The Effects of Human Immunodeficiency Virus Type 1 (HIV-1) Antigen-Expanded Specific T-Cell Therapy and Vorinostat on Persistent HIV-1 Infection in People With HIV on Antiretroviral Therapy.

BACKGROUND: The histone deacetylase inhibitor vorinostat (VOR) can reverse human immunodeficiency virus type 1 (HIV-1) latency in vivo and allow T cells to clear infected cells in vitro. HIV-specific T cells (HXTCs) can be expanded ex vivo and have been safely administered to people with HIV (PWH) on antiretroviral therapy. METHODS: Six PWH received infusions of 2 × 107 HXTCs/m² with VOR 400 mg, and 3 PWH received infusions of 10 × 107 HXTCs/m² with VOR. The frequency of persistent HIV by multiple assays including quantitative viral outgrowth assay (QVOA) of resting CD4+ T cells was measured before and after study therapy. RESULTS: VOR and HXTCs were safe, and biomarkers of serial VOR effect were detected, but enhanced antiviral activity in circulating cells was not evident. After 2 × 107 HXTCs/m² with VOR, 1 of 6 PWH exhibited a decrease in QVOA, and all 3 PWH exhibited such declines after 10 × 107 HXTCs/m² and VOR. However, most declines did not exceed the 6-fold threshold needed to definitively attribute decline to the study intervention. CONCLUSIONS: These modest effects provide support for the strategy of HIV latency reversal and reservoir clearance, but more effective interventions are needed to yield the profound depletion of persistent HIV likely to yield clinical benefit. Clinical Trials Registration. NCT03212989.

Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

BACKGROUND: Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODS: In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTS: We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONS: Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

Ben Pimlott Memorial Lecture 2018The Women's Suffrage Movement in the Balfour Family.

Given on the centenary of women's suffrage, this lecture explores the tensions and conflicts the claim for the vote raised among elite women already enmeshed in parliamentary and political circles. Drawing on the unbuttoned and sometimes angry correspondence among A.J. Balfour's suffragist sisters-in-law Lady Frances Balfour and Lady Betty Balfour, Frances' collaborator (and suffragist leader) Millicent Fawcett, Lady Betty's militant suffragette sister Lady Constance Lytton, and their old friend (and wife of the anti-suffragist Prime Minister) Margot Asquith, it explores the appeal but also the costs of this democratic claim for such "incorporated" women - and explains why some nevertheless supported it.

Preclinical safety, pharmacokinetics, and pharmacodynamics of recombinant human interleukin-21 in cynomolgus macaques (Macaca fascicularis).

Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models. Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described. The rIL-21 (≤3.0 mg/kg per dose) was given intravenously to cynomolgus monkeys (Macaca fascicularis) once daily for 5 days, followed by 9 nondosing days (1 cycle) for ≤4 cycles. The rIL-21 pharmacokinetics was dose-dependent. Accumulation was not observed after repeated dosing, consistent with the short elimination half-life (t (1/2,λz); 0.4-0.8 hours). Safety findings included cyclical anemia and thrombocytopenia, clinical pathology changes consistent with acute-phase response, leukocyte infiltrates in hepatic sinusoids, and sporadic serum transaminase elevations (typically <3 times upper-limit of normal); all were reversible upon cessation of treatment. Decreased pharmacodynamic responses with time corresponded to the development of anti-rIL-21 antibodies; effects varied among individuals and were dose-dependent. These studies demonstrated rIL-21 to be generally well-tolerated when administered to cynomolgus monkeys, and all adverse effects were reversible upon treatment cessation. However, development of anti-rIL-21 antibodies may limit the use of this species in long-term studies.

Hormone therapy modulates ET(A) mRNA expression in the aorta of ovariectomised New Zealand White rabbits.

OBJECTIVE: To study the effect of 17beta-estradiol (E(2)) or conjugated equine estrogens (CEE) alone and in combination with norethisterone acetate (NETA) or medroxyprogesterone acetate (MPA) on the endothelin-1 (ET-1) system. METHODS: New Zealand White rabbits were treated with E(2), CEE, E(2) + NETA, CEE + MPA or placebo. The thoracic aorta and the epicardial coronary artery were used for mRNA expression and myograph analyses, respectively. RESULTS: E(2) and CEE alone significantly reduced ET-1 receptor subtype A (ET(A)) mRNA expression compared with placebo treatment. The E(2)-induced reduction in ET(A) mRNA expression persisted with the co-administration of NETA, but the CEE induced reduction in ET(A) mRNA expression was not maintained with the co-administration of MPA. Treatment with CEE alone significantly increased endotelin-1 converting enzyme (ECE) mRNA expression and CEE combined with MPA reduced prepro-endothelin-1 (ppET-1) mRNA expression when compared with placebo. ET-1 receptor subtype B mRNA expression and ET-1 induced vasocontraction was unaffected by treatment. CONCLUSIONS: E(2) and CEE treatment exert potentially beneficial vascular effects through regulation of the ET(A) receptor. The effect was maintained with the co-administration of NETA, but not MPA. The differential effects of specific hormone components may explain the variable effects of hormone therapy on the arterial wall.

