[24-hour esophageal pH monitoring. An analysis of 21 cases]. Esophageal pH monitoring was carried out with self-made portable pH recorder in 21 subjects for 24 hours under normal conditions. The results were as follows: the number of physiological gastroesophageal reflux (GER, pH < 4) was less than 23 times; the percentage of GER duration calculated by dividing the cumulative time of pH less than 4 by the total monitoring time was less than 1.4; the percentage was about 2 in upright position and less than 0.2 in lying position; the duration of the longest reflux episode was less than 5 minutes; the physiological gastroesophageal reflux occurred more often in upright position; while the pathological GER took place both in upright and lying position. Our study also indicated that the degree of esophagitis had no relation with the type of GER.


[Analysis of 59 cases of non-traumatic sudden death in various neurological diseases]. Sudden death is a common complication of myocardial infarction, necrotic pancreatitis and other diseases. Physicians usually neglect the possibility of neurological disorders. 59 cases of sudden death among 314 autopsied cases with neurological diseases were analyzed. The most frequent cause of neurological sudden death was cerebrovascular disease (CVD). It was present in 53 (89.9%) cases. 48 of them had hemorrhagic CVD. 37 of these 48 cases were due to hypothalamic lesions. In 37 cases general autopsy was performed; pathological abnormalities of heart, lungs, stomach etc, were found in 28 of them. In conclusion, the size and location of the lesion correlated with the prognosis of the disease. Concomitant multiple organ damage may deteriorate the lesion. Awareness of sudden death resulting from CVD may elevate the rate of correct diagnosis.


[A comparative trial of levo-praziquantel and praziquantel in the treatment of human Clonorchis sinensis infection]. Seventy patients with clonorchis sinensis infection were divided randomly into two groups and treated with levo-praziquantel and praziquantel in the same dosage of 12.5 mg/kg twice a day for two consecutive days (total dosage of 75 mg/kg). Follow-up stool examination three and six months after treatment showed that the egg negative conversion rates with levo-praziquantel group were 92.86% and 92.59%, while those of praziquantel group were 58.62% and 53.57% respectively. The results showed that levo-praziquantel was significantly superior to praziquantel (P < 0.001). The side reactions in both group were mild and transient.


[A laboratory and clinical study of induced differentiation therapy by all trans-retinoic acid in acute promyelocytic leukemia]. According to investigations, it was shown that peripheral blood WBC count increased, percentage of promyelocytes increased, differentiation features emerged, protein kinase C (PK-C) activity elevated, intracellular lysozyme content increased, CFU-F productivity increased and typical t (15; 17) disappeared, when induced differentiation therapy with all trans-retinoic acid (RA) was carried out in patients with acute promyelocytic leukemia. Comparison between RA group and RA+Harringtonin/Ara-C group showed no significant difference in most of the parameters; the curative effect was same in both groups. Complete remission (CR) rate was achieved in 92.6% (25/27 cases) of the patients in the entire group. In order to increase CR rate, prevention and treatment for haemorrhagic complications are critical. Patients with hyperleukocytosis (WBC > or = 100 x 10(9)/L) should be treated with intensive combined therapy as well as aggressive prevention of haemorrhage and pathological changes of lung and brain.


The action of interleukin 6 and leukaemia inhibitory factor on liver cells. The hepatic action of cytokines has generally been analysed in terms of the acute-phase response of the liver. The qualitative and quantitative changes in the expression of plasma proteins serve as defining criteria for cytokine function. Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) are representatives of a group of cytokines which display strikingly similar effects in both human and rodent liver cells. Hallmarks of the action of these cytokines are the stimulation of type 2 acute-phase plasma proteins and enhancement of the effect of interleukin 1 (IL-1) or tumour necrosis factor alpha (TNF-alpha) on type 1 acute-phase plasma proteins. The transcriptional activation of the various acute-phase plasma protein genes involves common cis-acting regulatory elements whose sequences and location relative to the transcription start site vary from gene to gene. The activity of the IL-6- and LIF-responsive genes depends in part on transcription factors including several members of the C/EBP family, JunB and the glucocorticoid receptor. The expression of these transcription factors is in turn under cytokine-specific control. In a few cases, expression is temporally correlated with the activation of 'late' acute-phase protein genes. The finding that structurally distinct cytokines interact with separate receptors but elicit an almost identical liver cell response demands a reassessment of the contribution of each factor to the in vivo acute-phase response.


Further studies of the distribution of CDF/LIF mRNA. Differentiation choices in the haemopoietic and nervous systems are controlled in part by instructive factors. The cholinergic differentiation factor (CDF, also known as leukaemia inhibitory factor, LIF) affects the development of cultured cells from both systems. To understand the role of CDF/LIF during normal development in vivo, we have begun to localize its mRNA in the late fetal and postnatal rat. Application of reverse transcriptase-polymerase chain reaction and RNase protection methods reveals that CDF/LIF mRNA levels are developmentally modulated in both haemopoietic and neural tissues. A target tissue of cholinergic sympathetic neurons, the footpads that contain the sweat glands, express high levels of this mRNA (relative to mRNA for actin and beta 2-microglobulin). Levels in targets of noradrenergic neurons are lower, but do undergo significant changes during development. Signals are also detected in selective regions of the adult brain, and in embryonic skeletal muscle. This finding in muscle may be significant for motor neurons, because CDF/LIF is a trophic factor for these neurons in culture. Embryonic liver, neonatal thymus and postnatal spleen express CDF/LIF mRNA, and expression in gut is the highest of all tissues examined. The selective tissue distribution and developmental modulation of CDF/LIF mRNA expression support a role for this factor in the normal development of several organ systems.


Leukaemia inhibitory factor and bone cell function. A bone-resorbing product of mouse spleen cells found to have differentiation-inducing activity was most probably leukaemia inhibitory factor (LIF). This revealed that LIF is a cytokine active on bone, in addition to its several other sites of action. In organ culture of newborn mouse bone, recombinant LIF promoted bone resorption by a prostaglandin-dependent process. Resorption by isolated rat osteoclasts was also promoted by LIF through an initial action on osteoblasts which was receptor-mediated. Incorporation of [3H]thymidine into DNA was increased by LIF in cells (most probably osteoblasts) of the newborn mouse bones. Osteoblasts have been shown to produce LIF, and the amount is increased by treatment with retinoic acid or TNF-alpha. LIF also acts directly on osteoblasts to inhibit plasminogen activator activity, by stimulating the synthesis of plasminogen activator inhibitor 1 mRNA and protein. The latter actions are very similar to those of TGF-beta. Again like TGF-beta, LIF was ineffective in promoting bone resorption in vitro in fetal rat long bones. These results, together with the in vivo data showing that high circulating levels of LIF in the mouse are accompanied by a substantial increase in trabecular bone mass, indicate that LIF is another cytokine with potent actions on bone and potentially important interactions with other osteotrophic factors.


The role of interleukin 6 in megakaryocyte formation, megakaryocyte development and platelet production. Megakaryocytopoiesis is the cellular amplification and differentiation of precursors into immature megakaryocytes, and the cytoplasmic maturation of these megakaryocytes, a process terminating in the release of platelets into the circulation. Interleukin 6 (IL-6) stimulates megakaryocytopoiesis in the bone marrow, increasing platelet numbers in the circulation. IL-6 alone is poorly active on the growth of stem cell populations, but acts in synergy with stem cell factor (c-kit ligand) to expand the committed myeloid progenitor compartments but not the megakaryocyte progenitors. IL-6 has a direct action on megakaryocyte progenitors but only in synergy with low doses of interleukin 3 (IL-3), increasing the number of immature megakaryocytes and enhancing the processes of development into mature megakaryocytes. IL-6 is about 10 times more active on megakaryocytes than on megakaryocyte progenitors in cell culture. It is active alone and will stimulate increases in cell size and DNA content. IL-6 does not appear to stimulate the process of platelet release. IL-6 is found in bone marrow, in both macrophage subsets and megakaryocytes, indicating that it may be an important physiological regulator of both paracrinal (microenvironmental) and autocrinal mechanisms controlling megakaryocyte development in bone marrow.


Actions of leukaemia inhibitory factor on megakaryocyte and platelet formation. Leukaemia inhibitory factor (LIF) is able to potentiate megakaryocyte colony formation in cultures of mouse bone marrow cells in the presence of multi-CSF (interleukin 3). Membrane receptors for LIF are present on mouse megakaryocytes and receptor numbers increase with increasing maturation of the cells. When injected into normal mice at doses of 0.2-2 micrograms two to three times daily, LIF induced a rise in platelet numbers, which reached up to twice normal values during the second week of injections. This rise was preceded by a rise first in megakaryocyte progenitor numbers, then in mature megakaryocytes in the bone marrow and spleen. Injections of LIF also marginally accelerated platelet regeneration in mice pre-injected with 5-fluorouracil or subjected to whole-body irradiation and transplantation of marrow cells. In view of similar responses to LIF in parallel studies in primates, clinical trial of LIF in patients with thrombocytopenia is warranted.


The role of interleukin 6 in plasmacytomagenesis. Interleukin 6 (IL-6) is a polyfunctional cytokine which regulates the immune response, the acute-phase reaction and haemopoiesis. IL-6 plays a critical role in differentiation of B cells into plasma cells, and is a potent growth factor for plasmacytomas and myelomas. A relationship between IL-6 and polyclonal plasma cell abnormalities has been demonstrated. Abnormal production of IL-6 was first suggested to be related to hypergammaglobulinaemia with autoantibody production in patients with cardiac myxoma. A role of IL-6 in the generation of plasmacytoma has also been indicated. In support of these clinical and experimental observations, we demonstrated that transgenic C57BL/6 mice carrying the human IL-6 gene showed a massive polyclonal plasmacytosis with production of autoantibodies. However, the tumour was not transplantable to syngeneic animals. Susceptibility to pristane-induced plasmacytomagenesis is genetically determined--pristane can induce plasmacytomas in BALB/c but not in C57BL/6 mice. IL-6 transgenic C57BL/6 mice were backcrossed to BALB/c mice to elucidate the genetic influence on plasmacytomagenesis. Transplantable monoclonal plasmacytoma with a t(12;15) chromosomal translocation was generated in some of the backcrossed mice, indicating that IL-6 plays a key role in the multistep oncogenesis of plasma cell neoplasia.


