Meropenem-RPX7009 Concentrations in Plasma,Epithelial Lining Fluid,and Alveolar Macrophages of Healthy Adult Subjects

The steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows: C_max = 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml, V_ss = 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, and t_1/2 = 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC_0–8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.     

Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.     

Inhibition of Aminoglycoside 6′-N-Acetyltransferase Type Ib-Mediated Amikacin Resistance in Klebsiella pneumoniae by Zinc and Copper Pyrithione

The in vitro activity of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] was inhibited by CuCl₂ with a 50% inhibitory concentration (IC₅₀) of 2.8 μM. The growth of an amikacin-resistant Klebsiella pneumoniae strain isolated from a neonate with meningitis was inhibited when amikacin was supplemented by the addition of Zn²⁺ or Cu²⁺ in complex with the ionophore pyrithione. Coordination complexes between cations and ionophores could be developed for their use, in combination with aminoglycosides, to treat resistant infections.     

Real-time modulation of visual feedback on human full-body movements in a virtual mirror: development and proof-of-concept

Background

Virtual reality (VR) provides interactive multimodal sensory stimuli and biofeedback, and can be a powerful tool for physical and cognitive rehabilitation. However, existing systems have generally not implemented realistic full-body avatars and/or a scaling of visual movement feedback. We developed a “virtual mirror” that displays a realistic full-body avatar that responds to full-body movements in all movement planes in real-time, and that allows for the scaling of visual feedback on movements in real-time. The primary objective of this proof-of-concept study was to assess the ability of healthy subjects to detect scaled feedback on trunk flexion movements.

Methods

The “virtual mirror” was developed by integrating motion capture, virtual reality and projection systems. A protocol was developed to provide both augmented and reduced feedback on trunk flexion movements while sitting and standing. The task required reliance on both visual and proprioceptive feedback. The ability to detect scaled feedback was assessed in healthy subjects (n = 10) using a two-alternative forced choice paradigm. Additionally, immersion in the VR environment and task adherence (flexion angles, velocity, and fluency) were assessed.

Results

The ability to detect scaled feedback could be modelled using a sigmoid curve with a high goodness of fit (R² range 89-98%). The point of subjective equivalence was not significantly different from 0 (i.e. not shifted), indicating an unbiased perception. The just noticeable difference was 0.035 ± 0.007, indicating that subjects were able to discriminate different scaling levels consistently. VR immersion was reported to be good, despite some perceived delays between movements and VR projections. Movement kinematic analysis confirmed task adherence.

Conclusions

The new “virtual mirror” extends existing VR systems for motor and pain rehabilitation by enabling the use of realistic full-body avatars and scaled feedback. Proof-of-concept was demonstrated for the assessment of body perception during active movement in healthy controls. The next step will be to apply this system to assessment of body perception disturbances in patients with chronic pain.     

Organic light emitting diode improves diabetic cutaneous wound healing in rats

A major complication for diabetic patients is chronic wounds due to impaired wound healing. It is well documented that visible red wavelengths can accelerate wound healing in diabetic animal models and patients. In vitro and in vivo diabetic models were used to investigate the effects of organic light emitting diode (OLED) irradiation on cellular function and cutaneous wound healing. Human dermal fibroblasts were cultured in hyperglycemic medium (glucose concentration 180 mM) and irradiated with an OLED (623 nm wavelength peak, range from 560 to 770 nm, power density 7 or 10 mW/cm² at 0.2, 1, or 5 J/cm²). The OLED significantly increased total adenosine triphosphate concentration, metabolic activity, and cell proliferation compared with untreated controls in most parameters tested. For the in vivo experiment, OLED and laser (635 ± 5 nm wavelength) treatments (10 mW/cm², 5 J/cm² daily for a total of seven consecutive days) for cutaneous wound healing were compared using a genetic, diabetic rat model. Both treatments had significantly higher percentage of wound closure on day 6 postinjury and higher total histological scores on day 13 postinjury compared with control. No statistical difference was found between the two treatments. OLED irradiation significantly increased fibroblast growth factor‐2 expression at 36‐hour postinjury and enhanced macrophage activation during initial stages of wound healing. In conclusion, the OLED and laser had comparative effects on enhancing diabetic wound healing.     

Genotype–Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers

The genotype–phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi‐ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi‐Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0–12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation‐specific counseling and be more aggressively managed for risk reduction.