Generation of highly effective and stable murine alloreactive Treg cells by combined anti‐CD4 mAb,TGF‐β, and RA treatment

The transfer of alloreactive regulatory T (aTreg) cells into transplant recipients represents an attractive treatment option to improve long‐term graft acceptance. We recently described a protocol for the generation of aTreg cells in mice using a nondepleting anti‐CD4 antibody (aCD4). Here, we investigated whether adding TGF‐β and retinoic acid (RA) or rapamycin (Rapa) can further improve aTreg‐cell generation and function. Murine CD4⁺ T cells were cultured with allogeneic B cells in the presence of aCD4 alone, aCD4+TGF‐β+RA or aCD4+Rapa. Addition of TGF‐β+RA or Rapa resulted in an increase of CD25⁺Foxp3⁺‐expressing T cells. Expression of CD40L and production of IFN‐γ and IL‐17 was abolished in aCD4+TGF‐β+RA aTreg cells. Additionally, aCD4+TGF‐β+RA aTreg cells showed the highest level of Helios and Neuropilin‐1 co‐expression. Although CD25⁺Foxp3⁺ cells from all culture conditions displayed complete demethylation of the Treg‐specific demethylated region, aCD4+TGF‐β+RA Treg cells showed the most stable Foxp3 expression upon restimulation. Consequently, aCD4+TGF‐β+RA aTreg cells suppressed effector T‐cell differentiation more effectively in comparison to aTreg cells harvested from all other cultures, and furthermore inhibited acute graft versus host disease and especially skin transplant rejection. Thus, addition of TGF‐β+RA seems to be superior over Rapa in stabilising the phenotype and functional capacity of aTreg cells.     

Chronic rhinosinusitis with and without nasal polyps and asthma: Omalizumab improves residual anxiety but not depression

BackgroundChronic rhinosinusitis (CRS) has a high prevalence of anxiety and depression. It is currently uncertain if treatment in patients with CRS with or without nasal polyps (CRSwNP and CRSsNP) has any impact on improving mental health outcomes. The aims here were to document anxiety and depression in patients with severe CRS and asthma already treated with appropriate medical therapy. We then evaluated whether further maximal treatment with omalizumab improved anxiety and/or depression alongside improvements in CRS and coassociated asthma.MethodsHospital Anxiety and Depression Scale (HADS) scores along with measures of CRS and asthma severity were recorded according to CRSwNP and CRSsNP status in n = 95 patients with severe CRS and asthma. Of this group, a further n = 23 had omalizumab for associated allergic asthma. Follow‐up measures were collected 16 weeks after omalizumab treatment.ResultsHADS anxiety and depression prevalence in CRS were 49.47 % and 38.95%, respectively. Within the CRSwNP and CRSsNP group 53.06% and 45.66% had raised HADS‐anxiety scores. Abnormal HADS‐depression scores were present in 40.82% and 36.95% of the CRSwNP and CRSsNP groups, respectively. Correlations for sinonasal outcome test‐22 (SNOT‐22) versus HADS total was r = 0.59 p < 0.0001, HADS‐anxiety r = 0.56 p < 0.0001 and HADS‐depression r = 0.49 p < 0.0001. Omalizumab improved anxiety in CRS (p < 0.0001) regardless of nasal polyp status (CRSwNP p = 0.0042 and CRSsNP p = 0.0078). Depression scores did not improve in either group. SNOT‐22 (p = 0.0006), asthma control questionnaire‐7 (p = 0.0019) and mini‐asthma quality of life questionnaire including emotional function (p = 0.0003 and p = 0.0009, respectively) all improved in both subgroups.ConclusionIn CRS and asthma, anxiety scores but not depression improved after omalizumab treatment. Anxiety may be closely related to airway disease severity, but depression may be independent of airway disease itself. If so, a separate mental health care pathway is needed for CRS patients with depression.     

The Impact of Infidelity on Combat‐Exposed Service Members

This study examined relationships between combat‐exposed Operation Enduring Freedom/Operation Iraqi Freedom veterans’ experiences related to infidelity during deployment (i.e., indicating that a partner was unfaithful or reporting concern about potential infidelity) and postdeployment mental health, as well as the role of subsequent stress exposure and social support in these associations. The sample consisted of 571 individuals (338 men). There were 128 participants (22.2%) who indicated that their partners were unfaithful during their most recent deployment. Of the remaining 443 participants, 168 (37.8%) indicated that they were concerned that their partners might have been unfaithful. Individuals who indicated that their partners were unfaithful exhibited higher levels of posttraumatic stress symptomatology (β = .08; f²= .18) and depression symptom severity (β = .09; f² = .14), compared to individuals who did not indicate that their partners were unfaithful. For both men and women, reported infidelity was associated with mental health indirectly via postdeployment life stressors, whereas infidelity concerns were indirectly associated with mental health via postdeployment life stressors for men only. Findings suggested that infidelity can have a significant impact on combat‐exposed veterans’ mental health and highlight the need for additional research on this understudied topic within the military population.     

