Acute Kidney Injury and Renal Replacement Therapy in COVID-19 Versus Other Respiratory Viruses: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-2019 (COVID-19). Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, to its viral receptor, angiotensin converting enzyme 2 (ACE2), results in viral entry and may cause AKI. OBJECTIVES: We performed a systematic review and meta-analysis of the frequencies of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients and compared those frequencies with patients who were infected by respiratory viruses that bind or downregulate ACE2 (ACE2-associated viruses) and viruses that do not bind nor downregulate ACE2 (non-ACE2-associated viruses). DESIGN: Systematic review and meta-analysis. SETTING: Observational studies on COVID-19 and other respiratory viral infections reporting AKI and RRT were included. The exclusion criteria were non-English articles, non-peer-reviewed articles, review articles, studies that included patients under the age of 18, studies including fewer than 10 patients, and studies not reporting AKI and RRT rates. PATIENTS: Adult COVID-19, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza patients. MEASUREMENTS: We extracted the following data from the included studies: author, year, study location, age, sex, race, diabetes mellitus, hypertension, chronic kidney disease, shock, vasopressor use, mortality, intensive care unit (ICU) admission, ICU mortality, AKI, and RRT. METHODS: We systematically searched PubMed and EMBASE for articles reporting AKI or RRT. AKI was defined by authors of included studies. Critical illness was defined by ICU admission. We performed a random effects meta-analysis to calculate pooled estimates for the AKI and RRT rate within each virus group using a random intercept logistic regression model. RESULTS: Of 23 655 hospitalized, critically ill COVID-19 patients, AKI frequencies were not significantly different between COVID-19 patients (51%, 95% confidence interval [CI]: 44%-57%) and critically ill patients infected with ACE2-associated (56%, 95% CI: 37%-74%, P = .610) or non-ACE2-associated viruses (63%, 95% CI: 43%-79%, P = .255). Pooled RRT rates were also not significantly different between critically ill, hospitalized patients with COVID-19 (20%, 95% CI: 16%-24%) and ACE2-associated viruses (18%, 95% CI: 8%-33%, P = .747). RRT rates for both COVID-19 and ACE2-associated viruses were significantly different (P < .001 for both) from non-ACE2-associated viruses (49%, 95% CI: 44%-54%). After adjusting for shock or vasopressor use, AKI and RRT rates were not significantly different between groups. LIMITATIONS: Limitations of this study include the heterogeneity of definitions of AKI that were used across different virus studies. We could not match severity of infection or do propensity matching across studies. Most of the included studies were conducted in retrospective fashion. Last, we did not include non-English publications. CONCLUSIONS: Our findings suggest that viral ACE2 association does not significantly alter the rates of AKI and RRT among critically ill patients admitted to the ICU. However, the rate of RRT is lower in patients with COVID-19 or ACE2-associated viruses when compared with patients infected with non-ACE2-binding viruses, which might partly be due to the lower frequencies of shock and use of vasopressors in these two virus groups. Prospective studies are necessary to demonstrate whether modulation of the ACE2 axis with Renin-Angiotensin System inhibitors impacts the rates of AKI and whether they are beneficial or harmful in COVID-19 patients.

