The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: A randomized factorial design trial

Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals. Forty-eight non-exercising individuals (mean age 70 ± 4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training & Alagebrium (200 mg/day); exercise training & placebo; no exercise training & Alagebrium (200 mg/day); and no exercise training & placebo. We performed a maximal exercise test (VO₂max) and measured endothelial function using venous occlusion plethysmography and intra-arterial infusion of acetylcholine, sodium nitroprusside and N^G-monomethyl-l-arginine. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS). In the exercise training groups, LRS and VO₂max improved significantly (23.9 ± 4.5 to 27.2 ± 4.6mLO₂/min/kg, p < 0.001). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging.     

Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia

Background

C-type lectin-like molecule-1 is a transmembrane receptor expressed on myeloid cells, acute myeloid leukemia blasts and leukemic stem cells. To validate the potential of this receptor as a therapeutic target in acute myeloid leukemia, we generated a series of monoclonal antibodies against the extracellular domain of C-type lectin-like molecule-1 and used them to extend the expression profile analysis of acute myeloid leukemia cells and to select cytotoxic monoclonal antibodies against acute myeloid leukemia cells in preclinical models.

Design and Methods

C-type lectin-like molecule-1 expression was analyzed in acute myeloid leukemia cell lines, and in myeloid derived cells from patients with acute myeloid leukemia and healthy donors. Anti-C-type lectin-like molecule-1 antibody-mediated in vitro cytotoxic activity against acute myeloid leukemia blasts/cell lines and in vivo anti-cancer activity in a mouse xenograft model were assessed. Internalization of C-type lectin-like molecule-1 monoclonal antibodies upon receptor ligation was also investigated.

Results

C-type lectin-like molecule-1 was expressed in 86.5% (45/52) of cases of acute myeloid leukemia, in 54.5% (12/22) of acute myeloid leukemia CD34⁺/CD38⁻ stem cells, but not in acute lymphoblastic leukemia blasts (n=5). Selected anti-C-type lectin-like molecule-1 monoclonal antibodies mediated dose-dependent complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity specifically against acute myeloid leukemia-derived cell lines. Exogenous expression of the transmembrane receptor in HEK293 cells rendered the cells susceptible to antibody-mediated killing by monoclonal antibodies to the receptor. Furthermore, these monoclonal antibodies demonstrated strong complement-dependent cytotoxicity against freshly isolated acute myeloid leukemia blasts (15/16 cases; 94%). The monoclonal antibodies were efficiently internalized upon binding to C-type lectin-like molecule-1 in HL-60 cells. Moreover, a lead chimeric C-type lectin-like molecule-1 monoclonal antibody reduced the tumor size in xenograft mice implanted with HL-60 cells.

Conclusions

Our results demonstrate that targeting C-type lectin-like molecule-1 with specific cytotoxic monoclonal antibodies is an attractive approach which could lead to novel therapies for acute myeloid leukemia.     

Clinical, sonographic, and epidemiologic features of second- and early third-trimester spontaneous antepartum uterine rupture: a cohort study

OBJECTIVE: To present prenatal findings and maternal and neonatal outcomes following second- and early third-trimester spontaneous antepartum uterine rupture events in our institute. METHOD: Charts of patients with full-thickness second- or early third-trimester symptomatic uterine ruptures locally treated between 1984 and 2007 were evaluated. RESULTS: There were seven events involving six women, all requiring emergency laparotomy, and cesarean section (CS). During the study period in our institute, there were 120 636 singleton deliveries (> or =22 weeks' gestation), including 5 of our cases, while in 2 cases, the rupture occurred earlier (<22 weeks' gestation). The rupture occurred after > or = 1 previous CSs in five cases. Six events were associated with abnormal placentation: placenta previa (n = 3), placenta percreta (n = 1), or both (n = 2). Other associated events included short, interpregnancy (IP) interval (n = 3) and past uterine rupture (n = 2). Pregnant women at gestational age > or = 22 weeks, who had the combination of placenta previa, and previous CS (n = 3), had a higher chance for spontaneous symptomatic antepartum uterine rupture when compared to women with placenta previa without a previous CS (OR 29.3, 95% CI 1.5-569.3, p = 0.007). There were no maternal deaths. Three of the five viable neonates survived. CONCLUSIONS: Spontaneous symptomatic second- or early third-trimester uterine rupture in nonlaboring women is a very rare, obstetric emergency, which is hard to diagnose. Maternal and neonatal outcomes can be optimized by awareness of risk factors, recognition of clinical signs and symptoms, and availability of ultrasound to assist in establishing diagnosis, and enabling prompt surgical intervention.     

