The Ability of Stroke Volume Variation Measured by a Noninvasive Cardiac Output Monitor to Predict Fluid Responsiveness in Mechanically Ventilated Children

Continuous noninvasive cardiac output monitoring (NICOM) is a clinically useful tool in the pediatric setting. This study compared the ability of stroke volume variation (SVV) measured by NICOM with that of respiratory variations in the velocity of aortic blood flow (△Vpeak) and central venous pressure (CVP) to predict of fluid responsiveness in mechanically ventilated children after ventricular septal defect repair. The study investigated 26 mechanically ventilated children after the completion of surgery. At 30 min after their arrival in an intensive care unit, a colloid solution of 10 ml/kg was administrated for volume expansion. Hemodynamic variables, including CVP, stroke volume, and △Vpeak in addition to cardiac output and SVV in NICOM were measured before and 10 min after volume expansion. The patients with a stroke volume increase of more than 15 % after volume expansion were defined as responders. The 26 patients in the study consisted of 13 responders and 13 nonresponders. Before volume expansion, △Vpeak and SVV were higher in the responders (both p values <0.001). The areas under the receiver operating characteristic curves of △Vpeak, SVV, and CVP were respectively 0.956 (95 % CI 0.885–1.00), 0.888 (95 % CI 0.764–1.00), and 0.331 (95 % CI 0.123–0.540). This study showed that SVV by NICOM and △Vpeak by echocardiography, but not CVP, reliably predicted fluid responsiveness during mechanical ventilation after ventricular septal defect repair in children.     

Effect of Gleason scores of lymph node metastases on prognosis of patients with prostate cancer

The long-term mortality risk from prostate cancer increases in lymph node (LN) positive patients. This study was done to assess the effect of lymph node Gleason score (LNGS) on prognosis in patients with LN-positive prostate cancer. Among the 1,415 patients who received pelvic lymph node dissection (PLND), 117 (8.4%) patients had a positive LN. The PGS of the prostate specimens and the LNGS of the positive LNs were assessed by uropathologists. The median age of patients at surgery was 67 years (interquartile range [IQR], 62-71 years) and the median follow-up duration was 44.3 months (IQR, 27.0-78.5 months). Pathologic Gleason scores (PGS) of 6-9 included one (0.9%), 53 (49.5%), 22 (20.6%), and 31 (29.0%) patients. The median total number of retrieved LNs was 9.0 (IQR, 5.3-12.8). The median number of positive LNs was one (IQR, 1-2). Cancer architecture with a Gleason pattern and score were observed in LNs as in ordinary prostate specimens. LNGS 6-9 included nine (8.1%), 57 (51.4%), 31 (27.9%), and 14 (12.6%) patients. The speaman’s analysis showed the meaningful correlation between PGS and LNGS (P = 0.249, P = 0.011). The univariate analysis showed that the number of positive LNs and LNGS were significantly associated with prostate cancer-specific survival (P = 0.028; P = 0.005). The same architecture that is seen in the prostate was seen in positive LNs, and LNGS may be a significant prognostic factor in patients with LN-positive prostate cancer.     

Fabrication of fine-pored polydimethylsiloxane using an isopropyl alcohol and water mixture for adjustable mechanical,optical, and thermal properties

Porous polydimethylsiloxane (PDMS) has garnered interest owing to its large inner surface area, high deformability, and lightweight, while possessing inherent properties, such as transparency, flexibility, cost-effectiveness, ease of fabrication, chemical/mechanical stability, and biocompatibility. For producing porous PDMS, gas foaming, sacrificial template, and emulsion template techniques have been used extensively. However, the aforementioned methods have difficulty in achieving submicron-sized inner pores, which is advantageous for improving flexibility and transparency. This study demonstrates a simple fabrication method for obtaining porous PDMS with fine pores partially down to the sub-micron scale. This is possible by the use of cheap, volatile, and easily accessible isopropyl alcohol (IPA) as a co-solvent in water and pre-PDMS emulsion. IPA shows an affinity towards both water and prepolymer, resulting in an increased distribution of small water particles inside PDMS before curing. These water particles evaporate while curing the prepolymer emulsion, thereby generating fine pores. The fine size and number density of pores are controlled by water and the added amount of IPA, resulting in adjustable mechanical, optical, and thermal properties of porous PDMS.

A fabrication method for obtaining fine-pored PDMS is presented. Low-cost, volatile, and easily accessible IPA is used as a co-solvent in water and PDMS emulsions, allowing porous PDMS with adjustable mechanical, optical and thermal properties.     