Interleukin 6 determination in the detection of microbial invasion of the amniotic cavity. A growing body of evidence suggests a role for cytokines in the mechanisms responsible for preterm parturition associated with intrauterine infection. Interleukin 6, a polyfunctional cytokine that is secreted by tissues in the feto-maternal interface in response to microbial products, has been implicated in the host response to intrauterine infection. The purpose of this study was to establish whether measurement of amniotic fluid concentrations of interleukin 6 could be of value in the diagnosis of microbial invasion of the amniotic cavity. Fluid was obtained by transabdominal amniocentesis from patients with preterm labour and intact chorioamniotic membranes and cultured for aerobic and anaerobic bacteria and mycoplasmas. Interleukin 6 concentrations were determined by an ELISA validated for human amniotic fluid. An interleukin 6 concentration above 11.2 ng/ml had a 93.7% sensitivity and a 92.3% specificity in the diagnosis of intra-amniotic infection. Moreover, patients with an amniotic fluid interleukin 6 level above 11.2 ng/ml and a negative amniotic fluid culture failed to respond to tocolysis, delivered a preterm infant and showed histological evidence of chorioamnionitis, and their neonates were at risk for congenital infections.


Distribution and binding properties of receptors for leukaemia inhibitory factor. The pleiotropic biological actions of leukaemia inhibitory factor (LIF) on haemopoietic cells (macrophages and megakaryocytes), hepatocytes, osteoblasts, pre-adipocytes, embryonic stem cells, myoblasts and neuronal cells must be mediated through the interactions of LIF with specific cellular receptors. The demonstration by equilibrium binding analysis and autoradiography of LIF receptors on all of the above cells and cell lines suggests that each of these pleiotropic effects of LIF is mediated by direct interactions with the responding cells rather than by the indirect release of secondary cytokines. Despite the differing biological effects of LIF on these cells, equilibrium binding, kinetic analyses and receptor internalization studies have all suggested that these cells display essentially identical high affinity LIF receptors. Nevertheless, there is evidence on some cell types (granulocyte-macrophage colony-stimulating factor [GM-CSF] transgenic peritoneal cells and F9 embryonal carcinoma cells) for a second class of low affinity LIF receptors (Kd = 1.5 nM versus Kd = 30 pM for high affinity receptors) which, LIF receptors (Kd = 1.5 nM versus Kd = 30 pM for high affinity receptors) which differ from the high affinity receptors only in kinetic dissociation rate. Moreover, the evidence suggests that low and high affinity receptors are structurally related and interconvertible, because detergent solubilization of LIF receptors from any cell type results in the quantitative conversion of high affinity receptors into low affinity receptors. As is the case for other related cytokine receptors, these data suggest that high affinity LIF receptors may be composed of two protein subunits--one responsible for LIF-specific low affinity binding and the other responsible for affinity conversion and cell signalling by the receptor. Such a model provides a possible explanation for the pleiotropy of LIF's biological actions.


Molecular biology of the leukaemia inhibitory factor gene. Leukaemia inhibitory factor (LIF) is a polyfunctional cytokine that has been identified and characterized in several laboratories by virtue of a number of different biological activities. LIF is encoded by a unique gene located at 11A1 in the mouse and at 22q12 in man. However, loci related to sequences in the 3' untranslated region of the mRNA have been detected and located elsewhere in the genome. The LIF gene from four mammalian species has been cloned and sequenced; the sequences are highly conserved within the coding regions and largely non-conserved within the non-coding regions. However, a number of non-coding segments displaying high interspecies similarity are evident; these are candidate control regions. Intriguingly, an exon corresponding to the 5' end of a variant LIF transcript in the mouse that encodes a potentially matrix-associated form of LIF is not conserved in the human, ovine and porcine genes. The promoter region of the LIF gene contains four well-conserved TATA elements, and two start sites of transcription have been identified. Three regions within the 5' flanking region have been identified as important for the function of the LIF promoter, including a candidate repressor sequence. The LIF gene is transcribed at only very low levels in normal tissues, but its expression can be increased by various stimuli.


Reconstitution of high affinity leukaemia inhibitory factor (LIF) receptors in haemopoietic cells transfected with the cloned human LIF receptor. cDNA clones encoding the human leukaemia inhibitory factor (hLIF) receptor were isolated by screening a placental cDNA expression library in COS-7 cells with 125I-hLIF. The cloned LIF receptor is a member of the haemopoietin receptor family and comprises a signal sequence (44 amino acids), an extracellular region of two haemopoietin receptor domains and three fibronectin type III domains (789 amino acids), a transmembrane domain (26 amino acids) and a cytoplasmic domain (238 amino acids). The LIF receptor is expressed in COS-7 cells as a 190 kDa glycoprotein that specifically binds human LIF with low affinity, but does not bind mouse LIF. Clones encoding a soluble form of the homologous mouse LIF receptor have been isolated, suggesting complex interactions between the various forms of LIF ligand and receptor in vivo. The LIF receptor is most related to the gp130 signal-transducing component of the IL-6 receptor, a feature that may provide a molecular basis for the intertwined biologies of LIF and IL-6 in the absence of obvious structural similarly between the ligands. Mouse B9 plasmacytoma cells transfected with the human LIF receptor display novel high affinity LIF receptors that are presumed to consist of transfected receptors in association with endogenous mouse high affinity-converting subunits. Unlike the low affinity human LIF receptor, the mixed species high affinity receptor is capable of binding mouse LIF.


The molecular biology of interleukin 6 and its receptor. Functional pleiotropy and redundancy are characteristic features of cytokines. Interleukin 6 (IL-6) is a typical example: IL-6 induces cellular differentiation or expression of tissue-specific genes; it is involved in processes such as antibody production in B cells, acute-phase protein synthesis in hepatocytes, megakaryocyte maturation, cytotoxic T cell differentiation, and neural differentiation of PC12 (pheochromocytoma) cells. It promotes growth of myeloma/plasmacytoma cells, T cells, keratinocytes and renal mesangial cells, and it inhibits growth of myeloid leukaemic cell lines and certain carcinoma cell lines. The IL-6 receptor consists of two polypeptide chains, a ligand-binding chain (IL-6R) and a non-ligand-binding, signal-transducing chain (gp130). Interaction of IL-6 with IL-6R triggers the association of gp130 and IL-6R, and the signal can be transduced through gp130. Association of gp130 with IL-6R is involved in the formation of high affinity binding sites. This two-chain model has been shown to be applicable to receptor systems for several other cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-5 and nerve growth factor (NGF). The pleiotropy and redundancy of cytokines may be explained on the basis of this unique receptor system.


The action of interleukin 6 on lymphoid populations. We have analysed the role of IL-6 in activation of human lymphocytes isolated from peripheral blood. We found little effect of IL-6 on proliferation of T cells. IL-6 did stimulate production of IgM by B cells. However, it did not behave as a terminal differentiation factor and was required only during the first two days of the culture. Under most conventional stimulation conditions T cells themselves produce little or no IL-6. High IL-6 production could be induced by stimulating the cells with a combination of phorbol-12-myristate 13-acetate (PMA) and anti-CD28 antibodies.


Regulation of leukaemic cells by interleukin 6 and leukaemia inhibitory factor. Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) can have pleiotropic effects on different cell types. M1 myeloid leukaemic cells respond to IL-6 with activation of a terminal differentiation programme which includes activation of genes for certain haemopoietic regulatory proteins (IL-6, IL-1 alpha, IL-1 beta, granulocyte-macrophage colony-stimulating factor [GM-CSF], M-CSF, tumour necrosis factor and transforming growth factor [TGF] beta 1) and for receptors for some of these proteins, thus establishing a network of positive and negative regulatory cytokines. IL-6 and some other cytokines also induce during differentiation sustained levels of transcription factors that can regulate and maintain gene expression in the differentiation programme. M1 leukaemic cells induced to differentiate with IL-6 undergo programmed cell death (apoptosis) on withdrawal of IL-6, and can be rescued from apoptosis by IL-6, IL-3, M-CSF, G-CSF or IL-1, but not by GM-CSF. These differentiating leukaemic cells can also be rescued from apoptosis by the tumour promoter TPA (12-O-tetradecanoylphorbol-13-acetate) but not by the non-tumour-promoting isomer 4-alpha-TPA, and rescue from apoptosis can be achieved by different pathways. Apoptosis can also be induced in undifferentiated M1 leukaemic cells by expression of the wild-type form of the tumour suppressor p53 protein and IL-6 can rescue the cells from this wild-type p53-mediated apoptosis. There are clones of M1 cells that differentiate with IL-6 but not with LIF and another M1 clone that differentiates with either IL-6 or LIF. Differentiation induced by IL-6 or LIF is inhibited by TGF-beta 1. The pleiotropic effects of LIF, like those of IL-6, are presumably also in a network of interacting regulatory proteins.


Regulation of gene expression in the hypothalamus: hybridization histochemical studies. Hybridization histochemistry has bridged molecular biology and neuroanatomy to provide nearly dynamic views of gene expression in the brain--perhaps especially in the hypothalamus. These snapshots of transcript levels with precise anatomical localization have revealed new insights into gene regulation in the hypothalamus under specific conditions. Magnocellular neurons in the paraventricular and supraoptic nuclei produce vasopressin and oxytocin. Transcript levels for these hormones are affected by hyperosmolality, as are those for many other neuropeptides. Patterns of gene expression in the magnocellular neurons in these nuclei during development and under different physiological conditions have been studied less extensively. The parvocellular neurons of the paraventricular nucleus produce corticotropin-releasing factor and thyrotropin-releasing hormone. Expression of the corticotropin-releasing factor gene is regulated by glucocorticoids. Physiological stresses, which activate the hypothalamo-pituitary-adrenal axis, also affect gene expression in the parvocellular paraventricular nucleus. Thyrotropin-releasing hormone is synthesized in a different set of parvocellular neurons in the paraventricular nucleus and in other neurons of the hypothalamus. Expression of the thyrotropin-releasing hormone gene is regulated by thyroid hormone. The suprachiasmatic nucleus contains neurons that produce vasopressin or vasoactive intestinal polypeptide in a circadian rhythm. Future studies using combinations of classical neuroanatomical techniques, hybridization histochemistry and immunohistochemistry will further our understanding of hypothalamic responses to various stimuli.


Feedback regulation of thyrotropin-releasing hormone gene expression by thyroid hormone in the hypothalamic paraventricular nucleus. Hypothyroidism caused by chemical or surgical thyroidectomy or hypophysectomy causes a substantial increase in the content of thyrotropin-releasing hormone (TRH) mRNA and proTRH exclusively in cells of the medial and periventricular paravocellular subdivisions of the hypothalamic paraventricular nucleus (PVN). This response may be important to raise the anterior pituitary thyrostat to promote increased secretion of thyroid-stimulating hormone (TSH) and to induce the secretion of a more biologically active TSH. The increase in TRH mRNA can be obliterated by stereotaxic implants of hormonally active L-triiodothyronine (T3) placed into the anterior hypothalamus but not by implants of the hormonally inactive 3,5'-diiodo-L-thyronine (T2); we therefore suggested that T3 has a direct action on TRH-containing cells of the PVN. Ablation of brainstem catecholaminergic projection fields to the PVN (known to stimulate TRH secretion) has no effect on TRH mRNA expression; beta 1 thyroid hormone receptor mRNA is present in extracts of the PVN. Euthyroid levels of serum T3 in hypothyroid animals achieved via intraperitoneally implanted osmotic minipumps are not associated with a return of PVN levels of TRH mRNA to normal unless circulating T3 levels are raised into the hyperthyroid range (1.7 times normal). This requirement is similar to that needed to normalize nuclear thyroid hormone receptor levels in the anterior pituitary of hypothyroid animals, suggesting that in addition to circulating T3 monodeiodination of T4 to T3 within the brain must also contribute to feedback inhibition of TRH mRNA. As Type II deiodinase activity is absent or very low in the PVN and does not rise with hypothyroidism, we propose that an alternative source for T4 monodeiodination exists within the central nervous system.