Pain relief by continuous intraperitoneal nebulization of ropivacaine during gynecologic laparoscopic surgery--a randomized study and review of the literature

STUDY OBJECTIVE: To evaluate the efficacy of intraperitoneal nebulization of ropivacaine on pain relief during and after gynecologic laparoscopic procedures including a review of the literature. DESIGN: Double-blinded, randomized, controlled, clinical trial (Canadian Task Force classification I). SETTING: University hospital ambulatory gynecoendoscopic department. PATIENTS: Forty patients (20 patients in each arm) undergoing elective gynecologic same-day outpatient laparoscopic surgery including unilateral/bilateral salpingo-oophorectomy or unilateral/bilateral ovarian cystectomy. INTERVENTIONS: The study group received 10 mL of 1% ropivacaine and the control group received 10 mL of sterile water by intraperitoneal nebulization. During surgery, vital signs were recorded and summarized. Postoperatively patients were followed up for 24 hours including visual analog scale scores and analgesic use. MEASUREMENTS AND MAIN RESULTS: No significant differences existed between the groups during surgery and at the recovery department in terms of arterial blood pressure (p = .42) or heart rate (p = .60). Regarding postoperative analgesia, no difference existed between the groups in terms of morphine consumption (p = .52) or other analgesics (p = .53). No significant difference existed between the groups in postoperative visual analog scale scores including visceral, abdominal wall, and shoulder pain during rest and during cough at the different time frames (30, 60, and 120 minutes and 6 and 24 hours after surgery). CONCLUSION: Our study is the first to examine the effects of intraperitoneal nebulization of ropivacaine throughout laparoscopic gynecologic procedures on patients undergoing general anesthesia. Nebulization of 100 mg of ropivacaine under our specific regimen of anesthesia does not improve patients' outcome in terms of intraoperative and postoperative pain along with consumption of analgesics. Further research with other regimens is required.     

Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma

The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment, surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEGF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing.     

Poor Health‐related Quality of Life After Severe Preeclampsia

Abstract: Background: Preeclampsia is a major complication of pregnancy associated with increased maternal morbidity and mortality, and adverse birth outcomes. The objective of this study was to describe changes in all domains of health‐related quality of life between 6 and 12 weeks postpartum after mild and severe preeclampsia; to assess the extent to which it differs after mild and severe preeclampsia; and to assess which factors contribute to such differences. Methods: We conducted a prospective multicenter cohort study of 174 postpartum women who experienced preeclampsia, and who gave birth between February 2007 and June 2009. Health‐related quality of life was measured at 6 and 12 weeks postpartum by the RAND 36‐item Short‐Form Health Survey (SF‐36). The population for analysis comprised women (74%) who obtained scores on the questionnaire at both time points. Results: Women who experienced severe preeclampsia had a lower postpartum health‐related quality of life than those who had mild preeclampsia (all p < 0.05 at 6 wk postpartum). Quality of life improved on almost all SF‐36 scales from 6 to 12 weeks postpartum (p < 0.05). Compared with women who had mild preeclampsia, those who experienced severe preeclampsia had a poorer mental quality of life at 12 weeks postpartum (p < 0.05). Neonatal intensive care unit admission and perinatal death were contributing factors to this poorer mental quality of life. Conclusions: Obstetric caregivers should be aware of poor health‐related quality of life, particularly mental health quality of life in women who have experienced severe preeclampsia (especially those confronted with perinatal death or their child’s admission to a neonatal intensive care unit), and should consider referral for postpartum psychological care. (BIRTH 38:3 September 2011)     

Chemical composition and toxicity of the essential oils from Cunila species (Lamiaceae) on the cattle tick Rhipicephalus (Boophilus) microplus

The essential oils obtained from the aerial parts of five species of Cunila (Lamiaceae) native to Southern Brazil were analyzed by GC and GC/MS. The oil of Cunila angustifolia was characterized by sabinene; Cunila incana is rich in α-pinene and β-pinene, Cunila spicata and Cunila microcephala presented menthofuran as the main component, and in the essential oil of Cunila incisa, the major component was 1,8-cineole. Laboratory tests were carried out to determine the effect of the essential oils of the above cited plants on larvae of the cattle tick Riphicephalus (Boophilus) microplus. C. angustifolia, C. incana, and C. spicata were the most active samples killing almost the totality of the larvae. C. incisa and C. microcephala showed low acaricidal effect.     

Acute focal infections of dental origin

This article describes the most important pus‐producing acute oral infections (dental infections) that can spread extra‐orally. Most of these infections are spread by bacteria entering the bloodstream. However, dental infections have a number of other pathways for dissemination. By forming abscesses or phlegmon they can reach facial spaces that communicate with each other and then spread downwards to the mediastinum or upwards to the brain. In such cases dental infections can become, if not properly treated, life‐threatening. It seems that early diagnosis and treatment are imperative, and potentially infectious foci should be traced and eliminated. Dental hygiene and prophylaxis to prevent dental biofilm formation are important measures to reduce the risk of these calamities. The more compromised the host defense is, the more importance should be put on these measures. Although commensal bacteria are often involved in these infections, attention should also be paid to specific periodontal pathogens, and a proper microbial diagnosis, obtained using molecular methods plus bacterial sensitivity testing, can provide the patient with optimal care. Drainage of pus must be established where possible so that the optimal effect of antibiotics can be achieved. Penicillin is still the drug of first choice in settings where suspicion of methicillin‐resistant Staphylococcus aureus is low.