MISE EN CONTEXTE: L'insuffisance rénale aiguë (IRA) est une complication potentiellement mortelle de la maladie à coronavirus-2019 (COVID-19). Obligatoire du Coronavirus 2 du Syndrome Respiratoire Aigu Sévère (SARS-CoV-2), le virus responsable du COVID-19, à son récepteur, l'enzyme de conversion de l'angiotensine 2 (ACE2), entraîne une entrée virale et peut provoquer une IRA. OBJECTIFS DE L'ÉTUDE: Nous avons effectué une revue systématique et une méta-analyse des fréquences de l'IRA et de la thérapie de remplacement renal (RRT) chez les patients COVID-19 gravement malades et a comparé ces fréquences avec les patients qui ont été infectés par des voies respiratoires virus qui lient ou régulent négativement l'ACE2 (virus associés à l'ACE2) et les virus qui ne régulent pas négativement ni ne lient l'ACE2 (virus non associés à l'ACE2). CADRE ET TYPE D'ÉTUDE: Revue systématique et méta-analyse. Des études d'observation sur le COVID-19 et d'autres infections virales respiratoires signalant une AKI et une RRT ont été incluses. Les critères d'exclusion étaient des articles non anglophones, des articles non évalués par des pairs, des articles de revue, des études incluant des patients moins de 18 ans, les études incluant moins de 10 patients et les études ne rapportant pas les taux d'IRA et de RRT. PATIENTS: Adultes COVID-19, syndrome respiratoire aigu sévère (SRAS), syndrome respiratoire du Moyen-Orient (MERS) et malades de la grippe. MESURES: Nous avons extrait les données suivantes des études incluses : auteur, année, lieu de l'étude, âge, sexe, race, diabète sucré, hypertension, maladie rénale chronique, état de choc, utilisation de vasopresseurs, mortalité, admission en unité de soins intensifs (USI), Mortalité en soins intensifs, AKI et RRT. MÉTHODOLOGIE: Nous avons systématiquement recherché dans PubMed et EMBASE les articles rapportant AKI ou RRT. AKI a été défini par les auteurs des études incluses. La maladie grave a été définie par l'admission aux soins intensifs. Nous avons effectué une méta-analyse à effets aléatoires pour calculer estimations regroupées pour le taux d'IRA et de RRT au sein de chaque groupe de virus à l'aide d'un modèle de régression logistique d'interception aléatoire. RÉSULTATS: Sur 23 655 patients hospitalisés et gravement malades COVID-19, les fréquences AKI n'étaient pas significativement différentes entre patients COVID-19 (51 %, intervalle de confiance à 95 % [IC] : 44 %-57 %) et patients gravement malades infectés par l'ACE2 associé (56 %, IC à 95 % : 37 % à 74 %, P = 0,610) ou des virus non associés à l'ACE2 (63 %, IC à 95 % : 43 % à 79 %, P = 0,255). Tarifs RRT groupés n'étaient pas non plus significativement différents entre les patients hospitalisés gravement malades atteints de COVID-19 (20 %, IC à 95 % : 16 % à 24 %) et virus associés à l'ACE2 (18 %, IC à 95 % : 8 % à 33 %, P = 0,747). Taux de RRT pour les virus associés au COVID-19 et à l'ACE2 étaient significativement différents (P < 0,001 pour les deux) des virus non associés à l'ACE2 (49 %, IC à 95 % : 44 % à 54 %). Après ajustement pour le choc ou l'utilisation de vasopresseurs, les taux d'IRA et de RRT n'étaient pas significativement différents entre les groupes. LIMITES DE L'ÉTUDE: Les limites de cette étude incluent l'hétérogénéité des définitions de l'IRA qui ont été utilisées pour différents virus études. Nous n'avons pas pu faire correspondre la gravité de l'infection ou faire une correspondance de propension entre les études. La plupart des études incluses ont été menées de manière rétrospective. Enfin, nous n'avons pas inclus les publications non anglophones. CONCLUSIONS: Nos résultats suggèrent que l'association virale ACE2 ne modifie pas de manière significative les taux d'IRA et de RRT parmi les patients gravement malades admis aux soins intensifs. Cependant, le taux de RRT est plus faible chez les patients atteints de COVID-19 ou associés à l'ACE2 virus par rapport aux patients infectés par des virus ne se liant pas à l'ACE2, ce qui pourrait être dû en partie à la plus faible fréquences de choc et utilisation de vasopresseurs dans ces deux groupes de virus. Des études prospectives sont nécessaires pour démontrer si la modulation de l'axe ACE2 avec les inhibiteurs du système rénine-angiotensine a un impact sur les taux d'IRA et si ells sont bénéfiques ou nocifs chez les patients COVID-19.