Co-localization of neuroactive substances in the endocrine hypothalamus. In addition to their characterizing secretory products, both magnocellular and parvocellular neurosecretory neurons are now known to express other neuroactive substances. Parvocellular neurons that make corticotropin-releasing factor (CRF) for example are capable of synthesizing at least seven neuropeptides. Some of these, like arginine vasopressin (AVP), interact with CRF at the level of the anterior pituitary to promote corticotropin secretion, and, like CRF, are regulated negatively by glucocorticoids and positively by at least some stressors. others are inert in these two contexts but are responsive to various challenges. Magnocellular neurosecretory oxytocin- and AVP-containing neurons are capable of producing similarly broad and distinctive complements of neuroactive principles. These are typically expressed at levels far lower than those of the nonapeptides, suggesting local modulatory effects on oxytocin and/or AVP secretion at the level of the posterior lobe. Differential regulation of coexisting molecules within magnocellular neurons by systemic challenges and steroid hormones has also been described. Secretory products of magnocellular neurons may gain access to the anterior pituitary via exocytotic release at the level of the median eminence or through vascular links between the posterior and anterior lobes, suggesting another form of 'co-localization' by which the two neurosecretory cell types may interact in the control of stress and perhaps other pituitary-mediated responses.


Gene memory in neuroendocrine and behavioural systems. Several examples of sex steroid hormone actions on rat brain and behaviour show that initial hormone exposures may be followed by enduring neuronal alterations, apparent long after the hormone itself has disappeared. Precedents from non-neuronal systems led to the concept of 'gene memory'. We are studying genomic structural alterations in rat hypothalamic neurons to account for these effects. The preproenkephalin gene is turned on by oestradiol in rat brain neurons in a tissue-specific and genetic sex-specific manner. Levels of preproenkephalin mRNA in the ventromedial hypothalamus correlate tightly with oestradiol-dependent reproductive behaviour. Our results indicate a tissue-specific pattern of DNA methylation in the enkephalin promoter. Putative binding sites for several transcription factors have been described in the preproenkephalin gene promoter; a role for some of these factors in regulating expression of the gene has been demonstrated.


Neuronal-glial and synaptic remodelling in the adult hypothalamus in response to physiological stimuli. Activation of certain neurosecretory systems of the mammalian hypothalamus induces remodelling of the conformation of their neurons and glial cells. During stimulation of the hypothalamo-neurohypophysial system, astrocytic coverage of oxytocinergic somata and dendrites diminishes and their surfaces become extensively juxtaposed. In the neurohypophysis and median eminence, stimulation evokes a retraction of glial processes and an increase in the contact area between neurosecretory terminals and the perivascular space. These changes are reversible and glial coverage returns to normal upon cessation of stimulation. Neuronal-astrocytic rearrangements also occur in the arcuate nucleus in response to changes in sex steroid levels. The significance of such modifications is a matter of speculation. In the hypothalamic nuclei they may permit synaptic remodelling that takes place concurrently; in the neurohaemal structures they may facilitate neuropeptide release. We know little about the cellular mechanisms involved but glia and neurons of these systems express certain molecules implicated in cell-cell interactions in the developing central nervous system, such as the polysialylated isoform of the neural cell adhesion molecule; this may allow them to manifest their capacity for morphological plasticity in adulthood. The factors inducing the changes vary in the different structures: while oxytocin, in synergy with steroids, appears essential to the induction of the changes in the oxytocinergic system, oestrogen alone is critical in the arcuate nucleus; in the neurohypophysis noradrenaline appears important.


Neural control of the synthesis and release of luteinizing hormone-releasing hormone. Preovulatory surges of luteinizing hormone (LH) depend upon neurotransmitter activation of neurons that secrete LH-releasing hormone (LHRH, gonadotropin-releasing hormone GnRH) and noradrenaline plays a pivotal role in this critical event. The interaction is amongst noradrenaline and other neurotransmitters such as GABA (gamma-aminobutyric acid), opiates, serotonin and excitatory amino acids (N-methyl-D-aspartate, NMDA) on LHRH neuronal activity are complex. GABA and opiates suppress the presynaptic release of noradrenaline but only GABA also directly affects the responsiveness of LHRH neurons to noradrenaline. Morphine induces the release of serotonin which either directly or indirectly via other neurotransmitters (e.g. dopamine) sensitizes LHRH neurons to the stimulatory effects of noradrenaline. NMDA rapidly induces LH release but whether this drug directly affects the activity of LHRH neurons is not known. The neuronal release of LHRH is modulated by the action of oestrogen on these various neurotransmitter systems. Antioestrogens, when placed into the medial preoptic area of otherwise completely oestrogenized rats, block LH surges; LHRH mRNA levels in such animals resemble those in 9-day castrated rats. Normally, LHRH message levels increase about the time of increased noradrenaline secretion just before the LH surge. NMDA rapidly releases LH and LHRH mRNA levels are significantly raised within 15 minutes and remain so over the next 45 minutes. Thus, it seems that stimuli which evoke LHRH release also increase LHRH mRNA transcription to replenish the hormone released during the LH surge.


The neurobiology of primate puberty.

The neurobiology of primate puberty. In higher primates the protracted prepubertal phase of development is occasioned by a mechanism that suppresses pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion from late infancy until the onset of puberty and thereby guarantees, in the juvenile, the quiescence of the pituitary-gonadal axis. Studies from our laboratory have employed the rhesus monkey, a representative higher primate, as an experimental paradigm. GnRH release has been measured using luteinizing hormone secretion by the in situ pituitary as a bioassay for the hypothalamic hormone. The nature of the prepubertal brake on pulsatile GnRH release in the monkey has been probed using physiological, neuroanatomical and neuropharmacological approaches. Such studies have led to the view that the prepubertal hiatus in pulsatile GnRH release results from a withdrawal in late infancy of a synchronized frequency-facilitated afferent neural input to the GnRH network, which in all other respects appears to exhibit properties identical to those in the postpubertal animal. The mechanism timing the onset of puberty, i.e. that responsible for the reactivation of synchronous activity in the GnRH network, is posited to be under the control of a central neural time- or growth-tracking device.


Hypothalamic transplantation.

Hypothalamic transplantation. Tissue transplantation aided in formulating the neurohumoral hypothesis of anterior pituitary function. The concept of a hypophysiotropic region within the hypothalamus stemmed from experiments in which pituitary tissue was transplanted into the brain. Restoration of aberrant function of the central nervous system by transplants has been reported in two neuroendocrine models: the antidiuretic hormone-deficient Brattleboro rat and the gonadotropin-releasing hormone-deficient hypogonadal mouse. Neural transplants into the Brattleboro rat result in the survival of axons containing antidiuretic hormone but reversal of the physiological defect has not been confirmed. In the hypogonadal mouse grafts of preoptic area tissue into the third ventricle have restored pituitary hormone synthesis and secretion and gonadal activity, leading to nearly normal reproductive function. The gonadotropin-releasing hormone axons specifically innervate the median eminence of the hypothalamus, their normal target, which raises interesting questions of neurobiological graft/host interactions. The hpg model has been used to investigate factors affecting graft survival; by suitable immunosuppression it has been possible to reverse the hypogonadism with grafts of rat preoptic area tissue. Perhaps the most dramatic recent development has been the restoration of circadian rhythmicity to suprachiasmatic nucleus-lesioned hamsters by grafts of similar tissue. The rhythmicity restored is typical of the donor tissue.


Regulation of prolactin transformation in the rat pituitary. We have investigated the mechanisms involved in the inhibition by dopamine of the transformation of prolactin within the anterior pituitary of the lactating rat. The degree of inhibition depends on the intracellular age of prolactin, being greater in newly synthesized (<1 hour) and in older (>12 hours since biosynthesis) hormone and lesser in prolactin synthesized 4-8 hours earlier. Transformation occurs in prolactin granules and involves an increase in oligomeric forms of prolactin at the expense of the monomeric form. A reversible disulphide-linked mechanism may be involved in dopamine inhibition of prolactin transformation; it is dependent upon the intracellular and/or intragranular pH via a Na+/H+ exchange mechanism. Transient suppression of dopamine inhibition may lower the intracellular/intragranular pH and subsequently cause transformation of the hormone. Developmentally, dopamine secretion by tuberoinfundibular neurons is seriously impaired and the response of pituitary lactotrophs to dopamine is reduced in adult rats deprived of milk prolactin during Days 2-5 post partum. These results suggest milk prolactin ingested during a critical post partum period may exert an organizational effect upon dopamine secretion and its function on the pituitary lactotroph during adulthood.


What can we learn from sampling hypophysial portal blood? Since it has become possible to sample hypophysial portal blood from sheep without totally compromising pituitary function, several important features of the secretion of hypothalamic hormones have been elucidated. The secretion of gonadotropin-releasing hormone (GnRH) has been detailed most thoroughly with the important observation that each pulsatile discharge of luteinizing hormone (LH) is the direct result of a large secretory episode of GnRH from the hypothalamus. There is high fidelity in the GnRH relationship in terms of frequency and amplitude. During the LH surge, additional factors such as an alteration in the degree of enzymic degradation of GnRH may be important physiological mechanisms. The secretion of factors that control the release of growth hormone (GH), prolactin and adrenocorticotropic hormone (ACTH) have also been studied. Hypothalamic factors controlling GH and ACTH release do not bear such an explicit relationship to the secretory episodes of pituitary hormone as seen with the GnRH/LH axis. The factor involved in the acute stress-induced release of prolactin has not yet been identified in sheep.


[A morphological study of retinal damages by intraocular lead]. The morphological changes in the retina were observed by light and electron microscopy at intervals after implantation of lead into the vitreous of rabbit eyes. The results revealed progressive structural disorders under both modalities of examination, indicating that lead had toxic effects on the retina.


