Ambulatory Blood Pressure Monitoring in Individuals with HIV: A Systematic Review and Meta-Analysis

Introduction

Abnormal diurnal blood pressure (BP) rhythms may contribute to the high cardiovascular disease risk in HIV-positive (HIV⁺) individuals. To synthesize the current literature on ambulatory BP monitoring (ABPM) in HIV⁺ individuals, a systematic literature review and meta-analysis were performed.

Methods

Medical databases were searched through November 11, 2015 for studies that reported ABPM results in HIV⁺ individuals. Data were extracted by 2 reviewers and pooled differences between HIV⁺ and HIV-negative (HIV^-) individuals in clinic BP and ABPM measures were calculated using random-effects inverse variance weighted models.

Results

Of 597 abstracts reviewed, 8 studies with HIV⁺ cohorts met the inclusion criteria. The 420 HIV⁺ and 714 HIV^- individuals in 7 studies with HIV^- comparison groups were pooled for analyses. The pooled absolute nocturnal systolic and diastolic BP declines were 3.16% (95% confidence interval [CI]: 1.13%, 5.20%) and 2.92% (95% CI: 1.64%, 4.19%) less, respectively, in HIV⁺ versus HIV^- individuals. The pooled odds ratio for non-dipping systolic BP (nocturnal systolic BP decline <10%) in HIV⁺ versus HIV^- individuals was 2.72 (95% CI: 1.92, 3.85). Differences in mean clinic, 24-hour, daytime, or nighttime BP were not statistically significant. I² and heterogeneity chi-squared statistics indicated the presence of high heterogeneity for all outcomes except percent DBP dipping and non-dipping SBP pattern.

Conclusions

An abnormal diurnal BP pattern may be more common among HIV⁺ versus HIV^- individuals. However, results were heterogeneous for most BP measures, suggesting more research in this area is needed.     

Pharmacokinetic studies of radiolabelled rat monoclonal antibodies recognising syngeneic sarcoma antigens

Summary The object of our current investigations is to explore the potential of antibodies for localisation and treatment of disseminated disease, using as a model rat monoclonal antibodies (mAbs) raised against syngeneic tumourspecific antigens. As part of this study, antibodies of differing isotypes with specificity for either HSN or MC24 sarcoma were labelled with¹²⁵iodine and injected intravenously into normal rats or those bearing paired tumours in contralateral flanks. The blood clearance rates of the radiolabelled antibodies were found to be influenced by immunoglobulin subclass (IgG2b > IgG2a > IgG1) and to be increased non-specifically by the presence of growing tumours. The tumour and normal tissue distributions of the antibodies tested were also found to vary according to their apparent degree of interaction with host Fc-receptor-bearing cells, to the extent that tumour specificity in vitro was not necessarily reflected in selectivity of localisation in vivo. Three IgG2b monoclonal antibodies showed preferential uptake in the spleens of syngeneic rats and non-specific accumulation in tumours. This effect was not observed with antibodies of IgG2a or IgG1 subclass, and was abolished by the use of IgG2b F(ab)₂ preparations. In spite of the use of immunoglobulin fragments, varying the assay time and testing tumours of different sizes, specific tumour localisation was low with all seven monoclonal antibodies tested. The maximum uptake achieved was less than 1% of the injected dose of antibody per gram of tumour. Much higher levels of antibody localisation have been reported for human tumour xenografts growing in nude mice, but these are rarely achieved in other systems. We propose that the use of autologous monoclonal antibodies recognising tumour-associated antigens of relatively low epitope density in syngeneic hosts provides a valid alternative model in which to investigate the factors limiting more effective, specific immunolocalisation of malignant disease.     

