Surgical management of giant pituitary neuroendocrine tumors: Meta-analysis and consensus statement on behalf of the EANS skull base section.

The optimal surgical treatment for giant pituitary neuroendocrine tumors(GPitNETs) is debated. The aim of this paper is to optimize the surgical management of these patients and to provide a consensus statement on behalf of the EANS Skull Base Section. We constituted a task force belonging to the EANS skull base committee to define some principles for the management of GPitNETs. A systematic review was performed according to PRISMA guidelines to perform a meta-analysis on surgical series of GPitNETs. Weighted summary rates were obtained for the pooled extent of resection and according to the surgical technique. These data were discussed to obtain recommendations after evaluation of the selected articles and discussion among the experts. 20articles were included in our meta-analysis, for a total of 1263 patients. The endoscopic endonasal technique was used in 40.3% of cases, the microscopic endonasal approach in 34% of cases, transcranial approaches in 18.7% and combined approaches in 7% of cases. No difference in terms of gross total resection (GTR) rate was observed among the different techniques. Pooled GTR rate was 36.6%, while a near total resection (NTR) was possible in 45.2% of cases. Cavernous sinus invasion was associated with a lower GTR rate (OR: 0.061). After surgery, 35% of patients had endocrinological improvement and 75.6% had visual improvement. Recurrent tumors were reported in 10% of cases. After formal discussion in the working group, we recommend the treatment of G-PitNETs tumors with a more complex and multilobular structure in tertiary care centers. The endoscopic endonasal approach is the first option of treatment and extended approaches should be planned according to extension, morphology and consistency of the lesion. Transcranial approaches play a role in selected cases, with a multicompartmental morphology, subarachnoid invasion and extension lateral to the internal carotid artery and in the management of residual tumor apoplexy

Placental CD4(+) T cells from preeclamptic patients cause autoantibodies to the angiotensin II type I receptor and hypertension in a pregnant rat model of preeclampsia

AIM: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4(+) T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4(+) T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4(+) T cells from normal pregnant (NP) women. However, the role of PE CD4(+) T cells to cause AT1-AA as a mechanism of hypertension is not known. Our goal was to determine if PE CD4(+) T cells stimulate AT1-AA in pregnant nude-athymic rats. METHODS: CD4(+) T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4(+) T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4(+) T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained. RESULTS: MAP [114 ± 1 mmHg (n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4(+) T cells compared to NP nude + NP CD4(+) T cells [98 ± 2 mmHg (n = 7, P < 0.05) and 1.3 ± 0.9 bpm (n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4(+) T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4(+) T cells. CONCLUSIONS: These results show that placental CD4(+) T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy

Theory of the first-order isostructural valence phase transitions in mixed valence compounds YbIn_{x}Ag_{1-x}Cu_{4}

For describing the first-order isostructural valence phase transition in mixed valence compounds we develop a new approach based on the lattice Anderson model. We take into account the Coulomb interaction between localized f and conduction band electrons and two mechanisms of electron-lattice coupling. One is related to the volume dependence of the hybridization. The other is related to local deformations produced by f- shell size fluctuations accompanying valence fluctuations. The large f -state degeneracy allows us to use the 1/N expansion method. Within the model we develop a mean-field theory for the first-order valence phase transition in YbInCu_{4}. It is shown that the Coulomb interaction enhances the exchange interaction between f and conduction band electron spins and is the driving force of the phase transition. A comparison between the theoretical calculations and experimental measurements of the valence change, susceptibility, specific heat, entropy, elastic constants and volume change in YbInCu_{4} and YbAgCu_{4} are presented, and a good quantitative agreement is found. On the basis of the model we describe the evolution from the first-order valence phase transition to the continuous transition into the heavy-fermion ground state in the series of compounds YbIn_{1-x}Ag_{x}Cu_{4}. The effect of pressure on physical properties of YbInCu_{4} is studied and the H-T phase diagram is found.Comment: 17 pages RevTeX, 9 Postscript figures, to be submitted to Phys.Rev.

