Morphologic and functional remodeling of the right ventricle in pulmonary hypertension by real time three dimensional echocardiography

The aims of this study were to assess the right ventricle in different causes of pulmonary hypertension (PH) and to assess the changes of the tricuspid apparatus during this remodeling. The functional and morphologic changes of the right ventricle and the tricuspid apparatus in relation to different causes of PH remain elusive. A total of 141 consecutive patients were prospectively recruited, of whom 55 had pulmonary arterial hypertension (PAH), 32 had chronic thromboembolic disease (CTED), and 34 had PH secondary to mitral regurgitation (MR). Twenty age- and gender-matched healthy volunteers were also studied to serve as controls. Real-time 3-dimensional echocardiography was used to assess right ventricular (RV) volumes and tricuspid valve mobility. Overall, RV diastolic volumes were greater and RV ejection fractions lower in patients with PAH compared to those with CTED and MR (186.4 ± 48.8 vs 113.5 vs 109.4 ml, p < 0.001, and 33.2% vs 36.8% vs 66.8%, p < 0.001, respectively). Among the 3 PH groups, tricuspid valve mobility was most restricted in the CTED group and least restricted in the MR group. Tricuspid tenting volume was greater in the CTED and PAH groups than in the MR group (p < 0.01). Most patients with PAH (54.6%) had at least moderate tricuspid regurgitation, while in the CTED group, most (59.4%) had mild and only 37.5% had moderate tricuspid regurgitation (p < 0.01). Conversely, patients with MR (85%) had only mild tricuspid regurgitation. There was no correlation between RV systolic pressures and the RV ejection fraction or tenting volume. In conclusion, this study demonstrates that different causes of PH may lead to diverse RV remodeling, with the most adverse remodeling being in patients with PAH. In addition, changes of the tricuspid apparatus also differed, with the most adverse effects seen in patients with CTED.     

Fusion Protein Comprising Factor H Domains 6 and 7 and Human IgG1 Fc as an Antibacterial Immunotherapeutic

The emergence of antimicrobial resistance among several medically important pathogens represents a serious threat to human health globally and necessitates the development of novel therapeutics. Complement forms a key arm of innate immune defenses against invading pathogens. A mechanism of complement evasion employed by many pathogens is binding of complement inhibitors, including factor H (FH), a key downregulator of the alternative pathway. Most FH-binding bacteria engage FH through regions in FH spanned by domains 6 and 7 and/or 18 through 20. We created a chimeric protein that comprised human FH domains 6 and 7 fused to human IgG1 Fc (FH6,7/HuFc) and tested its activity as an immunotherapeutic against Neisseria meningitidis, which binds FH through domains 6 and 7. FH6,7/HuFc bound to meningococci and effectively blocked FH binding to bacteria. FH6,7/HuFc enhanced human C3 and C4 deposition and facilitated complement-mediated killing in a dose-responsive manner; complement activation and killing were classical pathway dependent. To investigate in vivo efficacy, infant Wistar rats were treated intraperitoneally (IP) with different doses of FH6,7/HuFc and challenged 2 h later with serogroup C strain 4243 given IP. At 8 to 9 h after the challenge, the FH6,7/HuFc-treated rats had >100-fold fewer CFU per ml of blood than control animals pretreated with phosphate-buffered saline (PBS) or FH18–20/HuFc, which does not bind to meningococci (P < 0.0001). These data provide proof of concept of the utility of FH/Fc fusion proteins as anti-infective immunotherapeutics. Because many microbes share a common binding region(s) in FH, FH/Fc chimeric proteins may be a promising candidate for adjunctive therapy against drug-resistant pathogens.     

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Kaposi’s sarcoma (KS) is the most commonly reported tumor in parts of Africa and is the most common tumor of AIDS patients world-wide. KS-associated herpesvirus (KSHV) is the etiologic agent of KS. Although KS tumors contain many cell types, the predominant cell is the spindle cell, a cell of endothelial origin that maintains KSHV latency. KSHV activates many cell-signaling pathways but little is known about how KSHV alters cellular metabolism during latency. The Warburg effect, a common metabolic alteration of most tumor cells, is defined by an increase in aerobic glycolysis and a decrease in oxidative phosphorylation as an energy source. The Warburg effect adapts cells to tumor environments and is necessary for the survival of tumor cells. During latent infection of endothelial cells, KSHV induces aerobic glycolysis and lactic acid production while decreasing oxygen consumption, thereby inducing the Warburg effect. Inhibitors of glycolysis selectively induce apoptosis in KSHV-infected endothelial cells but not their uninfected counterparts. Therefore, similar to cancer cells, the Warburg effect is necessary for maintaining KSHV latently infected cells. We propose that KSHV induction of the Warburg effect adapts infected cells to tumor microenvironments, aiding the seeding of KS tumors. Additionally, inhibitors of glycolysis may provide a unique treatment strategy for latent KSHV infection and ultimately KS tumors.     

Kaposi sarcoma in a HIV uninfected man who has sex with men

Kaposi''s sarcoma (KS) is a rare angioproliferative tumor associated with human herpesvirus 8 (HHV-8) infection. Four clinical variants of KS have been described: classic, endemic, iatrogenic and HIV-associated. We describe a 53-year-old men who had sex with men with a rapidly growing nodule on his left foot. Histologically KS was confirmed. Our patient did not match the clinical subgroups as HIV infection or other immune disorders could be ruled out. KS in HIV-negative MSM has only been reported sporadically. It was shown that KS in these patients clinically resembles classic KS but occurs at a younger age, is limited to the skin, and is associated with a good prognosis.     

Utility of sleep stage transitions in assessing sleep continuity

Study Objectives:

Sleep continuity is commonly assessed with polysomnographic measures such as sleep efficiency, sleep stage percentages, and the arousal index. The aim of this study was to examine whether the transition rate between different sleep stages could be used as an index of sleep continuity to predict self-reported sleep quality independent of other commonly used metrics.

Design and Setting:

Analysis of the Sleep Heart Health Study polysomnographic data.

Participants:

A community cohort.

Measurements and Results:

Sleep recordings on 5,684 participants were deemed to be of sufficient quality to allow visual scoring of NREM and REM sleep. For each participant, we tabulated the frequency of transitions between wake, NREM sleep, and REM sleep. An overall transition rate was determined as the number of all transitions per hour sleep. Stage-specific transition rates between wake, NREM sleep, and REM sleep were also determined. A 5-point Likert scale was used to assess the subjective experience of restless and light sleep the morning after the sleep study. Multivariable regression models showed that a high overall sleep stage transition rate was associated with restless and light sleep independent of several covariates including total sleep time, percentages of sleep stages, wake time after sleep onset, and the arousal index. Compared to the lowest quartile of the overall transition rate (< 7.76 events/h), the odds ratios for restless sleep were 1.27, 1.42, and 1.38, for the second (7.77–10.10 events/h), third (10.11–13.34 events/h), and fourth (≥ 13.35 events/h) quartiles, respectively. Analysis of stage-specific transition rates showed that transitions between wake and NREM sleep were also independently associated with restless and light sleep.

Conclusions:

Assessing overall and stage-specific transition rates provides a complementary approach for assessing sleep continuity. Incorporating such measures, along with conventional metrics, could yield useful insights into the significance of sleep continuity for clinical outcomes.

Citation:

Laffan A; Caffo B; Swihart BJ; Punjabi NM. Utility of sleep stage transitions in assessing sleep continuity. SLEEP 2010;33(12):1681-1686.