Prostaglandin 15-hydroxy dehydrogenase and Δ13 reductase levels in the lungs of maternal,fetal and neonatal rabbits

The levels of prostaglandin 15-hydroxy dehydrogenase and reductase have been studied in the lungs of maternal, fetal and neonatal rabbits. Fetal lungs obtained at gestational age of 28–30 days (full term 31 days) had the same levels of prostaglandin dehydrogenase as the adults, while the reductase levels in the fetal lungs were only one fourth that in the adults. The lungs of maternal rabbits at near term possessed very high levels of prostaglandin dehydrogenase — approximately twenty-fold higher than in the adult non-pregnant female controls. The Δ¹³ reductase appeared slightly elevated during pregnancy. Neonatal animals at different ages showed the same levels of both enzymes as the near term fetus and/or the non-pregnant adults, which suggests that the development of the ability for prostaglandin metabolism is completed at least several days before birth. The high dehydrogenase levels in the near term maternal lungs indicated the requirement for extra protection against prostaglandin release during late pregnancy.     

Characteristics of rhizobia isolated from three legumes indigenous to the Canadian high arctic:Astragalus alpinus,Oxytropis maydelliana,andOxytropis arctobia

Summary Forty-eight strains of rhizobia were isolated from the root nodules ofAstragalus alpinus (21),Oxytropis maydelliana (19) andOxytropis arctobia (8), three species of arctic legumes found in the Melville Peninsula, Northwest Territories, Canada. On the basis of 74 characteristics (cultural, physiological, biochemical and host nodulation range) the 48 arctic rhizobia could be divided into 11 distinct groups by numerical analysis techniques. All 48 arctic rhizobia were able to nodulate the three arctic legume species and also sainfoin (Onobrychis viciifolia), however, milkvetch (Astragalus cicer) was only nodulated by 33 strains. In general, the arctic rhizobia showed properties found in both Rhizobium and Bradyrhizobium. The adaptation of the arctic strains to low temperature is indicated by their ability to grow in liquid culture at 5°C. Contribution no 293 of Agriculture Canada Research Station at Sainte-Foy.     

Use of APACHE II classification to evaluate outcome of patients receiving hemodialysis in an intensive care unit.

We retrospectively reviewed the medical records of all patients who were admitted to the medical and surgical intensive care units of a university center (N = 100) and its affiliated veterans'' hospital (N = 46) between 1982 and 1986 to receive dialysis. The APACHE II severity-of-disease classification was used to identify the cases in which the prognosis was so poor that no long-term benefit would accrue from hemodialysis treatment. A "risk of death" was calculated for each patient. At a risk of death of 70% or greater, the system correctly predicted the demise of patients with 100% specificity regardless of what interventions were carried out. Sensitivity and predicted negative value were low in all cases, however, indicating a poor predictability of those who will survive. Withholding the average of 6 dialysis treatments that this group of patients received would probably have reduced patient suffering during a lingering terminal illness and led to a savings of about $4,500 per patient.     

Detection of mutation in transgenic CHO cells using green fluorescent protein as a reporter

A novel approach was developed for rapidly estimating the frequency of specific mutations in genetically engineered Chinese hamster ovary (CHO) cells. We designed double-transgenic CHO cell lines that contain a transgene consisting of the sequence coding for green fluorescent protein under the control of a tetracycline (Tet) responsive promoter and a second transgene coding for the constitutively expressed Tet repressor. Cultures of these CHO cells were treated with gamma-radiation, N-methyl-N-nitrosourea or methyl methanesulfonate, and the fluorescence of individual cells from both control and treated cultures was measured by flow cytometry. The treatments increased the number of highly fluorescent cells, those with presumed mutations in the Tet-repressor gene. Mutant cells from gamma-radiation-exposed cultures were isolated by fluorescence-activated cell sorting, cultured, and individual clones expanded. A PCR-based analysis indicated that the highly fluorescent expanded cells had lost the transgene coding for the Tet repressor, suggesting that the system mainly detects large genetic alterations. A similar approach may be useful for making high-throughput in vivo models for mutation detection.     

