Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice

Inhibitors of microsomal prostaglandin E synthase 1 (mPGES-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E₂ (PGE₂), but increasing the biosynthesis of prostacyclin (PGI₂). In low-density lipoprotein receptor–deficient (Ldlr^–/–) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE₂ accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr^–/– mice, whereas, despite the direct vasodilator properties of PGI₂, deletion of the I prostanoid receptor (Ipr) suppressed this response. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1^–/– mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high-salt diet (HSD). This is attributable to the protective effect of estrogen in Ldlr^–/– mice and in Ipr^–/– Ldlr^–/– mice. Thus, estrogen compensates for a deficiency in PGI₂ to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors.     

Witnessed resuscitation: beneficial or detrimental?

This article explores the existing literature and discusses the benefits and disadvantages of witnessed resuscitation for health professionals, relatives, and patients themselves. Keywords "witnessed resuscitation," "patient perspective," "health professionals," and "resuscitation room" were entered into MEDLINE, Medscape, and Science Direct databases. The issue of witnessed resuscitation, along with the benefits and disadvantages of its implementation, is discussed widely with increasing controversy among health professionals. Many authors accept the existence of benefits of witnessed resuscitation, but they each have reservations on certain aspects of the practice. Although witnessed resuscitation has demonstrable benefits, the dearth of research literature on the subject makes it difficult to come to a concrete conclusion about its value in practice. More studies are needed focusing on the impact of witnessed resuscitation on staff, family members, and patients. Larger sample sizes are needed in future studies, and studies are needed in which geographical, cultural, religious, and sociological factors are taken into consideration.     

Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells

Kaposi's sarcoma (KS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and consists of proliferating spindle cells, which are related to lymphatic endothelial cells (LEC). Angiopoietin-2 (Ang2) is a secreted proangiogenic and lymphangiogenic molecule. Here, we show the expression of Ang2 protein in KS and confirm that KSHV infection up-regulates Ang2 in LEC. We show that a paracrine mechanism contributes to this up-regulation. A lentiviral library of individual KSHV-encoding genes, comprising the majority of known latent genes and a selection of lytic viral genes, was constructed to investigate the underlying mechanism of this up-regulation. Two lytic genes, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR), up-regulated Ang2 expression in LEC. Both vIL6 and vGPCR are expressed in KSHV-infected LEC and caused up-regulation of Ang2 in a paracrine manner. KSHV, vIL6, and vGPCR up-regulated Ang2 through the mitogen-activated protein kinase (MAPK) pathway. Gene expression microarray analysis identified several other angiogenic molecules affected by KSHV, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis, which is also affected by vIL6 and vGPCR in LEC, and matrix metalloproteinases, which could act in concert with Ang2 to contribute to KS development. These findings support the paracrine and autocrine roles of the lytic KSHV-encoded proteins, vIL6 and vGPCR, in KS pathogenesis and identify Ang2 as a potential therapeutic target for this neoplasm.     

Dental arch spatial changes after premature loss of first primary molars: a systematic review of controlled studies

Studies investigating dental arch spatial changes following first primary molar premature loss are controversial regarding clinical significance. The purpose of this review was to systematically investigate the relevant literature. Controlled studies investigating changes before and after premature loss of first primary molars were searched in various databases. Split-mouth design studies were considered eligible for inclusion. The risk of bias was judged according to ADA Clinical Practice Guidelines. Only two analyzable split-mouth studies on mandibular first primary molar loss were identified. Space loss in the extraction side was greater at 2, 4, 6 and 8-month follow-ups, reaching a ?1.5 mm difference in the final examination (95% Confidence Interval: ?2.080 to ?0.925; p = 0.000; random effects model). Studies were judged to be at unclear risk of bias. The amount of space decrease after premature loss of first primary molars may have management implications under certain circumstances. Comprehensive assessment of the various characteristics of each patient should precede management decisions in individual cases.     

Effect of fuzzy partitioning in Crohn’s disease classification: a neuro-fuzzy-based approach

Crohn’s disease (CD) diagnosis is a tremendously serious health problem due to its ultimately effect on the gastrointestinal tract that leads to the need of complex medical assistance. In this study, the backpropagation neural network fuzzy classifier and a neuro-fuzzy model are combined for diagnosing the CD. Factor analysis is used for data dimension reduction. The effect on the system performance has been investigated when using fuzzy partitioning and dimension reduction. Additionally, further comparison is done between the different levels of the fuzzy partition to reach the optimal performance accuracy level. The performance evaluation of the proposed system is estimated using the classification accuracy and other metrics. The experimental results revealed that the classification with level-8 partitioning provides a classification accuracy of 97.67 %, with a sensitivity and specificity of 96.07 and 100 %, respectively.     