Blockade of CD40 ligand for intercellular communication reduces hypertension, placental oxidative stress, and AT1-AA in response to adoptive transfer of CD4(+) T lymphocytes from RUPP rats

Preeclampsia (PE) is associated with altered immune activation during pregnancy. We have previously shown that adoptive transfer of CD4+ T cells from the reduced uterine perfusion pressure (RUPP) rat model of PE increases blood pressure, oxidative stress (ROS), and inflammation in normal pregnant recipient rats. The objective of this study was to determine if blockade of communication via the CD40-CD40 ligand (CD40L) interaction between placental ischemia-induced CD4+ T cells with endogenous normal pregnant (NP) cells would improve pathophysiology that was previously observed in NP recipient rats of RUPP CD4+ T cells. Splenic CD4+ T lymphocytes were magnetically separated, incubated with 2.5 {mu}g/ml anti-CD40 ligand ({alpha}CD40L) overnight, and transferred into NP rats on day 12 of gestation (NP+RUPP CD4+ T+anti-CD40L). On day 19 of gestation, blood pressure (MAP), blood, and tissues were collected. MAP was 99 +/- 2 in NP (n = 13), 116 +/- 4 in NP+RUPP CD4+ T cells (n = 7; P < 0.01); MAP only increased to 104 +/- 2 in NP+RUPP CD4+ T cells+CD40L (n = 24) (P < 0.05 vs. NP+RUPP CD4+ T cells). Mechanisms of hypertension in response to RUPP CD4+ T cells include endothelin-1 (ET-1), ROS, and angiotensin II type I receptor (AT1-AA) were analyzed. Inhibition of CD40L binding reduced placental ET-1 to 2.3-fold above NP rats and normalized placental ROS from 318.6 +/- 89 in NP+RUPP CD4+ T cells (P < 0.05) to 118.7 +/- 24 in NP+RUPP CD4+ T+anti-CD40L (P < 0.05). AT1-AA was also normalized with inhibition of CD40L. These data suggest that placental ischemia-induced T-cell communication via the CD40L is one important mechanism leading to much of the pathophysiology of PE