[An epidemiological survey of blindness and low vision in Hebei Province]. Following the national unified criteria and methods, an epidemiological survey of blindness and low vision was carried out in Hebei Province from April to June, 1987. In 77,948 persons examined, there were 291 cases of bilateral blindness, representing a prevalence of 0.37% (male 0.29%, female 0.45%, urban areas 0.19%, plain areas 0.42%, and mountainous areas 0.36%). The prevalences of monocular blindness, bilateral and monocular low vision were 0.72%, 0.57% and 0.30% respectively. Subjects over 60 years of age had significantly higher prevalences of bilateral blindness and low vision. The chief blinding diseases were cataract, trachoma complications, corneal disease and glaucoma, in order of importance.


[A microdialmeter for measurement of the anterior chamber depth]. A microdialmeter is designed to measure the anterior chamber depth by determining the distance advanced by the slitlamp that is focused first on the posterior surface of the cornea and then on the anterior surface of the lens. An isosceles right triangular block is fixed onto the slitlamp to transform its anterior-posterior movement into the transverse direction to be measured conveniently by the microdial with a precision of 0.01 mm.


[Genetic segregation analysis of retinitis pigmentosa]. Comprehensive genetic segregation analysis performed in 150 pedigree of retinitis pigmentosa (RP) showed that the disease manifested genetic heterogeneity. Families of the mating type Affected x Normal were autosomal dominant (AD), with 80% of penetrance and no sporadic cases. Families of the mating type Normal x Normal were 80% autosomal recessive (AR), with 20% of sporadic cases. In the present series, the RP pedigrees were AD in 13.3%, X-linked in 2.7%, AR in 67.3% and sporadic in 16.7%, and most sporadic cases were nongenetic. It was also demonstrated that, with the conventional mode of pedigree analysis, the proportions of AR and AD cases were underestimated, and the proportion of sporadic RP was overestimated.


[Parafoveal retinal telangiectasis and changes of the capillary free zone in non-diabetic patients]. Microaneurysms, hard exudates, hemorrhages and/or edema in the macular region were observed in 10 eyes of 10 non-diabetic patients. By fluorescein angiography, parafoveal retinal telangiectasis was found in all cases. Deformation, enlargement and boundary disruption of the foveolar avascular zone were discernible in most cases, as were unevenness of capillary spacing, small areas of non-perfusion and leakage of dye in some cases. Analysis and calculations of the foveolar avascular zone were done with the Model-970 Quantmet computerized image analysis system. The data showed that the values of circumference, vertical diameter and roundness of the avascular zone differed significantly from those of the 10 normal control eyes.


[Exudative retinal detachment in the pregnancy-induced hypertension syndrome]. 22 cases of pregnancy-induced hypertension syndrome with exudative retinal detachment were studied. Fluorescein angiography performed in 5 patients 7-14 days post-parturition revealed choroidal circulatory disturbances and retinal pigment epithelial damages, while the retinal capillaries also showed damages of varying degrees. The authors regarded the former as the primary pathological basis for the retinal detachment, with the latter also playing a pathogenic role. The incidence and the source of fluid of the retinal detachment in relation to general edema, proteinuria, and hypertension were discussed.


[Vitrectomy plus air tamponade for treatment of retinal detachment with proliferative vitreoretinopathy]. Closed vitrectomy, membrane peeling, intraocular air tamponade and scleral encircling were performed for 35 consecutive cases of retinal detachment with proliferative vitreoretinopathy (PVR), comprising 2 cases of grade C2, 4 cases of grade C3, 6 cases of grade D1, 17 cases of grade D2, and 6 cases of grade D3. 21 eyes (60%) attained anatomic retinal reattachment with improved visual acuity in 20 eyes. The authors believed that vitrectomy combined with membrane peeling was a logical approach to the treatment of retinal detachment with PVR. The surgical success was related to the extent of membrane peeling, and intraocular air tamponade was a simple and effective adjunctive measure.


[Vitrectomy of vitreal cryoextraction for treatment of intravitreal cysticercosis]. Thirteen (13) patients of intravitreal cysticercosis were treated by vitrectomy (10 patients) or vitreal cryoextraction (3 patients) with successful removal of the parasites. The surgical procedure was described with discussions. Vitrectomy was especially advantageous to late cases of the disease.


[Clinical analysis of radiation optic neuropathy]. As a result of enhanced cure rate and survival time of patients with nasopharyngeal carcinoma (NPC) treated by radiotherapy, sequelae of radiation injury to the optic nerve are becoming important, of which the authors report 5 cases (6 eyes) observed in the past 2 years. The diagnoses were based on rapid visual deterioration or blindness in one or both eyes, with visual field defects, signs of papillary ischemic optic atrophy under fluorescein angiography, normal ERG but reduced amplitude and prolonged latency or even extinction of VEP, onset of the malady within 7 years after the initial session of radiotherapy, and survival of the patient over 1 year with no signs of NPC recurrence or metastasis. Good vision was saved in 2 eyes treated with hyperbaric oxygen.


[An image analysis system for optic disc in glaucoma]. An image analysis system for glaucomatous optic disc was developed. The key for optic disc measurement was to trace accurately the boundaries of the optic cup and disc. The 2-dimension measurement modality adopted was the heuristic boundary tracing method, and the 3-dimension measurement was performed by observation of the photographs, arbitrary selection of points, and automatic plotting and calculation. In order to measure accurately the optic disc in glaucoma follow-up, the authors made use of the cross correlation line by line scanning method, after proper correction of the photographs, to detect any positional shift in two photographs. By clinical verification, the 95% confidence criterion of normal optic cup boundary shifting was 1.7 pixels. The optic disc diameter of the disc images was over 200 pixels, and any shift over 2 pixels (1%) would have clinical significance, which was a high degree of precision.


[Analysis of penetrating corneal regrafting in 29 cases]. Repeated penetrating keratoplasty was retrospectively analyzed in 29 cases followed up 1-4 years postoperatively. The regraft remained clear in 10 eyes (34.5%). The major causes of regrafting failure were similar to those of the initial keratoplasty, i.e. immunologic rejection, postoperative angle-closure glaucoma, and donor graft failure.


[The effect of horizontal strabismus surgery on the refractive status in children]. The refractive changes in 84 children (155 eyes) following horizontal strabismus surgery and in 97 children (181 eyes) without surgical intervention were studied. The results indicated that the spherical refraction and axis of astigmatism were not significantly affected by the operation, especially when both recession and resection were done on the same eye; however, the cylindrical refraction changed markedly within 6 weeks of surgery. These changes would be minimized and become stable 6 weeks after the operation, suggesting that the proper time for a cycloplegic refraction was 6 weeks after a horizontal strabismus surgery.


[The purification of bovine IRBP and its uveitogenic action]. The interphotoreceptor retinoid-binding protein, IRBP, shuttles the retinoid between photoreceptor cells and the pigment epithelium. It also induces experimental autoimmune uveoretinitis (EAU). The authors first purified IRBP in China by Con A Sepharose affinity chromatography in conjunction with the purification of bovine retinal S-antigen by ion-exchange chromatography. EAU was successfully induced by injection of emulsified IRBP 50 micrograms with Freund's complete adjuvant into the footpad of Lewis rats. It was characterized by panophthalmia with severe damage to the posterior retina, and lymphocytes predominated the inflammatory infiltration that included mononuclear and polymorphonuclear cells.


Balloon expulsion test facilitates diagnosis of pelvic floor outlet obstruction due to nonrelaxing puborectalis muscle. We compared balloon expulsion, defecography, colonic transit times, anal manometry, and electromyography in 21 patients with severe constipation. Defecography demonstrated nonrelaxation of the sphincter during straining in all patients. Only 12 patients were unable to expel a balloon. Colonic transit was normal (five) or showed rectosigmoid delay (seven). All 12 patients were offered biofeedback. The nine patients able to expel a balloon had normal colonic transit (six) or colonic inertia (two). Rectosigmoid delay was due to severe intussusception in one patient. Anal manometry and pudendal nerve latencies revealed no difference between those who could and those who could not expel a balloon. Balloon expulsion seems to be a more reliable way to diagnose pelvic floor outlet obstruction due to nonrelaxation of the puborectalis muscle. Nonrelaxation of the sphincter on defecography should be correlated with balloon expulsion and colonic transit studies.


Internal rectal intussusception: results of surgical repair. Twenty-four patients with obstructed defecation due to rectal intussusception diagnosed by defecography were treated with rectopexy either by the Wells technique (9 patients) or by Orr's operation (15 patients). After follow-up from one to eight years, defecography demonstrated disappearance of the intussusception in 22 patients. None of the patients were completely relieved of their symptoms. Nine (41 percent; 95 percent confidence limits: 21-64) were improved and 13 were unchanged (59 percent; 95 percent confidence limits: 36-79), with no difference between the two procedures. One patient with solitary rectal ulcer was improved, and the ulcer disappeared. Four patients with moderate preoperative incontinence became continent postoperatively, but obstructed defecation was only improved in two of these patients. It is concluded that rectal intussusception is probably a secondary phenomenon in patients with obstructed defecation and that a conservative attitude toward surgery should be adopted.


Combined anorectal manometry and defecography in 50 consecutive adults with fecal incontinence. Fifty consecutive patients presenting with fecal incontinence were evaluated prospectively with anorectal manometry, defecography, and other tests of anorectal function to assess the clinical utility of defecography in fecal incontinence. Leakage of contrast at rest and failure to narrow the anorectal angle with pelvic squeezing were specific but not sensitive predictors of decreased sphincter pressures as determined by manometry. Thus, after manometry, defecography provided no additional information regarding sphincter strength. Retention of contrast in large rectoceles or incomplete rectal evacuation at defecography had excellent correlation with the presence of clinical symptoms of outlet obstruction constipation (present concurrently with incontinence) and indicated an etiology of outlet obstruction symptoms. Defecography may provide useful information in incontinent patients with outlet obstruction constipation symptoms but has little additive value to anorectal manometry in incontinent patients without such symptoms.


Prognostic significance of location of lymph node metastases in colorectal cancer. The prognostic value of stage of lymph node metastases was evaluated in 357 patients who underwent curative resection for colorectal cancer. Subdivision of Dukes C patients according to the number of positive nodes revealed that the five-year disease-free survival rate (5DFS) was 63 percent in the patients with one to three nodes and 53 percent in those with four or more nodes (not significantly different). Classification according to the location revealed that 5DFS was 70 percent in those who had only local node metastases (n1+), compared with 40 percent in those who had distant node metastases along the major vessels (n2+) (P < 0.001). Twelve of 38 n2+ patients had only one distant node metastasis with no local node involvement (skip metastasis). They had lower 5DFS than the n1+ patients who had three or more positive local nodes (35 percent vs. 57 percent). We conclude that the location, rather than the number, of nodal metastases has a higher impact on prognosis in colorectal cancer patients.