More Is Not Always Better: Coinfections with Defensive Symbionts Generate Highly Variable Outcomes.

Animal-associated microbes are highly variable, contributing to a diverse set of symbiont-mediated phenotypes. Given that host and symbiont genotypes, and their interactions, can impact symbiont-based phenotypes across environments, there is potential for extensive variation in fitness outcomes. Pea aphids, Acyrthosiphon pisum, host a diverse assemblage of heritable facultative symbionts (HFS) with characterized roles in host defense. Protective phenotypes have been largely studied as single infections, but pea aphids often carry multiple HFS species, and particular combinations may be enriched or depleted compared to expectations based on chance. Here, we examined the consequences of single infection versus coinfection with two common HFS exhibiting variable enrichment, the antiparasitoid Hamiltonella defensa and the antipathogen Regiella insecticola, across three host genotypes and environments. As expected, single infections with either H. defensa or R. insecticola raised defenses against their respective targets. Single infections with protective H. defensa lowered aphid fitness in the absence of enemy challenge, while R. insecticola was comparatively benign. However, as a coinfection, R. insecticola ameliorated H. defensa infection costs. Coinfected aphids continued to receive antiparasitoid protection from H. defensa, but protection was weakened by R. insecticola in two clones. Notably, H. defensa eliminated survival benefits conferred after pathogen exposure by coinfecting R. insecticola Since pathogen sporulation was suppressed by R. insecticola in coinfected aphids, the poor performance likely stemmed from H. defensa-imposed costs rather than weakened defenses. Our results reveal a complex set of coinfection outcomes which may partially explain natural infection patterns and suggest that symbiont-based phenotypes may not be easily predicted based solely on infection status.IMPORTANCE The hyperdiverse arthropods often harbor maternally transmitted bacteria that protect against natural enemies. In many species, low-diversity communities of heritable symbionts are common, providing opportunities for cooperation and conflict among symbionts, which can impact the defensive services rendered. Using the pea aphid, a model for defensive symbiosis, we show that coinfections with two common defensive symbionts, the antipathogen Regiella and the antiparasite Hamiltonella, produce outcomes that are highly variable compared to single infections, which consistently protect against designated enemies. Compared to single infections, coinfections often reduced defensive services during enemy challenge yet improved aphid fitness in the absence of enemies. Thus, infection with multiple symbionts does not necessarily create generalist aphids with "Swiss army knife" defenses against numerous enemies. Instead, particular combinations of symbionts may be favored for a variety of reasons, including their abilities to lessen the costs of other defensive symbionts when enemies are not present.

Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017

OBJECTIVE: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. PARTICIPANTS: A multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine. DESIGN/METHODS: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members. RESULTS: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2 < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence). CONCLUSIONS: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

Two-year follow-up of patients with septic shock presenting with low HDL: the effect upon acute kidney injury, death and estimated glomerular filtration rate.

BACKGROUND: Sepsis is associated with decreased levels of high-density lipoprotein (HDL) cholesterol. HDL has anti-inflammatory properties, and the use of Apo A-I mimetic peptides is associated with renal function improvement in animal models of sepsis. However, it is not known whether decreased HDL level results in impaired renal function in human sepsis. We investigated whether low levels of HDL conferred an increased risk of sepsis-associated acute kidney injury (AKI) or long-term decreased estimated glomerular filtration rate (eGFR) after sepsis. METHODS: HDL concentration (mg dL-1 ) was measured in plasma samples from 180 patients with septic shock at admission to the Emergency Department (ED). We divided the patients using median HDL as a cut-off value and assessed the frequency of sepsis-associated AKI and long-term decreased eGFR after sepsis. Univariate and multivariate analyses were performed. RESULTS: Patients with low HDL had a significantly greater frequency of KDIGO 2 or 3 sepsis-associated AKI [39/90 (43.3%) vs. 12/90 (13.3%), P < 0.001] and decreased long-term eGFR [24/58 (41.4%) vs. 11/57 (19.3%), P = 0.018] compared to those with high HDL. The adjusted OR for sepsis-associated AKI and decreased eGFR after sepsis in the lower HDL group was 2.80 (95% CI 1.08-7.25, P = 0.033) and 5.45 (95% CI 1.57-18.93, P = 0.008), respectively. CONCLUSION: Low HDL levels during sepsis are associated with increased risk of sepsis-associated AKI, and/or subsequent decreased eGFR. These results suggest that HDL may be involved and/or may be a marker of kidney injury during and after sepsis.