Evidence for a Second, High Affinity G�¦� Binding Site on G��i1(GDP) Subunits

It is well known that Gα_i1(GDP) binds strongly to Gβγ subunits to form the Gα_i1(GDP)-Gβγ heterotrimer, and that activation to Gα_i1(GTP) results in conformational changes that reduces its affinity for Gβγ subunits. Previous studies of G protein subunit interactions have used stoichiometric amounts of the proteins. Here, we have found that Gα_i1(GDP) can bind a second Gβγ subunit with an affinity only 10-fold weaker than the primary site and close to the affinity between activated Gα_i1 and Gβγ subunits. Also, we find that phospholipase Cβ2, an effector of Gβγ, does not compete with the second binding site implying that effectors can be bound to the Gα_i1(GDP)-(Gβγ)₂ complex. Biophysical measurements and molecular docking studies suggest that this second site is distant from the primary one. A synthetic peptide having a sequence identical to the putative second binding site on Gα_i1 competes with binding of the second Gβγ subunit. Injection of this peptide into cultured cells expressing eYFP-Gα_i1(GDP) and eCFP-Gβγ reduces the overall association of the subunits suggesting this site is operative in cells. We propose that this second binding site serves to promote and stabilize G protein subunit interactions in the presence of competing cellular proteins.The plasma membranes of cells are organized as a series of protein-rich and lipid-rich domains (1–3). Many of the protein-rich domains, in particular those organized by caveolin proteins, are thought to be complexes of functionally related proteins that transduce extracellular signals (2). There is increasing evidence that heterotrimeric G proteins exist in pre-formed membrane complexes with their receptors and their intracellular effectors (4–8).The G protein signaling system is initiated when an extracellular agonist binds to its specific G protein-coupled receptor (for review see Refs. 9–12). The ligand-bound receptor will then catalyze the exchange of GTP for GDP on the Gα subunit in the G protein heterotrimer. In the basal state, Gα(GDP) binds strongly to Gβγ, but in the GTP-bound state this affinity is reduced, allowing Gα(GTP) and Gβγ subunits to individually bind to a host of specific intracellular enzymes and change their catalytic activity.Although the interactions between G protein subunits have been studied extensively in vitro, their behavior in cells may differ. For example, in pure or semi-pure systems, activation of Gα(GDP) sufficiently weakens its affinity for Gβγ resulting in dissociation (13). However, in cells separation of the heterotrimer is observed under some circumstances, but not others (7, 14–17). The reason for these differences in behavior is not clear. There are four families of Gα subunits that each contain several members, and, additionally, there are many subtypes of Gβγ subunits (18). It is possible that differences in dissociation behavior reflect differences in affinity between G protein subunit subtypes (19), the presence of various protein partners, and/or differences in post-synthetic modifications of the subunits (20).The mechanism that allows activated G proteins to remain bound is not apparent from the crystal structure (21, 22). If G protein subunits do not dissociate in cells, then their interaction must change in such a manner as to expose the effector interaction site(s). We have found that phospholipase Cβ1 (PLCβ1),⁴ an important effector of Gα_q (23), is bound to Gα_q prior to activation and throughout the activation cycle (6) implying that Gα_q(GDP) interacts with PLCβ1 in a non-functional manner.We have evidence that signaling complexes are stabilized by a series of secondary interactions. Using purified proteins and model membranes, we have found that membranes of the Gα_q-Gβγ/PLCβ1/RGS4 signaling system have secondary, weaker binding sites to members of this signaling system in addition to their high affinity site(s) to their functional partner(s). We speculate that secondary contacts allow for self-scaffolding of signaling proteins. To understand the nature of these secondary contacts, we have studied the ability of the Gα_i1(GDP)-Gβγ heterotrimer to remain complexed through the activation cycle (24). Here, we present evidence that Gα_i1(GDP) has two distinct Gβγ binding sites that only differ in affinity by an order of magnitude and may allow for continued association between the subunits upon activation. We also find that this site plays an important role in stabilizing G protein associations in cells and provides a mechanism of self-scaffolding.