familial resemblance of blood pressure with residual household environmental effects in consanguineous and nonconsanguineous families from Andhra Pradesh, India.

Familial aggregation of blood pressure (BP), both systolic (SBP) and diastolic (DBP), was examined in consanguineous and nonconsanguineous families from southern India. Path analysis of BP suggests inbreeding effects, with the genetic variance for SBP being lower in the sample that included inbred families. Specifically, genetic heritability for SBP was 38% in the nonconsanguineous sample but only 23% in the combined sample. Genetic heritability for DBP (30%) did not vary by sample, nor were sample differences in cultural heritability detected for either SBP (over 35%) or DBP (about 18%). These findings are remarkably similar to those in a French-Canadian population of Quebec; both reports found a considerably larger effect of the home environment on BP than previous studies.


Importation route of the sickle cell trait into Portugal: contribution of molecular epidemiology.

To elucidate the origin and spread of the sickle cell trait into the Portuguese population, we examined nine polymorphic DNA markers within the beta globin gene cluster defining the haplotype. The population sample included 64 sickle-cell-gene-bearing individuals from defined Portuguese-speaking white, black, and Asian Indian populations. The nature and geographic distribution of the different beta S haplotypes in Portugal suggest that the sickle cell trait has been imported twice: between the eighth and the thirteenth centuries from the Mediterranean basin (in association with the Benin haplotype) and after the fifteenth century from black Africa over an Atlantic route (Senegal and Bantu haplotypes).


Genetic heterogeneity and population structure of Gond-related tribes in the Vidarbha region of Maharashtra.

Genetic heterogeneity in nine polymorphic loci is observed among Gond-related tribes in the Vidarbha region of Maharashtra. Pardhans, with their high ABO*A2 gene frequency (4.01%), low m gene frequency (57%), high P*1 gene frequency (42.7%), and high HbS trait (31.58%), differ significantly from other tribes. Per locus average heterozygosity among the studied tribes ranged from 36.24% to 40.37%, with Pardhans being more heterozygous. Analysis by FST and the empirical relationship between average allele frequencies and the ratio of within-gene to total gene diversity show that the tribes are isolated and that differentiation among them is at an early stage and approximately in conformity with expected differentiation under genetic drift. However, distances and principal components analysis reveal that Pardhans are far removed from the other tribes and from other central Dravidian tribes. Furthermore, of the various demographic parameters estimated, the high average heterozygosity in Pardhans is significantly correlated with mean marital distance (MMD), regression of MMD on wife's age, and effective population size. There is congruence between genetic and demographic data, showing that Pardhans are distinct. This conforms with Haimendorf's (1979) contention based on cultural traits that Pardhans are Gonds by historical accident and are later migrants to the Gond area from the north. The most significant and practical observation of the present study is that migration from an originally nontribal (Pardhan) to a tribal (Gond) area and admixture lead to severe disease course, differential selection pressure, and hence highly elevated HbS trait frequency.


Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas.

This report concerns the study of Ha-ras gene mutations and ras p21 expression in primary tumors of the urinary bladder. Polymerase chain reaction-based techniques and computerized image analysis were used. The data obtained were related to tumor grade, DNA ploidy, and tumor invasion. A point mutation (G-->T) at Ha-ras codon 12 was found in 30 of 67 tumors. The mutation frequency was greater in grade III (65%) than in grade II (44%) tumors; no mutations were observed in grade I tumors. The mutation was observed more often in aneuploid (58%) than in diploid (28%) tumors. No other substitution at codon 12 was seen and no codon 61 mutation was detected. The tumors were also tested for the A-->G mutation at position 2719 of Ha-ras intron D. Concurrent codon 12 and intron D mutations were identified in seven high-grade aneuploid tumors; six were invasive. The levels of the ras gene product p21 were approximately 10 times higher in tumors with intron D mutation than in those without. These findings confirm on human bladder tumors the observations of the effect of synchronous exon-intron mutations reported on the bladder cancer cell line T24. Our results are the first demonstration of Ha-ras intron D alterations in human tumor tissues and suggest that concurrent mutations at codon 12 and intron D of this gene within the same tumor may contribute to the aggressive behavior of human bladder carcinomas.