The Peptide Oxytocin Antagonist F-792, When Given Systemically, Does Not Act Centrally in Lactating Rats.

Oxytocin secreted by nerve terminals in the posterior pituitary has important actions for ensuring a successful outcome of pregnancy: it stimulates uterine contractions that lead to birth and it is essential in the milk-ejection reflex, enabling milk to be expelled from the mammary glands into the mouths of suckling young. Oxytocin also has important actions in the brain: released from dendrites of neurones that innervate the posterior pituitary, oxytocin auto-excites the neurones to fire action potentials in co-ordinated bursts, causing secretion of pulses of oxytocin. Central oxytocin actions are blocked by an oxytocin antagonist given into the brain and, consequently, milk transfer stops. Systemic peptide oxytocin antagonist (atosiban) treatment is used clinically in management of pre-term labour, a major obstetric problem. Hence, it is important to know whether an oxytocin antagonist given peripherally can enter the brain and interfere with central oxytocin actions. In the present study, we tested F792, a peptide oxytocin antagonist. In urethane-anaesthetised suckled rats, we show that the mammary gland responsiveness to oxytocin is blocked by i.v. injections of 7 µg/kg of F792, and the milk-ejection reflex is blocked when F792 is given directly into the brain at a dose of 0.2 µg. To critically test whether F792 given systemically can enter the brain, we recorded the suckling- and oxytocin-induced burst-firing of individual antidromically identified oxytocin neurones in the paraventricular nucleus. Given systemically at 100 µg/kg i.v., F792 acted only peripherally, blocking the milk-ejecting actions of oxytocin, but not the burst-firing of oxytocin neurones during suckling (n = 5 neurones in five rats). Hence, this peptide oxytocin antagonist does not enter the brain from the circulation to interfere with an essential oxytocin function in the brain. Furthermore, the functions of oxytocin in the brain evidently cannot be explored with a systemic peptide antagonist.

Older recipient age is paradoxically associated with a lower incidence of chronic GVHD in thymoglobulin recipients: a retrospective study exploring risk factors for GVHD in allogeneic transplantation with thymoglobulin GVHD prophylaxis.

Thymoglobulin (TG) given with conditioning for allogeneic haematopoietic SCT (alloHSCT) is effective in reducing the risk of acute and chronic GVHD (cGVHD). Whether conventional risk factors for GVHD apply to TG-conditioned alloHSCT is unknown. We retrospectively studied 356 adults from three centres who received TG 4.5 mg/kg prior to alloHSCT for haematologic malignancy. Donors were unrelated in 64%. At 3 years, OS was 61% (95% confidence interval (CI) 55-67%), cumulative incidence of relapse was 28% (95% CI 23-33%) and non-relapse mortality was 19% (14-24%). The cumulative incidences of grade 2-4, and grade 3-4 acute GVHD were 23% (95% CI 19-28%) and 10% (95% CI 6-13%), respectively. The cumulative incidence of cGVHD requiring systemic immunosuppression (cGVHD-IS) at 3 years was 32% (95% CI 27-37%). On multivariate analysis, counterintuitively, recipient age over 40 was associated with a significantly decreased risk of cGVHD-IS (P=0.001). We report for the first time a paradoxical association of older age with reduced cGVHD in TG recipients, and conclude that traditional risk factors for GVHD may behave differently in the context of pre-transplant TG.

Oxytocinase in the female rat hypothalamus: a novel mechanism controlling oxytocin neurones during lactation.