Retained mucosa after double-stapled ileal reservoir and ileoanal anastomosis. A study was undertaken to assess the incidence of inflammation and dysplasia in retained mucosa after double-stapled ileoanal reservoir (IAR) for mucosal ulcerative colitis (MUC). Between September 1988 and February 1992, 56 patients with MUC underwent an IAR. Forty-five patients had a double-stapled IAR (DS-IAR), seven patients had a transanal pursestring stapled IAR (PS-IAR), and four patients had a PS-IAR with mucosectomy. Distal donuts obtained from the stapled IAR were submitted for pathologic review in 55 patients. Nine patients had only small bowel, connective tissue, and/or muscle noted on review. Mucosa was qualified as squamous epithelium (SE), transitional epithelium (TE), or columnar epithelium (CE). All samples were examined for evidence of inflammation and dysplasia. Four patients had SE only, one patient had TE, and 18 had CE. In addition, three patients had SE and CE, seven patients had SE and TE, two patients had CE and TE, and nine patients had all three types. The distance from the dentate line to the anastomosis ranged from 0 to 2.5 cm (mean, 1 cm). In 19 patients (35 percent), the distal donut revealed MUC. Of these 19 patients, six had persistent MUC (43 percent) at the time of subsequent biopsy. An additional four patients had MUC evident on follow-up biopsy but not on distal donuts; two of these four patients had no mucosa in their distal donuts. Only one of the patients with evidence of MUC on donuts and/or biopsy experienced any symptoms referable to active MUC (1.8 percent). None of the specimens examined had any evidence of dysplasia. In 31 patients, no MUC was present in the initial donuts or follow-up biopsies. Although the double-stapled technique appears safe, periodic monitoring is suggested.


Postoperative adjuvant radiotherapy in Astler-Coller stages B2 and C rectal cancer. Between 1979 and 1983, 127 patients with Stages B2 or C rectal cancer treated with surgery plus postoperative adjuvant radiotherapy (RT group) and 122 patients treated with surgery alone (S group) were compared to evaluate the effect of postoperative radiotherapy on survival and disease recurrence. Each group was stratified into subgroups according to stage and tumor differentiation as follows: Subgroups BW (Stage B2 and well-differentiated tumor), BM (Stage B2 and moderately differentiated tumor), CW (Stage C and well-differentiated tumor), CM (Stage C and moderately differentiated tumor), and P (poorly differentiated tumor). Ninety-five percent of the patients were followed until death or, if alive, to five years after surgery. Postoperative radiotherapy was associated with a reduced five-year survival rate in Subgroup BW (67 vs. 87 percent; P = 0.02). In the remaining subgroups of the RT group, there was a statistically insignificant trend toward a worse survival rate (56 vs. 65 percent, 47 vs. 64 percent, 41 vs. 46 percent, and 50 vs. 36 percent for Subgroups BM, CW, CM, and P, respectively). The local failure rates for the S group and RT group were 10 vs. 23 percent (P = 0.15) in Subgroup BW, 32 vs. 21 percent (P = 0.4) in Subgroup BM, 24 vs. 25 percent (P = 0.6) in Subgroup CW, and 18 vs. 18 percent (P = 0.6) in Subgroup CM, respectively. Eight percent (9/127) had severe or life-threatening radiation-related complications. Postoperative adjuvant radiotherapy alone did not improve the survival of patients with Stages B2 or C rectal cancers. It may have led to worsened survival in the subgroup of patients with well-differentiated Stage B2 rectal cancer.


Outcome of ileorectal anastomosis for Crohn's colitis. One hundred thirty-one patients underwent ileorectal anastomosis (IRA) for Crohn's colitis. Preoperatively, 84 patients (63 percent) were found to have mild or moderate proctitis and 47 (37 percent) had rectal sparing. Sixty-eight (52 percent) had associated small bowel disease, and 20 (15 percent) had perianal disease. Sixty-five IRAs were performed at the time of subtotal colectomy, while 56 were done after previous surgery. Anastomotic leaks occurred in four patients. There were no operative deaths. Thirteen patients (10 percent) with protecting stomas never underwent closure. Among the remaining 118 patients with functioning IRAs, 30 (23 percent) required later proctectomy and 16 (13 percent) required proximal diversion, with the mean period with a functioning IRA in these 46 patients being 4.1 years (range, 6.2 months-12.7 years). An additional 13 patients required preanastomotic resection and neo-IRA, and 11 required proximal small bowel resection. The mean duration of function of all 118 IRAs was 9.2 years. At the time of review, after a mean follow-up of 9.5 years, 72 patients (61 percent) retained a functioning IRA, with 44 being free of disease, while 28 were being treated with steroids or antidiarrheal medication. The mean stool frequency was 4.7 per day. In patients with Crohn's colitis, IRA should be considered as an alternative to proctocolectomy if the rectum is not severely diseased and sphincter function is not compromised.


Incidence, outcome, and proposed management of isolated abscesses complicating acute left-sided colonic diverticulitis. A prospective study of 140 patients. In a prospective evaluation of 140 consecutive patients with acute left-sided colonic diverticulitis demonstrated by computerized tomography (CT) in all cases, 22 (16 percent) were found to have an associated abscess without peritonitis. Thirteen of these 22 required surgery (seven during the first stay and six from 2 to 11 months after the acute episode; median, three months). Nine patients were treated conservatively, eight of whom are now totally asymptomatic 24 months after the initial attack (range, 10-47 months). There were 10 mesocolic abscesses (seven treated with antibiotics alone), nine pelvic abscesses (seven requiring surgery), and three intra-abdominal abscesses, all operated upon. These results suggest that mesocolic abscesses can usually be managed conservatively without drainage; should surgery be necessary, en bloc resection with immediate anastomosis can usually be safely performed. Pelvic and intraabdominal abscesses behave more aggressively and usually require a two-stage surgical procedure when initial percutaneous drainage cannot be performed or is felt to be hazardous.


Sonography in acute colonic diverticulitis. A prospective study. The clinical value of high-resolution real-time sonography for the diagnosis of acute and complicated colonic diverticulitis was prospectively studied in 130 consecutive patients with abdominal complaints, because of which the disease entered into differential consideration. The results of ultrasound investigation were compared with those of clinical examination on admission. Regarding history and initial clinical evaluation, diverticulitis was graded as "highly suspected" in 19 (36.5 percent) out of a total of 52 patients with later proven colonic diverticulitis (prevalence 40 percent), as "possible but equivocal" in 24 (46.2 percent), and as "very unlikely" in the remaining nine (17.3 percent) patients. Ultrasonography enabled the diagnosis of diverticulitis with an overall accuracy of 97.7 percent, a sensitivity of 98.1 percent, and a specificity of 97.5 percent. The predictive values of positive and negative ultrasound examinations were 96.2 percent and 98.5 percent, respectively. The echomorphologic features of acute diverticulitis include visualization of a colon segment presenting with local tenderness on gradual compression, which showed hypoechogenic thickening of the wall and a targetlike appearance in transverse view due to inflammatory changes and muscular thickening. Sonographic signs of peridiverticulitis (hyperechoic halo) were found in 96 percent of patients, echogenic diverticula in 86 percent. Twelve (92 percent) of 13 abdominal abscesses were detected on initial ultrasound examination and could be treated by percutaneous drainage in seven cases, while six required surgical intervention. These results indicate that high-resolution sonography with graded compression is highly sensitive and specific for the imaging diagnoses of acute colonic diverticulitis and complicating abscess.


Clinical trial of oral diosmin (Daflon) in the treatment of hemorrhoids. A double-blind, comparative, controlled study on the effectiveness of the addition of oral diosmin (Daflon; Lab. Servier, Orléans, France) and placebo to a conservative regimen of bulk laxative in the treatment of acute symptoms of first-degree and second-degree internal hemorrhoids was undertaken in 100 patients. The diosmin and placebo groups, with 50 patients each, were comparable in age, sex, symptoms, and the severity of the underlying hemorrhoids. During the first four days, the patients received 12 tablets in three divided doses, and then they received two tablets twice daily for another 10 days. Subjective and objective changes were assessed at the 4th and 14th days of treatment. The diosmin group showed statistically significant objective improvement (P < 0.01) without accompanying subjective improvement on the fourth day. However, at day 14, there was no significant difference in either subjective or objective improvement between the two groups. Two cases in the placebo group were taken out of the trial on the fourth day owing to clinical deterioration. No side effect of diosmin was detected in this study.


Extensive varices of ileocecum. Report of a case. A man was admitted to our hospital because of intestinal reddish bleeding. Colonic varices were found at the cecum by colonoscopy. Angiography of the superior mesenteric artery showed that blood vessels were scant from the end of the ileum to the ascending colon. An operative view revealed the varices, but there was no trace of the ileocecal vein. This case, presenting a deficit of the ileocecal vein, indicated that the blood flow could not return via the ileocecal vein, and therefore there was an outflow through the varices to the surrounding intestine or abdominal veins. Such a case is probably unrepresented in the literature because it was caused by the total deficiency of the ileocecal vein and it was in the right colon.


Open sesame: tips for traversing the anal canal. The key points for a minimally traumatic and pain-free anal intubation are an informed patient, gentle technique, plenty of lubricant, a relaxed, supportive atmosphere, and gradual inward pressure on the instrument or finger. Also important are knowledge of the direction of the anal canal, sideways introduction of the flexible endoscope, and the technique of gaining anal relaxation by asking the patient to push down.


The present role of colostomy in the management of trauma. The role of colostomy in the treatment of abdominal trauma has changed over the past several decades. Primarily as a result of its successful use in military settings, colostomy initially was the mainstay of treatment for penetrating injury to the colon, rectal injury, and some forms of blunt trauma. Subsequent civilian experience with the techniques of primary repair of penetrating colon injury resulted in a decrease in the number of colostomies performed. Coupled with this experience, early data on adverse outcome from colostomy closure tended to support the trend of the ever-diminishing place of colostomy for trauma. Colostomy has always been used for two purposes in trauma care: prevention or arrest of fecal contamination of the peritoneal cavity and diversion of the fecal stream. Despite the decreased need for colostomy in some forms of penetrating colon injury, there are several conditions that still utilize colostomy to accomplish one or both of these purposes. Indications for colostomy can now be regarded as absolute or relative depending upon the need for diversion or the requirement to prevent contamination. There are relatively few contraindications to colostomy use. Present results of colostomy closure do not represent excessive risk to the patient and should not impact negatively on the decision to perform a colostomy for trauma.