Characterization of mGluR5R,a novel,metabotropic glutamate receptor 5-related gene

We report here the isolation of a novel gene termed mGluR5R (mGluR5-related). The N-terminus of mGluR5R is highly similar to the extracellular domain of metabotropic glutamate receptor 5 (mGluR5) whereas the C-terminus bears similarity to the testis-specific gene, RNF18. mGluR5R is expressed in the human CNS in a coordinate fashion with mGluR5. Although the sequence suggests that mGluR5R may be a secreted glutamate binding protein, we found that when expressed in HEK293 cells it was membrane associated and not secreted. Furthermore, mGluR5R was incapable of binding the metabotropic glutamate receptor class I selective agonist, quisqualate. Although mGluR5R could not form disulfide-mediated covalent homodimers, it was able to form a homomeric complex, presumably through noncovalent interactions. mGluR5R also formed noncovalent heteromeric associations with an engineered construct of the extracellular domain of mGluR5 as well as with full-length mGluR5 and mGluR1alpha. The ability of mGluR5R to associate with mGluR1alpha and mGluR5 suggests that it may be a modulator of class I metabotropic glutamate receptor function.     

Changing patterns in the clinical characteristics of Korean patients with breast cancer during the last 15 years

HYPOTHESIS: Breast cancer has become the most common cancer in Korean women in recent years, with continuously increased incidence rates attributed to westernized lifestyles. DESIGN: Retrospective case series evaluating the changing patterns of clinical characteristics in breast cancer during the last 15 years. SETTING: Hospitalized patients with breast cancer in a university medical center. PATIENTS: A total of 5001 breast cancer patients who underwent surgery between July 1989 and March 2004 at the Asan Medical Center. MAIN OUTCOME MEASURE: Clinicopathologic data were collected using the online Korea Breast Cancer Registration Program, including factors such as age, symptoms, stage, surgery, reconstruction, risk factors, and survival. RESULTS: The median age of patients slightly increased from 44 years in 1991 to 46 years in 2003. The most frequent age group was the fifth decade (41.7%) and premenopausal women younger than 50 years (64.9%). The proportion of asymptomatic patients detected by screening mammography increased from 3.8% in 1991 to 21.0% in 2003 (P<.001). The proportion of early breast cancer (stages 0 and I) increased from 34.2% in 1991 to 48.8% in 2003 (P=.013). Breast-conserving surgery has increased continuously from 5.1% in 1991 to 39.1% in 2003 (P<.001). Twelve percent of all patients who underwent mastectomies had immediate reconstruction, and the proportion showed an increasing trend, especially in skin-sparing mastectomy and transverse rectus abdominis myocutaneous flap reconstruction. Five-year observed survival rates were 84.1%. Five-year survival rates according to stages were as follows: (1) 98.5%, stage 0; (2) 95.3%, stage I; (3) 86.0%, stage II; (4) 65.0%, stage III; and (5) 29.3%, stage IV. The number of patients with specific risk factors, such as early menarche and late first delivery, significantly increased. Of 263 high-risk patients examined for the BRCA mutation, mutations were found in 20 patients (7.6%), with 13 cases with BRCA1 and 7 cases with BRCA2. CONCLUSIONS: The present study showed a continuous increase in the number of patients with breast cancer; the proportion of young patients, asymptomatic patients, early breast cancer, breast-conserving surgery, and immediate reconstruction after mastectomy; and the number of patients with risk factors. These results suggest that the clinical characteristics of Korean breast cancer patients reflect the patterns of Western countries.     

Effect of cenobamate on the single‐dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects

This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no‐effect interval (0.80–1.25). When co‐administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC_0–last) GMR (90% CIs) for midazolam was 0.734 (0.647–0.832). When co‐administered with cenobamate 200 mg/day, AUC_0–last GMRs (90% CI) for midazolam, bupropion, S‐warfarin, and omeprazole were 0.277 (0.238–0.323), 0.615 (0.522–0.724), 1.14 (1.10–1.18), and 2.07 (1.44–2.98), respectively. Co‐administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co‐administration of cenobamate led to omeprazole values which were outside and above the no‐effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co‐administration of cenobamate with these probes drugs was well‐tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose‐dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐drug interactions are a challenging aspect of managing epilepsy because many antiseizure medications (ASMs) induce or inhibit CYP450 enzymes, which are commonly involved in drug metabolism of many ASMs. Previous studies suggest that cenobamate, a US Food and Drug Administration (FDA)‐approved ASM for the treatment of adults with focal seizures, may affect the activity of certain CYP450 enzymes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study was designed to determine the effects of cenobamate on the pharmacokinetics of drugs known to affect the activity of these CYP450 enzymes, known as probe drugs. These probe drugs include bupropion, (CYP2B6), midazolam (CYP3A4/5), warfarin (CYP2C9), and omeprazole (CYP2C19).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results of this study indicate that cenobamate induces CYP2B6 activity, exhibits a dose‐dependent induction of CYP3A4/5 activity, inhibits CYP2C19 activity, and has a negligible effect on CYP2C9 activity.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These findings suggest that dose adjustments may be required when agents metabolized through these CYP450 pathways are used in conjunction with cenobamate.