In addition to its peripheral actions, oxytocin released within the brain is important for birth and essential for milk ejection. The oxytocinase enzyme (placental leucine aminopeptidase; P-LAP) is expressed both peripherally and centrally. P-LAP controls oxytocin degradation in the uterus, placenta and plasma during pregnancy, although its role in the hypothalamus is unclear. We investigated P-LAP expression and activity in the hypothalamus in virgin, pregnant and lactating rats, as well as its role in vivo during the milk-ejection reflex. P-LAP mRNA and protein were expressed in magnocellular neurones of the supraoptic (SON) and paraventricular (PVN) nuclei. Oxytocin neurones co-expressed P-LAP without strong subcellular co-localisation of oxytocin and P-LAP, indicating that they are packaged in separate vesicles. Examination of the intracellular distribution of oxytocin and P-LAP showed a redistribution of P-LAP to within 1 µm of the plasma membrane in the somata of oxytocin neurones during lactation. Both P-LAP mRNA expression and hypothalamic leucyl/cystinyl aminopeptidase activity in the soluble fraction were higher during lactation than in late pregnant or virgin states. Inhibition of central enzyme activity by i.c.v. injection of amastatin in anaesthetised suckling mothers increased the frequency of reflex milk ejections. Because hypothalamic P-LAP expression and activity increase in lactation, and the prevention of its action mimics central oxytocin administration, we conclude that P-LAP regulates auto-excitatory oxytocin actions during the suckling-induced milk-ejection reflex.

Prokaryote populations of extant microbialites along a depth gradient in Pavilion Lake, British Columbia, Canada.

Pavilion Lake in British Columbia, Canada, is home to modern-day microbialites that are actively growing at multiple depths within the lake. While microbialite morphology changes with depth and previous isotopic investigations suggested a biological role in the formation of these carbonate structures, little is known about their microbial communities. Microbialite samples acquired through the Pavilion Lake Research Project (PLRP) were first investigated for phototrophic populations using Cyanobacteria-specific primers and 16S rRNA gene cloning. These data were expounded on by high-throughput tagged sequencing analyses of the general bacteria population. These molecular analyses show that the microbial communities of Pavilion Lake microbialites are diverse compared to non-lithifying microbial mats also found in the lake. Phototrophs and heterotrophs were detected, including species from the recently described Chloroacidobacteria genus, a photoheterotroph that has not been previously observed in microbialite systems. Phototrophs were shown as the most influential contributors to community differences above and below 25 meters, and corresponding shifts in heterotrophic populations were observed at this interface as well. The isotopic composition of carbonate also mirrored this shift in community states. Comparisons to previous studies indicated this population shift may be a consequence of changes in lake chemistry at this depth. Microbial community composition did not correlate with changing microbialite morphology with depth, suggesting something other than community changes may be a key to observed variations in microbialite structure.

Systemic leptin increases the electrical activity of supraoptic nucleus oxytocin neurones in virgin and late pregnant rats.

In the rat hypothalamus, fasting attenuates the expression of oxytocin and this can be reversed by exogenous leptin administration. In the present study, we investigated the effects of systemically administered leptin on the electrical activity of magnocellular neurones in the supraoptic nucleus of urethane-anaesthetised rats. In virgin female rats, systemic leptin significantly excited identified oxytocin neurones with no detected effects on the patterning of activity, as reflected by hazard function analyses. The lowest dose that was consistently effective was 100 µg/i.v., and this dose had no significant effect on vasopressin neurones. In virgin rats fasted overnight, the spontaneous firing rate of oxytocin neurones was significantly lower than in unfasted rats, although leptin had a similar excitatory effect as in unfasted rats. In late pregnant rats (days 19-21 of pregnancy), spontaneous firing rates of oxytocin neurones were higher than in virgins, and the initial response to leptin was similar to that in virgin rats, although the increase in activity was more persistent. In fasted pregnant rats, the mean spontaneous firing rate of oxytocin neurones was again lower than in unfasted rats, although leptin had no significant effect even at the higher dose of 1 mg/rat. Thus, fasting reduced the spontaneous firing rates of oxytocin neurones in nonpregnant rats, and this effect could be reversed by the excitatory effects of leptin. Pregnant rats showed some evidence of leptin resistance but only after an overnight fast.