Effects of antiviral agents on chronic hepatitis B. Analysis using Cox proportional hazard model. Two hundred fifteen courses of antiviral treatment including interferon with or without steroid withdrawal, adenine arabinoside with steroid withdrawal, and steroid withdrawal alone were given to 175 patients with HBe-antigen positive chronic hepatitis B. The effectiveness was judged on loss of HBe antigen and formation of anti-HBe, and was compared with 80 controls. According to cumulative HBe seronegative and seroconversion rates as analyzed by the Kaplan-Meier method, interferon with steroid withdrawal increased both the cumulative HBe seronegative and seroconversion rates significantly (P < 0.0001). Adenine arabinoside with steroid withdrawal and interferon alone increased the cumulative HBe seronegative rate only (P < 0.001). The Cox proportional hazard regression model was fitted to the data of 188 cases whose pretreatment liver biopsy specimens were obtained. Among treatment protocols, interferon with steroid withdrawal shortened both the HBeAg-positive period and the duration until anti-HBe becomes reactive significantly (P < 0.0001). Interferon without steroid withdrawal and adenine arabinoside with steroid withdrawal shortened the HBeAg positive interval only (P < 0.05). Among patients' characteristics, female and advanced liver histology were favorable factors. Effects of treatment protocols were analyzed after averaging each parameter of the patients' characteristics. Interferon and adenine arabinoside with steroid withdrawal shortened the HBeAg-positive interval significantly (P < 0.0001 and P < 0.05, respectively), and interferon alone showed a tendency to shorten the interval. In particular, interferon with steroid withdrawal increased the chance of losing HBeAg 7.3 times more than control. The effectiveness of antiviral treatment on chronic hepatitis B, especially the priority of interferon with steroid withdrawal, was thought to be established through this study.


Evaluation of [14C]aminopyrine breath test, peripheral clearance of [99mTc]EHIDA, and serum bile acid levels in liver function and disease. The purpose of this study is to evaluate the diagnostic value of the following tests in the assessment of patients with chronic liver disease (CLD) and cholestatic syndrome (CS): (1) aminopyrine breath test, measuring 14CO2 excretion in the expired air, (2) peripheral clearance of [99mTc]EHIDA, and (3) postprandial levels of glycocholic acid (GCA) and glycochenodeoxycholic acid (GCDCA). The results indicate that: (1) 14CO2 2-hr excretion rate is a specific and sensitive marker of liver function, with good correlation with postprandial bile acid levels, [99mTc]EHIDA retention, and the conventional tests of serum albumin and prothrombin time. (2) Peripheral clearance and retention of [99mTc]EHIDA increased in both groups of CLD and CS vs controls, but it does not discriminate between the two. (3) Postprandial bile acids were elevated in CLD, particularly those of GCDCA, whereas GCA levels were significantly elevated in CS compared with CLD. This may be due to increased synthesis and entry into the blood. (4) The combination of [14C]aminopyrine breath test and postprandial levels of GCDCA enhance the diagnostic value, specificity, and sensitivity in the assessment of patients with CLD.


Effects of gastric inhibitory polypeptide and glucagon on portal venous and hepatic arterial flow in conscious dogs. Gastric inhibitory polypeptide (GIP) has considerable structural homology with glucagon, which is known to increase liver blood flow. We compared the effects of GIP on portal venous and hepatic arterial flow with those of glucagon in conscious dogs. Injection of GIP significantly increased portal venous flow in a dose-related manner (by 7%, 15%, and 46% at doses of 1, 100, and 500 pmol/kg, respectively). The increase in portal venous flow induced by GIP and glucagon was comparable; however, the increase in portal venous flow after GIP injection reached its peak significantly earlier than that after glucagon injection. Hepatic arterial flow decreased after GIP injection (by 17%, 21%, and 35% at doses of 1, 100, and 500 pmol/kg, respectively), whereas it was not altered by glucagon. Thus, GIP causes significant changes in both portal venous and hepatic arterial flow in conscious dogs. Although structurally related, GIP and glucagon may influence liver blood flow through different mechanisms.


Effect of erythromycin on gallbladder emptying in diabetic patients with and without autonomic neuropathy and high levels of motilin. A reduction of gallbladder emptying in response to neural or hormonal stimulation has been reported in patients with diabetes mellitus. Decreased gallbladder emptying may be a key factor in the pathogenesis of gallbladder stones. Few drugs, if any, are able to stimulate gallbladder emptying. However, in a previous study we demonstrated that erythromycin, a macrolide antibiotic, stimulates gallbladder emptying and motilin release in healthy human subjects by an atropine-sensitive pathway. Therefore, the present study was designed to evaluate the effect of erythromycin on gallbladder emptying and motilin release in diabetic patients with or without cardiac autonomic neuropathy (AN). Thirteen diabetic patients, six with AN, and 10 healthy subjects were enrolled in the study protocol. Gallbladder emptying was determined by sonography after ingestion of a standard meal and during infusion of erythromycin alone or together with 6 micrograms/kg/hr atropine. We found that 100 mg/hr erythromycin caused a significant reduction in gallbladder volume in both healthy subjects and diabetic patients. The ejection fraction (mean +/- SE) of 45.3 +/- 8.2% and 37.3 +/- 5.0% was similar. The presence of AN had no influence on gallbladder emptying induced by erythromycin. Basal motilin plasma levels were 111.5 +/- 14.5 pmol/liter in diabetic patients and 63.3 +/- 6.0 pmol/liter in healthy subjects (P < 0.01). However, patients with AN had higher (130.0 +/- 11.9 pmol/liter) motilin plasma levels than patients without (74.0 +/- 9.4 pmol/liter, P < 0.01). Erythromycin administration caused an approximately twofold increase in plasma motilin concentrations in healthy subject and patients without AN, but did not stimulate motilin release in neuropathic patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Postprandial gallbladder motility and plasma cholecystokinin at regular time intervals after injection of octreotide in acromegalics on long-term treatment. The increased risk of gallstone formation in acromegalics treated with the somatostatin analog octreotide has been related to an impaired gallbladder emptying. To determine the duration of these inhibitory effects, meal-stimulated gallbladder motility, plasma cholecystokinin (CCK), and pancreatic polypeptide (PP) were measured in five acromegalics treated for 6-32 months with 200-300 micrograms octreotide daily. Meal tests were performed 45 min, 8 hr and two weeks after the last 100-micrograms subcutaneous dose. Results were compared with those in normal subjects. Integrated postprandial gallbladder contraction (-125 +/- 194 cm3/120 min) and integrated PP secretion (-0.1 +/- 0.2 nmol/liter/120 min) were completely suppressed in the 45-min study, but significantly improved (P < 0.05) when measured 8 hr (1376 +/- 322 cm3/120 min and 3.0 +/- 1.0 nmol/liter/120 min) and two weeks (1437 +/- 263 cm3/120 min and 10.6 +/- 1.6 nmol/liter/120 min) after the last dose of octreotide. The integrated gallbladder contraction in acromegalics at 8 hr was comparable to that at two weeks and to that in normal subjects, but the integrated PP response at 8 hr was significantly smaller (P < 0.05 vs two weeks and vs normals). Integrated plasma CCK secretion at 45 min (0.13 +/- 0.06 nmol/liter/120 min) was not statistically significantly different from the response at 8 hr (0.15 +/- 0.02 nmol/liter/120 min) and from that in normal subjects, but it was significantly increased at two weeks after cessation of octreotide (P < 0.05 vs 45 min and 8 hr).(ABSTRACT TRUNCATED AT 250 WORDS)


Penetration of ceftriaxone and cefoperazone into bile and gallbladder tissue in patients with acute cholecystitis. The penetration of ceftriaxone and cefoperazone into bile and gallbladder tissue was prospectively studied in 21 adult patients undergoing early surgery for acute cholecystitis. Comparable tissue, bile, and serum concentrations of the drugs were demonstrable; however, significantly fewer preoperative doses of ceftriaxone were required for adequate perioperative treatment. In view of its higher serum half-life and superior antibacterial activity toward common biliary pathogens, ceftriaxone appears to be a useful drug for the perioperative management of acute cholecystitis.


Gastric surgery and bezoars.

Gastric surgery and bezoars. We present a series of 56 patients with gastrointestinal bezoar following previous gastric surgery for gastroduodenal peptic ulcer. The following parameters were studied: factors predisposing to bezoar formation (type of previous surgery, alimentation, and mastication), form of clinical presentation, diagnostic tests, and treatment. A bilateral truncal vagotomy plus pyloroplasty had been performed previously on 84% of patients, 44% revealed excessive intake of vegetable fiber, and 30% presented with bad dentition. The most frequent clinical presentation was intestinal obstruction (80%). This was diagnosed mainly by clinical data and simple abdominal radiology. The main exploratory technique for diagnosing cases of gastric bezoar was endoscopy. Surgery is necessary for treating the intestinal forms, and one should always attempt to fragment the bezoar and milk it to the cecum, reserving enterotomy and extraction for cases where this is not possible. The small intestine and stomach should always be explored for retained bezoars. Gastric bezoars should always receive conservative treatment, endoscopic extraction, and/or enzymatic dissolution; gastrotomy and extraction should be performed when this fails.


Effect of Aeromonas hydrophila enterotoxins on function of mouse phagocytes. Two enterotoxins produced by Aeromonas hydrophila isolate SSU have been characterized in this laboratory. One is a cholera toxin cross-reactive cytolytic enterotoxin (CTC toxin) and the other is a non-cholera toxin cross-reactive cytotonic enterotoxin (non-CTC toxin). The two enterotoxins are capable of causing fluid accumulation in animal models; however, only the CTC toxin is lethal to mice and expresses hemolytic as well as cytotoxic activities. In this study, we have investigated the effects of these two toxins on mouse phagocytes. Four hours after intraperitoneal injection of a sublethal dose (460 micrograms/kg of body weight) of CTC toxin, the chemiluminescence (CL) response of phagocytes in mouse blood was depressed significantly when compared with that observed for controls (intraperitoneal injection of only Hanks' balance salt solution, non-CTC toxin or before treatment with CTC toxin). When fresh whole blood was incubated with various concentrations (2.3, 11.5, 23, 230, 2300 ng/ml) of CTC toxin for 1.5 hr at 37 degrees C, the CL response of blood phagocytes was reduced strikingly in a dose-dependent fashion; however, non-CTC toxin did not inhibit the CL response. The inhibitory effect induced by CTC toxin of the phagocytic function not only was abolished completely, but phagocytosis was enhanced in the presence of interferon-gamma (IFN-gamma). In addition, IFN-gamma alone induced the largest enhancement of the CL response in mouse phagocytes. These results demonstrated that CTC toxin inhibits the phagocytic ability of phagocytes either in vivo or in vitro and that IFN-gamma pretreatment can overcome this toxic effect.(ABSTRACT TRUNCATED AT 250 WORDS)


Mucosal damage during intestinal anaphylaxis in the rat. Effect of betamethasone and disodium cromoglycate. In this study, two antiallergic compounds, betamethasone and disodium cromoglycate were tested in an animal model of intestinal anaphylaxis. Rats, immunized with Nippostrongylus brasiliensis, were challenged intravenously with whole worm antigen or saline. Antigen challenge resulted in significant abnormalities: epithelial damage with shorter villi, decreased activity of digestive enzymes, decreased levels of mucosal histamine, a mast cell mediator, and increased blood uptake of [51Cr]EDTA from the lumen. Low-dose betamethasone, 24 and 48 hr before antigen, was not effective in preventing the effects: villus damage and increased [51Cr]EDTA uptake were seen, although mucosal mast cell numbers were significantly reduced by the drug. High-dose betamethasone completely prevented intestinal anaphylaxis: villus height, digestive function, and [51Cr]EDTA recovery in antigen-challenged animals were not significantly different from controls. Mucosal histamine levels and mast cells were significantly reduced in the high dose betamethasone group. Oral disodium cromoglycate did not prevent the abnormalities but provided a slight beneficial effect.