Skin care interventions in infants for preventing eczema and food allergy

Background Eczema and food allergy are common health conditions that usually begin in early childhood and often occur in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective for preventing eczema or food allergy. Objectives Primary objective To assess the effects of skin care interventions such as emollients for primary prevention of eczema and food allergy in infants. Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy. Search methods We performed an updated search of the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase in September 2021. We searched two trials registers in July 2021. We checked the reference lists of included studies and relevant systematic reviews, and scanned conference proceedings to identify further references to relevant randomised controlled trials (RCTs). Selection criteria We included RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (≤ 12 months) without pre‐existing eczema, food allergy, or other skin condition. Eligible comparisons were standard care in the locality or no treatment. Types of skin care interventions could include moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow‐up was required. Data collection and analysis This is a prospective individual participant data (IPD) meta‐analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E‐mediated food allergy by one to three years, both measured at the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician‐assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen. Main results We identified 33 RCTs comprising 25,827 participants. Of these, 17 studies randomising 5823 participants reported information on one or more outcomes specified in this review. We included 11 studies, randomising 5217 participants, in one or more meta‐analyses (range 2 to 9 studies per individual meta‐analysis), with 10 of these studies providing IPD; the remaining 6 studies were included in the narrative results only. Most studies were conducted at children's hospitals. Twenty‐five studies, including all those contributing data to meta‐analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta‐analyses recruited infants at high risk of developing eczema or food allergy, although the definition of high risk varied between studies. Durations of intervention and follow‐up ranged from 24 hours to three years. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported information on our prespecified outcomes, 13 assessed emollients. We assessed most of the evidence in the review as low certainty and had some concerns about risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. We assessed the evidence for the primary food allergy outcome as high risk of bias due to the inclusion of only one trial, where findings varied based on different assumptions about missing data. Skin care interventions during infancy probably do not change the risk of eczema by one to three years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; risk difference 5 more cases per 1000 infants, 95% CI 28 less to 47 more; moderate‐certainty evidence; 3075 participants, 7 trials) or time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate‐certainty evidence; 3349 participants, 9 trials). Skin care interventions during infancy may increase the risk of IgE‐mediated food allergy by one to three years of age (RR 2.53, 95% CI 0.99 to 6.49; low‐certainty evidence; 976 participants, 1 trial) but may not change risk of allergic sensitisation to a food allergen by age one to three years (RR 1.05, 95% CI 0.64 to 1.71; low‐certainty evidence; 1794 participants, 3 trials). Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low‐certainty evidence; 1171 participants, 1 trial); however, this was only seen for cow’s milk, and may be unreliable due to over‐reporting of milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.33, 95% CI 1.01 to 1.75; risk difference 17 more cases per 1000 infants, 95% CI one more to 38 more; moderate‐certainty evidence; 2728 participants, 6 trials) and may increase the risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low‐certainty evidence; 2538 participants, 4 trials) and stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low‐certainty evidence; 343 participants, 4 trials), although CIs for slippages and stinging/allergic reactions were wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses showed that the effects of interventions were not influenced by age, duration of intervention, hereditary risk, filaggrin (FLG) mutation, chromosome 11 intergenic variant rs2212434, or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and eczema or food allergy development. Authors' conclusions Based on low‐ to moderate‐certainty evidence, skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema; may increase risk of food allergy; and probably increase risk of skin infection. Further study is needed to understand whether different approaches to infant skin care might prevent eczema or food allergy

Reduced uterine perfusion pressure T-helper 17 cells cause pathophysiology associated with preeclampsia during pregnancy

Preeclampsia is associated with chronic inflammation and an imbalance among T-helper cell subtypes with an increase in T-helper 17 (TH17) cells. The objective of this study was to determine a role for TH17s from the RUPP rat model of preeclampsia to cause hypertension and chronic inflammation during pregnancy. CD4+/CD25- T cells were isolated from rat spleens, cultured in TH17 media, and were verified as TH17s via flow cytometry. On day 12 of gestation, 1x106 TH17 cells from RUPP rats were adoptively transferred into NP rats, carotid catheters inserted on day 18, and on day 19 mean arterial pressure (MAP) was recorded, serum and plasma were collected, and oxidative stress and AT1-AA production were analyzed. MAP increased from 100.3+/-1.7 mmHg in NP (n=17), to 124.8±2.1 mmHg in RUPP (n=22, P<0.0001) and to 110.8+/-2.8 mmHg in NP+RUPP TH17 (n=11). Pup weights in NP+RUPP TH17s were decreased to 1.92+/-0.09 g from 2.39+/-0.14 in NP rats (p<0.01). AT1-AA significantly increased from 0.1+/-0.2 beats/min in NP to 15.6+/-0.7 beats/min in NP+RUPP TH17s. IL-6 was 22.3+/-5.7 pg/mL in NP and increased to 60.45+/-13.8 pg/mL in RUPP (p<0.05) and 75.9 +/-6.8 pg/mL in NP+RUPP TH17 rats (p<0.01). Placental and renal oxidative stress were 238+/-27.5 and 411+/-129.9 RLUs/min/mg in NP and 339±104.6 and 833±331.1 RLUs/min/mg in NP+RUPP TH17. In conclusion, RUPP TH17 cells induced intrauterine growth restriction and increased blood pressure, AT1-AA, IL-6, and tissue oxidative stress when transferred to NP rats, indicating a role for autoimmune associated TH17 cells, to cause much of the pathophysiology associated with preeclampsia

Progesterone supplementation attenuates hypertension and the autoantibody to the angiotensin II type I receptor in response to elevated interleukin-6 during pregnancy

