GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Characterisation of proteases involved in egg hatching of the sheep blowfly, Lucilia cuprina.

A number of proteases were identified in the egg shell washings (ESW) collected during the egg hatching of Lucilia cuprina (sheep blowfly). Characterization of these proteases indicated a pH optima in a similar pH range that was optimal for L. cuprina egg hatching. Mechanistic characterization of these proteases indicated that they were predominantly of the serine class. Several protease inhibitors were tested for their ability to inhibit L. cuprina egg hatching in vitro. Egg hatching was significantly (P<0.05) inhibited by PMSF (61%), 1,10-Phenanthroline (42%) and Pepstatin (29%). The inhibition of egg hatching by PMSF showed a strong concentration dependence, with its effects ranging from inhibition at high concentrations to enhancement of egg hatching at low concentrations. Addition of ESW to unhatched eggs, significantly (P<0.05) enhanced their rate of hatching above untreated control eggs. This enhancement of egg hatching was significantly (P<0.05) reversed by the protease inhibitors Elastatinal (40%), 1,10-Phenanthroline (40%) and PMSF (38%). These studies indicate a role for serine and/or metallo-proteases in facilitating L. cuprina egg hatch.

Biochemical aspects of egg hatch in endo- and ectoparasites: potential for rational drug design.

Control of parasites through rational drug design requires a thorough understanding of the parasite's lifecycle encompassing the biochemical and physiological processes which contribute to normal parasite homeostasis. The hatching of parasite eggs for example, represents an important process in the development of a parasitic infection. Previous studies in helminths have indicated that secreted enzymes often facilitate successful endoparasite egg hatch. In contrast, there are relatively few examples demonstrating a role for secreted enzymes in the egg hatching process of insects. An analysis of this process in the ectoparasite Lucilia cuprina suggests a role for secreted enzymes in the hatching of sheep blowfly eggs. Characterisation of the proteases collected at the time of egg hatch indicates the presence of serine proteases. Further purification and characterisation of these proteases may enable the design of specific inhibitors to interfere with the egg hatch process and therefore provide a novel means of control.

Combined Tc-99m MIBI and Tc-99m RBC for anatomic localization of ectopic mediastinal parathyroid adenomas.

Preoperative localization of abnormal parathyroid tissue in patients with persistent or recurrent hyperparathyroidism is recommended as a standard of care. A high percentage of these patients have ectopic tissue in the mediastinum. Tc-99m MIBI imaging alone for detection of ectopic parathyroid tissue in the mediastinum does not provide a sufficient number of anatomic landmarks, which makes communication regarding the exact location of any area of abnormal uptake difficult. We report the use of concomitant Tc-99m RBC and Tc-99m MIBI imaging for precise anatomic localization of ectopic mediastinal parathyroid tissue in 4 patients. It is thought that this combination of studies allows improved communication with referring physicians, surgeons, and radiologists for planning both surgical approach and correlative imaging studies. It is hoped that in the future this combination of studies may obviate the need for other imaging studies.

Helicobacter pylori reinfection rate, in patients with cured duodenal ulcer.

OBJECTIVE: To determine the reinfection rate of the gastric mucosa in patients previously cured of duodenal ulcers, following the eradication of Helicobacter pylori. Only those remaining H. pylori-negative beyond 12 months of follow-up were studied, to minimize the potential inclusion of patients with H. pylori recrudescence. METHODS: Patients with endoscopically proven duodenal ulcers who had been treated with triple therapy, resulting in documented eradication of H. pylori and cure of the ulcer for at least 4 years, were recalled and had their H. pylori status determined by the 14C-urea breath test. Those found positive for H. pylori underwent endoscopic confirmation of the infection. RESULTS: Of the 94 patients restudied, with a follow-up period range of 48-96 months or a total of 549.8 yr, only two (2.2%) were again H. pylori positive. This gives an effective reinfection rate of 0.36% per patient year. In the two H. pylori-positive patients, one had normal mucosa endoscopically, whereas duodenitis without active ulceration was present in the other. The former was asymptomatic, whereas the latter patient was using ranitidine daily for symptom control. CONCLUSION: In the Australian setting, following cure of duodenal ulcer disease by eradication of H. pylori, subsequent reinfection is an unusual phenomenon. We conclude that efforts aimed at eradication of H. pylori in duodenal ulcer are justified and are worthwhile.

Tratamiento de la enfermedad ulcerosa gastroduodenal / Treatment of ulcerous gastroduodenal disease

Los autores dan su opinión sobre el tema y solicitan la de los lectores. Postulan comenzar con el tratamiento médico y dejar el quirúrgico, se es necesario, para una segunda etapa. Insisten en que el tratamiento médico debe ser integral e individual, basándolo en un diagnóstico con iguales características, enfocando al enfermo en su integridad bio-psico-social. Respecto del tratamiento medicamentoso, preconizan que no debe ser el único, como sucede a menudo. Diferencian la enfermedad ulcerosa péptica duodenal o péptica antral de la trófica: úlcera de los dos tercios superiores del estómago. En la primera recurren a los antiácidos y bloqueadores H2. No tienen experiencia con el Omeprazol; pero piensan que no es aconsejable anular totalmente la secreción ácida gástrica. En el segundo prefieren los citoprotectores: bicitrato dipotásico de bismuto (que actúa también sobre C. pylorii) y el sucralfato. A menudo asocian ambos tipos de tratamiento. Afirman que es frecuente el retardo de la evacuación gástrica que combaten con clebopride o similares. Usan a veces ansiolíticos y antidepresivos junto con psicoterapia de apoyo. Combaten la constipación. Siguen el plana durante tres meses por lo menos, con controles periódicos. Una vez curada la úlcera no interrumpen abruptamente el tratamiento. mantienen las prescripciones sobre higiene alimentaria y nerviosa. Consideran indispensable la endoscopía así como la biopsia, que es obligatoria en las úlceras gástricas. No creen que la úlcera gástrica deba tratarse quirúrgicamente "de entrada". Consignan los motivos para indicar dicho tratamiento: las indicaciones absolutas son perforación libre o bloqueada, hemorragia masiva, estenosis pilórica esclerosa; las indicaciones relativas son presencia simultánea de varias úlceras duodenales, úlceras duodenal de la cara posterior, motivos "sociales", hemorragia massiva...