Prostaglandin- and theophylline-induced C1 secretion in rat distal colon is inhibited by microtubule inhibitors. The aim of the present study was to examine the possible role of microtubules in chloride secretion by distal rat colon stimulated by prostaglandin (PGE2) and theophylline. Distal colonic tissue from male rats was mounted in Ussing chambers, and short-circuit current (Isc) was measured to assess chloride secretion. Three microtubule inhibitors, colchicine, nocodazole, and taxol, all inhibited the stimulated Isc and reduced the 60-min integrated secretory response to PGE2 and theophylline (integral of Iscdt) by 39-52%, whereas the inactive colchicine analog lumicolchicine did not. Atropine and tetrodotoxin had no effect on stimulated chloride secretion. To confirm the source of Isc, unidirectional 22Na+ and 36Cl- fluxes were measured in tissues exposed to lumicolchicine (control) or colchicine. Control tissues absorbed both chloride [5.0 (1.1-8.6) (median and 95% confidence interval) mueq/cm2/hr] and sodium [2.8 (0.9-7.2) mueq/cm2/hr], and this net absorption was reduced by 96% and 79%, respectively, by treatment with PGE2 and theophylline due to an increase in serosal-to-mucosal chloride and sodium movement. Colchicine-treated tissues exhibited similar net basal chloride and sodium absorption that was reduced by 71% and 75%, respectively, by treatment with PGE2 and theophylline. Thus the PGE2- and theophylline-induced increase in chloride secretion was significantly reduced by colchicine (P < 0.05 by Wilcoxon rank-sum test), whereas colchicine had no effect on PGE2- and theophylline-induced changes in sodium fluxes. Furthermore, the colchicine-related changes in stimulated chloride secretion were numerically similar to colchicine-related changes in stimulated Isc.(ABSTRACT TRUNCATED AT 250 WORDS)


Rectal mucosal ornithine decarboxylase activity is not a useful marker of risk for colorectal neoplasia. Rectal mucosal ornithine decarboxylase activity has been reported to distinguish patients with adenomas from normal controls. In order to further explore this association, we assayed biopsy samples from 119 unselected individuals undergoing routine colonoscopic examinations. The overall mean ODC activity was 127.4 (+/- 93.1 SD) pmol/mg protein/hr. There were no differences by age, sex, or race. Tissue handling and storage influenced ODC activity. Specimens collected and transported on Dry Ice had higher ODC activity than specimens initially frozen in a -20 degrees C freezer. After adjusting for storage and collection method, the activity was similar in subjects with adenomas (126.3 pmol/mg/hr) compared to those without adenomas (128.8 pmol/mg/hr). We conclude that variations in assay technique make comparisons between laboratories difficult. Patients with large-bowel adenomas do not necessarily have higher ODC activity in uninvolved rectal mucosa. Further study of the environmental and genetic factors that influence rectal mucosal proliferation may improve our understanding of carcinogenesis in the large bowel.


Phenotypic characterization of isolated intraepithelial lymphocytes in patients with ulcerative colitis and normal controls. A method was developed to isolate colonic intraepithelial lymphocytes in patients with ulcerative colitis (N = 8) and normal controls (N = 13) in order to characterize their phenotype using a panel of monoclonal antibodies and flow cytometry. In both groups, the majority of the cells are of the CD3+CD8+ phenotype associated with cytotoxic/suppressor function. The CD4/CD8 ratios were similar. Virtually no B cells or macrophages were found. An increase in cells coexpressing the CD3 and HLA-DR molecules and a decrease in natural killer cells (CD3, CD16+CD56+) were found in ulcerative colitis, but this was not significant. There were no differences in the proportions of CD8+ and CD4+ cells expressing the Leu8 antigen between ulcerative colitis and controls. Thus a population of colonic intraepithelial lymphocytes has been isolated and, although they may be functionally different in ulcerative colitis compared with controls, this cannot be explained in terms of phenotypic characteristics.


Changes of colonic vasoactive intestinal peptide and cholinergic activity in rats with chemical colitis. The vasoactive intestinal peptide concentration was examined in the colonic wall and portal venous plasma of rats with chemical colitis by radioimmunoassay, and the colonic localization was determined with immunocytochemistry. Colonic acetylcholine esterase activity was also measured, and the response of vasoactive intestinal peptide to acetylcholine administration was determined. Colitis was induced by administration of dextran sulfate for three months. The chemical colitis was histologically similar to active human ulcerative colitis. We observed a significant increase of immunostained neurons and nerve fibers and a significant rise in the colonic wall vasoactive intestinal peptide content in chemical colitis rats, while plasma concentrations of the peptide did not change significantly. Colonic acetylcholine esterase activity was significantly elevated in colitis rats compared with control rats. Systemic administration of acetylcholine significantly increased the colonic and plasma vasoactive intestinal peptide concentrations in colitis rats. These findings demonstrated a positive association between colitis activity and an increase of vasoactive intestinal peptide and suggested that increased vagal tone promoted the peptide's release.


Motility of rabbit proximal colon. Relevance of cholinergic pathways and role of different muscarinic receptor subtypes. To better define the physiologic relevance of the cholinergic muscarinic input to the rabbit colon and the role of different muscarinic receptor subtypes, we studied the effects of atropine, telenzepine (MI antagonist) and DF594 (M3 antagonist) on colonic motility in eight conscious rabbits fitted with bipolar electrodes and strain gauges along the proximal colon. In some experiments, the chronotropic and mydriatic effect of the pharmacological agents were also assessed. Two main patterns of spike activity were identified: short spike bursts (SSBs), which were usually stationary, and long spike bursts (LSBs), which were usually propagated. Both myoelectrical patterns were dose-dependently inhibited by atropine (0.06-4 mumol/kg). Atropine, at the doses of 2-4 mumol/kg, abolished both myoelectrical and mechanical activity. Telenzepine (0.008-0.125 mumol/kg) dose-dependently inhibited migrating LSBs without significant effect on SSBs. Higher doses (0.25-0.5 mumol/kg) inhibited both LSBs and SSBs. DF594 (0.06-2 mumol/kg) dose-dependently inhibited both migrating LSBs and SSBs. The three antimuscarinic agents, at doses that inhibited colonic spike activity by approximately 80% (equiactive doses), behaved as follows on heart rate and pupil diameter: atropine induced tachycardia and mydriasis, telenzepine had no effect, and DF594 induced slight mydriasis with no effect on heart rate. We conclude that spontaneous motility in the rabbit proximal colon depends on a muscarinic excitatory input. M3 receptors are involved in the control of both LSBs and SSBs, while M1 receptors play an important role in the regulation of LSBs. The development of selective antimuscarinic drugs, acting on a given motility pattern and with minimal side effects, may offer new perspectives in the treatment of functional bowel motor disorders.


Hyperammoniemic coma in a patient with ureterosigmoidostomy and normal liver function. Hyperammoniemic encephalopathy has been reported after ureterosigmoidostomy. Its development is related to a problem of bacterial overgrowth and, most often, is favored by the presence of an underlying liver dysfunction. We report the case of a 43-year-old woman with a ureterosigmoidostomy done 28 years earlier who developed hyperammoniemic coma induced by an acute rectocolitis and in the absence of any detectable liver dysfunction. Neither administration of Lactilol and neomycin nor rectal tube drainage were effective; systemic antimicrobial therapy effective against the urease-producing gram-negative bacilli was required and led to a decrease in serum ammonia levels and a dramatic clinical improvement.


Interferon therapy is effective in treatment of hepatitis B-induced polyarthritis. A patient with acute hepatitis B developed significant polyarthritis. After 10 months of observation he had not cleared the virus and continued to have symptomatic joint problems, with migratory polyarthralgia, tenosynovitis of the left wrist, and a large knee effusion. Hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels were measured in the synovial fluid and were found to be virtually identical to serum levels, indicating the potential infectivity of this fluid. The patient was treated with 14 weeks of thrice-weekly lymphoblastoid interferon and cleared all markers of viral replication. The arthritis resolved with the disappearance of measurable HBsAg. Interferon may be effective therapy for this disorder.


Peritoneal sarcoidosis. An unrecognized cause of sclerosing peritonitis. In a Caucasian woman with a history of ocular and pulmonary sarcoidosis, the occurrence of sclerosing peritonitis with exudative ascites but without any of the well-known causes of this syndrome prompts us to consider that sclerosing peritonitis is a manifestation of sarcoidosis. The dramatic improvement that occurred on corticosteroid therapy adds credibility to this previously unreported association.


Reversible achalasia-like motor pattern of esophageal body secondary to postoperative stricture of gastroesophageal junction. Two cases are presented of benign stenosis of the cardia secondary to fibrosis following antireflux surgery in which the patients developed a motor alteration in the esophageal body similar to that of achalasia of the cardia. There was a complete absence of contractions in one patient, which had developed over a long period of time, and a vigorous pattern in the other patient, which had evolved over a short period. In both cases, after surgical treatment of the stenosis, normal motility in the esophageal body returned.


Esophageal ulcer due to ingestion of melted copper. We report a patient with esophageal stricture as a result of the accidental swallowing of melted copper by a 49-year-old male. As a result, esophagogastric ulcers developed and left a cicatrical stricture. The patient could only manage to swallow liquid food. Radiology of the upper gastrointestinal tract showed marked stricture of the esophagus from the middle thoracic portion to the esophagogastric junction and shortening of the lesser curvature of the stomach. The patient underwent a single-session total gastrectomy, and excision of the thoracic esophagus and construction of anterior thoracic esophagocolic and duodenocolic anastomoses were performed by right thoracotomy and laparotomy, respectively. Macroscopic findings of the surgical specimens showed extensive circular ulcers at the esophagus, and microscopic findings showed deep ulcers extending to the muscle layer with marked fibrosis. The postoperative course was uneventful.