Progestins oppose the effects of estradiol on the endothelin-1 receptor type B in coronary arteries from ovariectomized hyperlipidemic rabbits.

OBJECTIVE: Progestins may be associated with the adverse cardiovascular outcomes observed with estrogen plus progestogen therapy, but the mechanism is not resolved. In this study we examined the effect of 17beta-estradiol (E2) alone and in combination with two progestins on the endothelin-1 (ET-1) system in coronary arteries. DESIGN: Watanabe heritable hyperlipidemic rabbits were treated orally with either E2 (4 mg/d), medroxyprogesterone acetate (MPA) (10 mg/d), norethisterone acetate (NETA) (2 mg/d), E2 + MPA, E2 + NETA, or placebo for 16 weeks (n=10 in each group). Coronary arteries were used for mRNA and myograph analyses. RESULTS: E2 alone but not in combination with MPA or NETA increased ETB mRNA expression in coronary arteries. Accordingly, E2 alone but not in combination with MPA or NETA reduced the maximal contraction to ET-1, and the reduction was sustained after ETA but not after ETB blockade. E2 reduced preproendothelin-1 mRNA expression; however, this effect was not blunted by MPA or NETA. ETA and ET-converting enzyme-1 mRNA expression was unaffected by treatment. CONCLUSIONS: The data suggest that long-term E2 treatment selectively attenuates ET-1-induced vasoconstriction, possibly by increasing ETB gene expression in rabbit coronary arteries and that this effect is abolished by the two progestins investigated. This observation may help to explain how progestins oppose the supposed beneficial effects of estrogen on the arterial wall.

Medroxyprogesterone acetate attenuates long-term effects of 17beta-estradiol in coronary arteries from hyperlipidemic rabbits.

OBJECTIVE: The progestin component in hormone replacement treatment may oppose the effects of estrogen on vascular function. This study examined the effect of long-term treatment with 17beta-estradiol (E(2)) alone and in combination with two progestins on K(+) and Ca(2+)-mediated mechanisms in coronary arteries. METHODS: Watanabe heritable hyperlipidemic rabbits were treated orally with either E(2) (4 mg/day), medroxyprogesterone acetate (MPA) (10 mg/day), norethindrone acetate (NETA) (2 mg/day), E(2)+MPA, E(2)+NETA, or placebo for 16 weeks (n=10 in each group). Coronary arteries were used for mRNA and myograph studies. RESULTS: E(2) increased vasodilatation induced by sodium nitroprusside and decreased vasocontraction induced by potassium. The first but not the latter response was opposed by MPA. The combination of MPA and E(2), but neither compound alone enhanced nimodipine-induced vasodilatation and increased the expression of L-type voltage-gated Ca(2+) channel mRNA. NETA had no opposing effects. Hormone treatment did not affect large-conductance Ca(2+) activated or ATP-sensitive K(+) channels or cGMP-dependent protein kinase mRNA expression. Hyperlipidemia had no effect on vascular reactivity. CONCLUSION: When E(2) is administered with MPA, effects of E(2) on nitric oxide and Ca(2+)-mediated vascular reactivity in rabbit coronary arteries are modulated. The results suggest that the progestin component in hormone replacement treatment may interfere with the supposed beneficial vascular effects of estrogen.

Hormone therapy and cardiovascular risk markers and disease: focus on progestagens.

Biological studies have demonstrated estrogen's beneficial effect on cardiovascular risk factors, including plasma lipoproteins, atherogenesis, vascular reactivity, inflammation and antioxidative activity. Additionally, observational studies have supported a cardioprotective effect of hormone therapy (HT), although an underlying healthy-user effect may account for these observations. Progestagens are added to protect against an increased risk of endometrial cancer observed with unopposed estrogen treatment. The inclusion of progestagen in HT has been associated with possible adverse cardiovascular outcomes. Recent, large-scale, randomized clinical studies did not confirm a beneficial cardiovascular effect of HT. On the contrary, an increased risk was found with continuous combined estrogen-progestagen regimens. The progestagen used in these trials was medroxyprogesterone acetate and other progestagen components have only been sparsely elucidated. The purpose of the present review is to outline some of the modifying effects of different progestagens on the actions of estrogen on cardiovascular risk markers and clinical end points observed in biological, observational and clinical studies.