BACKGROUND: Preeclampsia is a multi-system disorder recognized as hypertension with proteinuria developing after 20 weeks gestation. Preeclampsia is associated with chronic immune activation characterized by increased T and B lymphocytes, cytokines and antibodies activating the angiotensin II type I receptor (AT1-AA). Hypertension in response to elevated Interleukin 6 (IL-6) during pregnancy occurs with increased renin activity, AT1-AA and reduced kidney function. STUDY DESIGN: We aim to determine whether 17-alpha-hydroxyprogesterone caproate (17-OHPC), progesterone, improved inflammatory pathways during elevated IL-6 in pregnant rats. IL-6 (5ng/day) was infused via miniosmotic pumps into normal pregnant rats (NP) beginning on day 14 of gestation and 17-OHP (3.32mg/kg) was diluted in normal saline and injected on day 18. Blood pressure (MAP) determination and serum collection were performed on day 19 of gestation. RESULTS: MAP in NP was 100+3mmHg which increased with IL-6 to 112+4mmHg, p <0.05. Pregnant rats given 17-OHP alone had a MAP of 99+3mmHg and MAP increased to 103+2 mmHg in IL-6+17-OHP. AT1-AA was 1.2+0.5 bpm in NP rats, increased to 17+9 bpm with IL-6 infusion but administration of 17-OHP significantly blunted AT1-AA to 4+0.8bpm in NP+IL-6+17-OHP. Total circulating nitrate/nitrite was significantly decreased and placental Ser1177-P-eNOS/eNOS was lowered with IL-6 infusion. 17 OHP supplementation significantly improved placental Ser1177-P-eNOS/eNOS however, circulating nitrate/nitrite was unchanged with 7OHPC supplementation. CONCLUSION: This study illustrates that 17-OHP attenuated hypertension, decreased AT1-AA activity and improved placental nitric oxide in response to elevated IL-6 during pregnancy and could lend hope to a new potential therapeutic for preeclampsia

Interleukin-4 supplementation improves the pathophysiology of hypertension in response to placental ischemia in RUPP rats

Preeclampsia (PE) is characterized by chronic inflammation, elevated agonistic autoantibodies to the Angiotensin II type 1 receptor (AT1-AA), ET-1, and uterine artery resistance index (UARI) during pregnancy. Previous studies report an imbalance among immune cells with TH2 being decreased during PE. We hypothesized that Interleukin-4 (IL-4) would increase TH2s and improve the pathophysiology observed in response to placental ischemia during pregnancy. IL-4, 600 ng/day, was administered via a mini-osmotic pump on day 14 of gestation into normal pregnant (NP) and RUPP rats. Carotid catheters were inserted and Doppler ultrasound performed on gestation day 18. Blood pressure (MAP), TNF-α, IL-6, AT1-AA, NK cells, TH2 and B cells were measured on GD 19. MAP in normal pregnant (NP) rats (n=9) was 97 + 2, 101 + 3 in NP+IL-4 rats (n=14), 137 + 4 mmHg in RUPP rats (n=8), which improved to 108 + 3 mmHg in RUPP+IL-4 rats (n=17), p< 0.05. UARI was 0.5+0.03 in NP, 0.8 in RUPP and normalized to 0.5 in RUPP+IL-4 rats, p< 0.05. Plasma nitrate nitrite levels increased in RUPP+IL-4 rats while placental PPET-1 expression, plasma TNF-α and IL-6 and AT1-AA decreased in RUPP+IL-4 rats compared to untreated RUPPs, p< 0.05. Circulating B cells and placental cytolytic NK cells decreased after IL-4 administration while TH2 cells were increased in RUPP+IL-4 treated rats compared to RUPP control rats. This study illustrates IL-4 decreased inflammation and improved TH2 numbers in RUPP rats which ultimately improved hypertension in response to placental ischemia during pregnancy