Anti-thymocyte globulins capable of binding to T and B cells reduce graft-vs-host disease without increasing relapse.

Anti-thymocyte globulin (ATG) is polyclonal, containing Ab specificities capable of binding to various immune-cell subsets implicated in the pathogenesis of GVHD, including T cells, B cells, natural killer cells, monocytes/macrophages, neutrophils and DC. We wished to determine which ATG specificities are important for GVHD prevention. We measured day 7 serum levels of 23 ATG specificities in 120 hematopoietic cell transplant recipients whose myeloablative conditioning included 4.5 mg/kg ATG (thymoglobulin). High levels of ATG specificities capable of binding to T- and B-cell subsets were associated with a low likelihood of acute GVHD (aGVHD). High levels of these ATG specificities were associated with increased rates of viral but not bacterial or fungal infections. They were not associated with an increased risk of malignancy relapse; on the contrary, high levels of ATG specificities capable of binding to regulatory T cells and invariant NKT cells were associated with a low risk of relapse. In conclusion, high levels of ATG antibodies to Ag(s) expressed on T and B cells are associated with a low risk of aGVHD and a high risk of viral but not bacterial or fungal infections. These antibodies have neutral or beneficial effects on relapse.

IL15 levels on day 7 after hematopoietic cell transplantation predict chronic GVHD.

Chronic GVHD (cGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). As preemptive therapy might be efficacious if administered early post transplant, we set out to determine whether cGVHD can be predicted from the serum level of a biomarker on day 7 or 28. In a discovery cohort of 153 HCT recipients conditioned with BU, fludarabine and rabbit antithymocyte globulin (ATG), we determined serum levels of B-cell-activating factor, vascular endothelial growth factor, soluble TNF-α receptor 1, soluble IL2 receptor α, IL5, IL6, IL7, IL15, γ-glutamyl transpeptidase, cholinesterase, total protein, urea and ATG. Patients with low levels of IL15 (<30.6 ng/L) on day 7 had 2.7-fold higher likelihood of developing significant cGVHD (needing systemic immunosuppressive therapy) than patients with higher IL15 levels (P<0.001). This was validated in a validation cohort of 105 similarly-treated patients; those with low IL15 levels had 3.7-fold higher likelihood of developing significant cGVHD (P=0.001). Low IL15 was not associated with relapse; it trended to be associated with acute GVHD and was associated with low infection rates. In conclusion, low IL15 levels on day 7 are predictive of cGVHD, and thus could be useful in guiding preemptive therapy.

Allopregnanolone and induction of endogenous opioid inhibition of oxytocin responses to immune stress in pregnant rats.