Hyperfibrinogenemia. An important risk factor for vascular complications in diabetes. To evaluate the determinants of elevated fibrinogen levels and the impact of hyperfibrinogenemia on vascular complications in diabetes. Plasma fibrinogen, glucose, HbA1, and lipids were measured in 116 ambulatory type I and type II diabetic patients with (n = 59) or without (n = 57) clinical evidence of micro- or macrovascular complications. In 56 of these patients, factor VII activity and CRP also were measured. Univariate and multivariate data analyses were conducted. Overall mean +/- SE fibrinogen levels in patients (339 +/- 7.3 mg/dl) were elevated markedly compared with control subjects (248 +/- 9.1 mg/dl). Fibrinogen levels were elevated disproportionately in patients with type II diabetes (P less than 0.0001), hypertension (P = 0.0001), obesity (P less than 0.0001), and vascular complications (P less than 0.0001). Fibrinogen was correlated significantly with age (P less than 0.001), cholesterol (P = 0.002), CRP (P less than 0.001), and factor VII activity (P = 0.032), but not with plasma glucose, triglycerides, HDL cholesterol, or disease duration. Stepwise multiple regression analyses revealed that type II diabetes and presence of vascular complications were major determinants of fibrinogen. For vascular complications, fibrinogen emerged as one of only three independent predictors, the other two being diabetes duration and hypertension.


Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. To determine the gestational ages at which maternal hyperglycemia is most closely related to fetal macrosomia; to determine whether macrosomia is related to elevations of fasting glucose, postprandial glucose, or both; and to assess the relationship of macrosomia to maternal insulin dose and caloric intake. One hundred eleven consecutive pregnant women with Class B through RF diabetes were studied longitudinally from 13 to 36 wk gestation. Macrosomia was defined by birthweight greater than 90th percentile for gestational age based on California norms. Women who delivered macrosomic infants were compared with those without macrosomic infants on pre- and postprandial blood glucose, GHb, insulin dose, macronutrient intake, and several other maternal variables. Macrosomia occurred in 32 (29%) cases, although several measures indicated reasonable glycemic control throughout pregnancy. Women delivering macrosomic infants did not differ from those without macrosomic infants in maternal age, prepregnant weight, duration of diabetes, White class, macronutrient intake, GHb, or fasting glucose. Macrosomia was associated with higher postprandial glucose levels up to 32 wk gestation and lower insulin doses from 29 to 36 wk gestation. In multiple logistic regression, macrosomia was significantly associated with postprandial glucose only between 29 and 32 wk gestation. Postprandial glucose values less than 7.3 mM (less than 130 mg/dl) were associated with a higher risk of small-for-gestational-age infants (18%) compared with values above this level (1%). Because macrosomia was related to postprandial glucose but not fasting glucose, we conclude that postprandial glucose measurement should be a part of routine care for diabetes in pregnancy. A target 1-h postprandial glucose value of 7.3 mM (130 mg/dl) may be the level that optimally reduces the incidence of macrosomia without increasing the incidence of small-for-gestational-age infants.


Effect of insulin therapy on blood pressure in NIDDM patients with secondary failure. To assess the effect of insulin therapy on blood pressure in NIDDM patients with secondary failure. The influence of insulin treatment on blood pressure was assessed retrospectively in a group of 80 NIDDM patients with secondary failure to diet and maximum doses of oral hypoglycemic agents. Weight, blood glucose, and blood pressure were recorded over a 3-mo period before and after the initiation of insulin therapy. There was a significant rise in systolic (131.8 +/- 1.7 to 148 +/- 1.9 mmHg, P less than 0.05) and diastolic (80.9 +/- 0.9 to 89.2 +/- 1.0 mmHg, P less than 0.02) blood pressures with insulin treatment. Insulin treatment was associated with a significant decrease in blood glucose (18.36 +/- 0.28 to 10.4 +/- 0.34 mM, P less than 0.01) and an increase in weight (72.1 +/- 1.6 to 78 +/- 1.7 kg, P = 0.01). A control group of 80 NIDDM patients matched for age, weight, BMI, and duration of diabetes demonstrated no significant change in blood pressure over a matched period of follow-up. This study has shown that insulin therapy is associated with significant elevation of both systolic and diastolic blood pressures.


Lack of effects of hypoglycemia on glucose absorption in healthy men. To assess the effects of hypoglycemia on glucose absorption by examining the systemic appearance of 3-OMG (a glucose analogue that is transported by the same mechanism as glucose) after oral administration. Six healthy males 22-31 yr of age were studied during a hypoglycemic (50 mg [2.7 mM]/100 ml) and a euglycemic (90 mg [5.0 mM]/100 ml) glucose clamp. At 50 min after exposure to insulin, an oral glucose load containing 20 g of glucose and 4.5 g of 3-OMG dissolved in 300 ml of tap water was administered. Insulin administration was interrupted 30 min after oral glucose administration. Plasma glucose was clamped at 88 +/- 1.3 mg (4.9 +/- 0.1 mM)/100 ml during euglycemia and at 50 +/- 1.9 mg (2.7 +/- 0.1 mM)/100 ml during hypoglycemia. Concentrations of glucagon, growth hormone, cortisol, and epinephrine were significantly elevated during hypoglycemia. After 60 min, circulating 3-OMG concentrations increased to zeniths of 11.4 +/- 0.2 mg (585 +/- 10.0 mM)/100 ml (hypoglycemia) and 11.6 +/- 1.1 mg (585 +/- 56.0 microM)/100 ml (euglycemia; P = 0.95). Absorption of 3-OMG was evident between 15 and 20 min after administrations in both situations. Serum insulin was significantly lower during hypoglycemia compared with the control situation (345 +/- 50 microM [hypoglycemia], 445 +/- 50 microM [euglycemia], P = 0.03). We conclude that hypoglycemia does not seem to affect intestinal absorption of glucose as judged by systemic appearance of 3-OMG.


Physical activity and proliferative retinopathy in people diagnosed with diabetes before age 30 yr. OBJECTIVE--To examine the relationships of past and current physical activity to the prevalence of PDR. RESEARCH DESIGN AND METHODS--Individuals diagnosed with diabetes less than 30 yr of age (n = 818), who were participants in the population-based Wisconsin Epidemiologic Study of Diabetic Retinopathy, were examined during 1984-1986. Stereoscopic fundus photographs were graded for presence of PDR. Physical activity was assessed by an interviewer-administered standardized questionnaire. RESULTS--Women diagnosed with diabetes less than 14 yr of age who reported a history of participation in team sports in high school or college were less likely to have PDR at examination (OR 0.46, 95% CI 0.23, 0.93). Those women who reported current strenuous activity levels were less likely to have PDR (OR 0.34, 95% CI 0.13, 0.87). There were no significant associations between past or current physical activity and PDR in men. Current levels of energy expenditure were not related to PDR in either sex. CONCLUSIONS--Higher levels of physical activity may be associated with a reduced risk of having PDR in women. However, the lack of similar findings in men suggests that physical activity may be a relatively unimportant factor in the etiology of PDR.


Permanent diabetes without serological evidence of autoimmunity after transient neonatal diabetes. To describe a probable association between TNDM and subsequent permanent IDDM. A longitudinal follow-up of a single case from birth to 12 yr of age was conducted analyzing sequential OGTTs, ICAs, AIAs, anti-GAD antibodies, and other organ-specific and nonspecific antibodies. A small-for-gestational-age infant developed hyperglycemia at 20 h of age and required insulin therapy for the 1st 14 wk of life (TNDM). Transient hyperglycemia and ketonuria were noted again at age 2 yr 10 mo during an intercurrent illness, but OGTT was normal; and ICA, AIA, anti-GAD65 and anti-GAD67 antibodies, antithyroid microsomal, anti-gastric parietal cell, antiadrenal, antisteroidal, and antinuclear antibodies were negative 3 wk later. At age 9 yr, hyperglycemia returned and persisted in the setting of hypoinsulinemia; ICA, AIA, anti-GAD65 and anti-GAD67 antibodies, and other organ-specific and nonspecific antibodies were again negative. Insulin therapy was initiated and has been maintained over 3 yr of follow-up. Our case is the fifth reported with permanent diabetes occurring after resolution of TNDM. The etiology of permanent diabetes in this setting is unknown but, unlike classical IDDM, appears unrelated to autoimmunity in our patient. The true frequency of this association remains unknown.


Greater effect of glycemia on incidence of hypertension in women than in men. In subjects with NIDDM, diabetic women have a greater relative excess of CHD relative to nondiabetic women than do diabetic men relative to nondiabetic men. This excess in diabetic women is explained partially by the particularly atherogenic pattern of lipoproteins in this group. We hypothesize that diabetic women also may have a higher incidence of hypertension than diabetic men. We examined the effect of NIDDM and IGT relative to NGT on the incidence of hypertension separately in men (n = 844) and women (n = 618) in the 8-yr follow-up of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Women had a greater risk of hypertension with worsening glucose tolerance (RR NIDDM/NGT = 2.65 and RR IGT/NGT = 1.94) compared with men (RR NIDDM/NGT = 1.61 and RR IGT/NGT = 0.91). Controlling for other possible confounding variables such as age, obesity, body fat distribution, and fasting insulin concentration did not alter the interaction of sex and glycemia on incidence of hypertension. The especially increased risk of hypertension in women with abnormal glucose tolerance may explain partly the high risk of CHD in this group.


Dyslipidemias among normoglycemic members of familial NIDDM pedigrees. To examine the hypothesis that hyperinsulinemia among relatives of NIDDM probands will increase the prevalence of DLPs, we measured insulin levels and examined the frequency of DLPs among NIDDM pedigree members. We performed 2-h 75-g OGTTs and measured lipid and insulin levels of 287 family members and 86 spouses from 16 large Utah pedigrees ascertained for greater than or equal to 2 siblings with NIDDM. One-hour insulin levels were higher among 206 family members with NGT than among 65 NGT spouses (483.3 vs. 361.7 pM, P = 0.05). Among the NGT family members, 32% had cholesterol levels at or above the age- and sex-specific 90th percentile level defined by the LRC studies, 33% had HDL levels less than or equal to 10th percentile, and 20% had triglyceride levels greater than or equal to 90th percentile. DLP (any of the three abnormalities) was found among 58% of NGT family members, which was significantly higher than the expected 27% (P less than 0.00001) and the prevalence among spouses of 45% (P less than 0.05). By NCEP criteria for hyperlipidemia, 40% of family members met criteria for diet and/or pharmacological therapy. Normoglycemic members of NIDDM pedigrees have a high prevalence of DLPs, which approaches the prevalence in patients with NIDDM. Our data suggest that members of NIDDM pedigrees should be screened carefully for lipid abnormalities.