Progestins used in hormonal replacement therapy display different effects in coronary arteries from New Zealand white rabbits.

OBJECTIVES: The aim of this study was in an animal model to assess the vascular effects of different progestins commonly used in hormonal replacement treatment. METHODS: Fifty-six non-atherosclerotic, ovariectomized New Zealand white rabbits were randomized into seven groups: (1) medroxyprogesterone acetate (MPA), (2) norethisterone acetate (NETA), (3) conjugated equine estrogens (CEE), (4) 17-beta-estradiol (E2), (5) MPA+CEE , (6) NETA+E2 , (7) or placebo (n=8) and given hormonal treatment through the diet for 4 weeks. Ring segments from the left proximal coronary artery and from the distal part of the left anterior descending coronary artery were microdissected and mounted for isometric tension recordings in a myograph. The vasoconstrictory responses induced by potassium, endothelin-1, calcium and Nw-nitro-L-arginine methyl ester, and the vasodilatory response induced by acetylcholine and sodiumnitroprusside were investigated. The maximum contraction/relaxation (Emax) and the concentration required to induce half the maximum response (EC50) were determined. EC50 values were expressed as the negative logarithm to the molar concentration, pD2=-log EC50. RESULTS: Treatment with MPA alone caused when compared to treatment with NETA an increase in tension development in the distal coronary artery after the addition of potassium ( 6.36+/-0.36 versus 4.31+/-0.42 P<0.005) (single dose response, mN/mm, mean+/-S.E.M.) and endothelin-1 (9.41+/-0.82 versus 6.43+/-0.73 P<0.05) (Emax, mN/mm, mean+/-S.E.M.). Treatment with MPA compared to placebo caused an endothelin-1 induced increase of Emax in the distal coronary artery (9.21+/-0.87 versus 6.51+/-0.65 P<0.05) and a calcium induced increase of pD2 in both coronary arteries (2.98+/-0.19 versus 2.42+/-0.12 P<0.05, proximal coronary artery) (3.26+/-0.09 versus 2.9+/-0.1 P<0.05, distal coronary artery) (pD2, mean+/-S.E.M.). Treatment with NETA compared to placebo in the proximal coronary artery, after the addition of sodiumnitroprusside caused a decrease of pD2 (5.33+/-0.19 versus 5.94+/-0.13 P<0.05). Treatment with E2 compared to treatment with CEE in the proximal coronary artery caused a decrease of pD2 after the addition of sodiumnitroprusside (5.00+/-0.16 versus 5.77+/-0.28 P<0.05). No significant differences were found between MPA+CEE and NETA+E2. CONCLUSION: Treatment with MPA alone seems to enhance the contractile response to potassium and endothelin-1 in the distal coronary artery compared to NETA, indicating that different progestins used in hormonal replacement treatment may display different effects on contractile functions of coronary arteries.

Tibolone and its metabolites acutely relax rabbit coronary arteries in vitro.

OBJECTIVES: To compare the acute effects of estradiol, tibolone and its metabolites on coronary arteries in vitro and to investigate possible vascular mechanisms. METHODS: Coronary artery ring segments from female rabbits were mounted in myographs for isometric tension recordings. Concentration-response curves to tibolone, 3 alpha-OH-tibolone, 3 beta-OH-tibolone, Delta 4-isomer and 17 beta-estradiol were obtained after precontraction with potassium 30 mmol/l and after addition of N omega-nitro-l-arginine methyl ester 10(-4) mol/l (l-NAME, an inhibitor of endothelial nitric oxide (NO) synthase) or tetraethylammonium chloride 10(-2) mol/l (TEA, an unspecific inhibitor of potassium channels). The effects of the different substances to calcium concentration-response curves were evaluated. Responses are expressed as maximal contraction (E max), concentration giving half maximal contraction (log EC50) or area under curve (AUC). RESULTS: Tibolone and its metabolites induced a concentration-dependent vasodilatation comparable to that of 17 beta-estradiol with the rank of potency: 3 beta-OH-tibolone approximately = to tibolone>3 alpha-OH-tibolone>Delta 4-isomer (ANOVA). l-NAME partly inhibited the relaxation to all substances. TEA induced a slight rightward shift of the relaxation to 3 alpha-OH-tibolone (log EC50: -5.05 versus -5.20; P<0.05; Student's t-test), but not to the other substances. Calcium concentration-dependent contraction curves were inhibited by all substances compared to controls (AUC, P<0.05, ANOVA). CONCLUSIONS: Our data indicate that the acute relaxation induced by tibolone and its metabolites in coronary arteries in vitro are probably mediated by endothelium independent inhibition of calcium channels but may also involve an endothelium-dependent mechanism via nitric oxide. The effect of tibolone is comparable to that of 17 beta-estradiol in this set-up.