In virgin rats, systemic administration of interleukin (IL)-1ß (i.e. to mimic infection), increases oxytocin secretion and the firing rate of oxytocin neurones in the supraoptic nucleus (SON). However, in late pregnancy, stimulated oxytocin secretion is inhibited by an endogenous opioid mechanism, preserving the expanded neurohypophysial oxytocin stores for parturition and minimising the risk of preterm labour. Central levels of the neuroactive metabolite of progesterone, allopregnanolone, increase during pregnancy and allopregnanolone acting on GABA(A) receptors on oxytocin neurones enhances inhibitory transmission. In the present study, we tested whether allopregnanolone induces opioid inhibition of the oxytocin system in response to IL-1ß in late pregnancy. Inhibition of 5α-reductase (an allopregnanolone-synthesising enzyme) with finasteride potentiated IL-1ß-evoked oxytocin secretion in late pregnant rats, whereas allopregnanolone reduced the oxytocin response in virgin rats. IL-1ß increased the number of magnocellular neurones in the SON and paraventricular nucleus (PVN) expressing Fos (an indicator of neuronal activation) in virgin but not pregnant rats. In immunoreactive oxytocin neurones in the SON and PVN, finasteride increased IL-1ß-induced Fos expression in pregnant rats. Conversely, allopregnanolone reduced the number of magnocellular oxytocin neurones activated by IL-1ß in virgin rats. Treatment with naloxone (an opioid antagonist) greatly enhanced the oxytocin response to IL-1ß in pregnancy, and finasteride did not enhance this effect, indicating that allopregnanolone and the endogenous opioid mechanisms do not act independently. Indeed, allopregnanolone induced opioid inhibition over oxytocin responses to IL-1ß in virgin rats. Thus, in late pregnancy, allopregnanolone induces opioid inhibition over magnocellular oxytocin neurones and hence on oxytocin secretion in response to immune challenge. This mechanism will minimise the risk of preterm labour and prevent the depletion of neurohypophysial oxytocin stores, which are required for parturition.

Inhibition of 5α-reductase activity in late pregnancy decreases gestational length and fecundity and impairs object memory and central progestogen milieu of juvenile rat offspring.

Psychological, physical and/or immune stressors during pregnancy are associated with negative birth outcomes, such as preterm birth and developmental abnormalities. In rodents, prenatal stressors can alter the expression of 5α-reductase enzymes in the brain and may influence cognitive function and anxiety-type behaviour in the offspring. Progesterone plays a critical role in maintaining gestation. In the present study, it was hypothesised that 5α-reduced progesterone metabolites influence birth outcomes and/or the cognitive and neuroendocrine function of the offspring. 5α-Reduced steroids were manipulated in pregnant Long-Evans rats via the administration of vehicle, the 5α-reduced, neuroactive metabolite of progesterone, 5α-pregnan-3α-ol-20-one (3α,5α-THP, allopregnanolone; 10 mg/kg/ml, s.c.), or the 5α-reductase inhibitor, finasteride (50 mg/kg/ml, s.c.), daily from gestational days 17-21. Compared to vehicle or 3α,5α-THP treatment, finasteride, significantly reduced the length of gestation and the number of pups per litter found in the dams' nests after parturition. The behaviour of the offspring in hippocampus-dependent tasks (i.e. object recognition, open field) was examined on post-natal days 28-30. Compared to vehicle-exposed controls, prenatal 3α,5α-THP treatment significantly increased motor behaviour in females compared to males, decreased progesterone content in the medial prefrontal cortex (mPFC) and diencephalon, increased 3α,5α-THP and 17ß-oestradiol content in the hippocampus, mPFC and diencephalon, and significantly increased serum corticosterone concentrations in males and females. Prenatal finasteride treatment significantly reduced object recognition, decreased hippocampal 3α,5α-THP content, increased progesterone concentration in the mPFC and diencephalon, and increased serum corticosterone concentration in female (but not male) juvenile offspring, compared to vehicle-exposed controls. Thus, inhibiting the formation of 5α-reduced steroids during late gestation in rats reduces gestational length, the number of viable pups per litter, and impairs cognitive and neuroendocrine function in the juvenile offspring.

PIERS proteinuria: relationship with adverse maternal and perinatal outcome.