Effect of Atrial Pressure Increase on Effective Refractory Period and Vulnerability to Atrial Fibrillation in Patients with Lone Atrial Fibrillation

Background: There is evidence suggesting that atrial fibrillation (AF) may be induced by acute increase of atrial pressure. The aim of the present study was to investigate the effect of alterations in atrial pressure, induced by varying the atrioventricular (AV) interval, on atrial refractoriness, and on the frequency of induction of (AF), in patients with a history of lone atrial fibrillation (LAF).Methods and Results: Twenty-five patients were included in this study. The patients were divided in two groups: the LAF group, and the control group. None of the patients in either group had organic heart disease. Effective refractory period (ERP) and duration of atrial extrastimulus electrogram (A₂) were measured at two right atrial sites (high lateral wall, atrial appendage) during AV pacing (cycle length: 500 msec) with different AV intervals. Peak, minimal and mean atrial pressure increased from 8.57 ± 2.37 to 18.14 ± 4.74 mm Hg, 2 ± 2.23 to 5.14 ± 2.60 mm Hg (p = 0.0001) and from 4.28 ± 1.6 mm Hg to 9.77 ± 2.9 mm Hg (p = 0.001), respectively during AV interval modification. During lateral and atrial appendage pacing, with a progressive decrease of AV interval to 160, 100, 80, 40, 0 msec, the ERP, the dispersion of ERP, functional refractory period (FRP), A2 and latency period (LP) did not change significantly, in both groups. The frequency of induction of AF was not statistically different in both lateral atrial wall and appendage, during pacing in different AV intervals.Conclusions: This study demonstrates that alterations in the intraatrial pressure does not have important effects on atrial refractoriness and does not increase vulnerability to AF in patients with a history of LAF.     

Once-yearly zoledronic acid in the prevention of osteoporotic bone fractures in postmenopausal women

Zoledronic acid is a nitrogen-containing, third-generation bisphosphonate that has recently been approved for the treatment of postmenopausal osteoporosis as an annual intravenous infusion. Zoledronic acid is an antiresorptive agent which has a high affinity for mineralized bone and especially for sites of high bone turnover. Zoledronic acid is excreted by the kidney without further metabolism. Zoledronic acid administered as a 5 mg intravenous infusion annually increases bone mineral density in the lumbar spine and femoral neck by 6.7% and 5.1% respectively and reduces the incidence of new vertebral and hip fractures by 70% and 41% respectively in postmenopausal women with osteoporosis. Most common side effects are post-dose fever, flu-like symptoms, myalgia, arthralgia, and headache which usually occur in the first 3 days after infusion and are self-limited. Rare adverse effects include renal dysfunction, hypocalcemia, atrial fibrillation, and osteonecrosis of the jaw.     

Conservative surgical treatment of medication related osteonecrosis of the jaw (MRONJ) lesions in patients affected by osteoporosis exposed to oral bisphosphonates: 24 months follow-up

The purpose of the study was to evaluate the efficacy of conservative surgical treatment of medication related osteonecrosis of the jaw (MRONJ) in patients affected by osteoporosis and exposed to oral bisphosphonates (BPs).Subjects diagnosed with MRONJ and osteoporosis under oral BPs that had undergone conservative surgery and had at least 24 months follow-up were included. All patients received medical-antibiotic therapy and then underwent conservative surgical treatment consisting of sequestrectomy, soft tissue debridement and bone curettage with limited or no extension.A total of 53 patients, mean age of 71.9 ± 10.2 years (range 41–87), were enrolled. Two years after conservative surgical therapy 45 patients (91.8%) showed complete healing. The presence of rheumatoid arthritis (p = 0.003) and a more severe initial MRONJ stage (p = 0.023) were associated with a negative surgical outcome while the presence of bone sequestrum was strongly associated with a positive outcome (p = 0.036).Conservative surgical treatment of MRONJ lesions in patients affected by osteoporosis and receiving only oral BPs may represent a valid therapeutic approach determining a high number of complete healing cases. Conservative surgery should be encouraged at early MRONJ stages and after medical therapy failure.