Interaction of cellular factors related to the Jun oncoprotein with the promoter of a replication-dependent hamster histone H3.2 gene.

The promoter region of a replication-dependent histone H3.2 gene contains a putative DNA binding site for the Jun oncoprotein within a 32-nucleotide regulatory domain. The hamster sequence differs by one nucleotide from the AP-1 consensus sequence found in several promoters responsive to phorbol 12-myristate 13-acetate. We have identified the factors interacting with this region as 42- and 45-kDa proteins by DNA affinity chromatography, immunoblotting, and UV crosslinking. These proteins, which are candidates for conferring high-level expression to the histone promoter, share an antigenic epitope with the DNA-binding domain of Jun but diverge from it at the amino terminus. The interaction of these proteins with the promoter of a replication-dependent cellular gene provides evidence that members of the Jun oncoprotein family may play specific roles in the expression of genes essential for progression of the cell cycle.     

The RNA of avian acute leukemia virus MC29.

The RNA of myelocytoma virus MC29, a replication-defective avian acute leukemia virus, was investigated. Sedimentation and electrophoretic analyses indicated that the virus contains a distinct 28S RNA with about 5700 nucleotides. It is the smallest avian tumor virus RNA detected to date. The small size of the RNA suggests that the defectiveness of the virus is due to deletions in replicative genes. The RNA shared 3 to 5 of 30 large RNase T1-resistant oligonucleotides with the RNA of other avian leukosis and sarcoma and may represent the transforming information of the virus. Sequences of the conserved transforming gene of avian sarcoma viruses were not detected in MC29 RNA define a new class of avian tumor viral transforming genes.     

Role of the Vascular Wall in Sodium Homeostasis and Salt Sensitivity

Excessive sodium intake is associated with both hypertension and an increased risk of cardiovascular events, presumably because of an increase in extracellular volume. The extent to which sodium intake affects extracellular volume and BP varies considerably among individuals, discriminating subjects who are salt-sensitive from those who are salt-resistant. Recent experiments have shown that, other than regulation by the kidney, sodium homeostasis is also regulated by negatively charged glycosaminoglycans in the skin interstitium, where sodium is bound to glycosaminoglycans without commensurate effects on extracellular volume. The endothelial surface layer is a dynamic layer on the luminal side of the endothelium that is in continuous exchange with flowing blood. Because negatively charged glycosaminoglycans are abundantly present in this layer, it may act as an intravascular buffer compartment that allows sodium to be transiently stored. This review focuses on the putative role of the endothelial surface layer as a contributor to salt sensitivity, the consequences of a perturbed endothelial surface layer on sodium homeostasis, and the endothelial surface layer as a possible target for the treatment of hypertension and an expanded extracellular volume.     

Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase

A human O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA-containing retrovirus was used to infect murine long-term primary bone marrow cultures. High levels of ATase expression were obtained, and colony- forming cells of the granulocyte-macrophage lineage from the cultures transduced with the human ATase retrovirus were three times more resistant to the alkylating agent, N-methyl-N-nitrosourea (MNU), than control cultures. Furthermore, expression of the human ATase protected long-term hematopoiesis, measured as the output of progenitor cells to the nonadherent fraction of the culture, against the cytotoxic effects of repeated exposures to MNU. These results clearly show that a human ATase cDNA-containing retrovirus can be used to infect long-term primary bone marrow cultures and that this attenuates their sensitivity to nitrosoureas.     

Mortality and Cardiovascular Risk in Patients With a History of Malignant Hypertension: A Case‐Control Study

The survival of patients with malignant hypertension (MHT) has considerably improved over the past decades. Data regarding the excess risk of mortality and the contribution of conventional cardiovascular risk factors are lacking. The authors retrospectively assessed cardiovascular risk factors and all‐cause mortality in 120 patients with a history of MHT and compared them with 120 normotensive and 120 hypertensive age‐, sex‐, and ethnicity‐matched controls. Total cholesterol, low‐density lipoprotein cholesterol, and body mass index were lower in MHT patients compared with hypertensive controls, whereas blood pressure, high‐density lipoprotein cholesterol, and smoking habit were similar. Median estimated glomerular filtration rate was lower in MHT patients compared with normotensive and hypertensive controls (both P<.01). The annual incidence of all‐cause mortality per 100 patient‐years was higher in MHT patients (2.6) compared with normotensive (0.2) and hypertensive (0.5) controls (both P<.01). Mortality of patients with a history of MHT remains high compared with normotensive and hypertensive controls. Patients with MHT had a more favorable cardiovascular risk profile compared with hypertensive controls but a higher prevalence of renal insufficiency.