OBJECTIVE: To examine the ability of three different proteinuria assessment methods (urinary dipstick, spot urine protein:creatinine ratio [Pr/Cr], and 24-hour urine collection) to predict adverse pregnancy outcomes. METHODS: We performed a prospective multicentre cohort study, PIERS (Preeclampsia Integrated Estimate of RiSk), in seven academic tertiary maternity centres practising expectant management of preeclampsia remote from term in Canada, New Zealand, and Australia. Eligible women were those admitted with preeclampsia who had at least one antenatal proteinuria assessment by urinary dipstick, spot urine Pr/Cr ratio, and/or 24-hour urine collection. Proteinuria assessment was done either visually at the bedside (by dipstick) or by hospital clinical laboratories for spot urine Pr/Cr and 24-hour urine collection. We calculated receiver operating characteristic area under the curve (95% CI) for each proteinuria method and each of the combined adverse maternal outcomes (within 48 hours) or adverse perinatal outcomes (at any time). Models with AUC ≥ 0.70 were considered of interest. Analyses were run for all women who had each type of proteinuria assessment and for a cohort of women ("ALL measures") who had all three proteinuria assessments. RESULTS: More women were proteinuric by urinary dipstick (≥ 2+, 61.4%) than by spot urine Pr/Cr (≥ 30 g/mol, 50.4%) or 24-hour urine collection (≥ 0.3g/d, 34.7%). Each proteinuria measure evaluated had some discriminative power, and dipstick proteinuria (categorical) performed as well as other methods. No single method was predictive of adverse perinatal outcome. CONCLUSION: The measured amount of proteinuria should not be used in isolation for decision-making in women with preeclampsia. Dipstick proteinuria performs as well as other methods of assessing proteinuria for prediction of adverse events.

Influence of comorbidities on transplant outcomes in patients aged 50 years or more after myeloablative conditioning incorporating fludarabine, BU and ATG.

Non-myeloablative (MA) and reduced intensity allo-SCT regimens are offered to older patients and/or those with comorbidities because the morbidity and mortality attributable to fully MA conditioning is thought to be unacceptably high. A total of 207 patients aged 50-66 years were treated between 1999 and 2008 with SCT after MA conditioning with fludarabine 50 mg/m(2) daily × 5 and i.v. BU 3.2 mg/kg daily × 4.90 (43%) had additional TBI 200 cGy × 2. GVHD prophylaxis was CsA, MTX and thymoglobulin (4.5 mg/kg total dose). As defined by the hematopoietic cell transplantation co-morbidity index (HCT-CI) scoring system 117 (57%) pts scored 0 and 90 (43%) 1. At 5 years OS was 39 vs 54% (P=0.008), disease-free survival 38 vs 49% (P=0.03), TRM 39 vs 19% (P=0.003) and relapse 36 vs 39% (P=ns) in those with scores of 0 and 1, respectively. Multivariate analysis confirmed the influence of HCT-CI scores on TRM (subhazard ratios=2.29; 95% confidence interval=1.29-4.08; P=0.005). We conclude that comorbidities as assessed by the HCT-CI do influence TRM with this regimen but that age alone should not be an indication to prefer a less intense protocol.

High incidence of post transplant lymphoproliferative disorder after antithymocyte globulin-based conditioning and ineffective prediction by day 28 EBV-specific T lymphocyte counts.

The largest study on post-allogeneic hematopoietic cell transplant lymphoproliferative disorder (PTLD) epidemiology showed a cumulative incidence of 1.7% in patients receiving antithymocyte globulin (ATG). We had noted an apparently higher incidence in our transplant recipients whose conditioning included ATG. Therefore, we formally determined the incidence of PTLD through chart review. We also evaluated whether counts of EBV-specific T lymphocytes measured by cytokine flow cytometry could identify patients at risk of developing PTLD. Among 307 allogeneic transplant recipients, 25 (8.1%) developed PTLD. This was biopsy proven in 11 patients, and was fatal in seven patients. Patient age, EBV serostatus, donor type/match or GVHD did not influence PTLD risk significantly. Median onset of PTLD was 55 (range, 28-770) days post transplant. Day 28 EBV-specific T lymphocyte counts were not significantly different in 11 patients who developed PTLD and 31 non-PTLD patients matched for published risk factors for PTLD. In summary, when using conditioning with thymoglobulin 4.5 mg/kg, the incidence of PTLD is relatively high and cannot be predicted by day 28 cytokine flow cytometry-determined EBV-specific T lymphocyte counts. Thus, in this scenario PTLD prevention may be warranted, for example, using EBV DNAemia monitoring with preemptive therapy.