Synthesis of new piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald–Hartwig cross-coupling reaction

Two series of piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives were prepared via a Buchwald–Hartwig cross-coupling reaction and then evaluated for their ability to inhibit the drug efflux activity of CaCdr1p and CaMdr1p transporters of Candida albicans overexpressed in a Saccharomyces cerevisiae strain. In the initial screening of twenty-nine piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives, twenty-three compounds behaved as dual inhibitors of CaCdr1p and CaMdr1p. Only four compounds showed exclusive inhibition of CaCdr1p or CaMdr1p. Further biological investigations were developed and for example, their antifungal potential was evaluated by measuring the growth of control yeast cells (AD1-8u⁻) and efflux pump-overexpressing cells (AD-CDR1 and AD-MDR1) after exposition to variable concentrations of the tested compounds. The MIC₈₀ values of nineteen compounds ranging from 100 to 901 μM for AD-CDR1 demonstrated that relative resistance index (RI) values were between 8 and 274. In comparison, only seven compounds had RI values superior to 4 in cells overexpressing Mdr1p. These results indicated substrate behavior for nineteen compounds for CaCdr1p and seven compounds for CaMdr1p, as these compounds were transported via MDR transporter overexpressing cells and not by the AD1-8u⁻ cells. Finally, in a combination assay with fluconazole, two compounds (1d and 1f) have shown a synergistic effect (fractional inhibitory concentration index (FICI) values ≤ 0.5) at micromolar concentrations in the AD-MDR1 yeast strain overexpressing CaMdr1p-protein, indicating an excellent potency toward chemosensitization.

Two series of piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives were prepared via a Buchwald–Hartwig cross-coupling reaction and then evaluated for their ability to inhibit the drug efflux activity of two Candida albicans transporters.     

Renal vascular damage in systemic sclerosis patients without clinical evidence of nephropathy

Objective. To evaluate the use of color-flow Doppler ultrasonography, a direct, noninvasive technique, for measurement of kidney blood flow in patients with systemic sclerosis (SSc). Methods. Twenty-five normal volunteers and 25 SSc patients (median disease duration 8 years, range 2–21 years) were studied. All were free of clinical symptoms of renal damage. The resistance index (RI) was determined on main, interlobar, and cortical vessels. Results. In SSc patients, the RI was significantly increased at every sampling site examined (P < 0.001). RI values were strongly correlated with disease duration (main artery r = 0.56, P < 0.04; interlobar artery r = 0.63, P < 0.02; cortical artery r = 0.75, P < 0.002). Regression analysis showed no relationship between RI and creatinine clearance values. Conclusion. Color-flow Doppler ultrasonography is a sensitive and noninvasive technique for evaluating vascular damage of the kidney in patients with SSc.     

Efficacy of tilt training in the treatment of neurally mediated syncope. A randomized study.

Recurrent neurally mediated syncope represents a common clinical event and a therapeutic challenge. Recently tilt training has been proposed for the treatment of recurrent neurally mediated syncope. To evaluate the efficacy of tilt training in preventing tilt-induced syncope and its feasibility, this controlled, randomized study was undertaken. Sixty-eight consenting patients (25 males and 43 females, mean age 40 +/- 19) with recurrent neurally mediated syncope and 2 consecutive positive nitroglycerin-potentiated head-up tilt tests were randomized to tilt training (35 patients) or no treatment (controls, 33 patients). The tilt training programme consisted of daily 30-min sessions of upright standing against a vertical wall 6 days a week for at least 3 weeks, until a reevaluation tilt test (3 patients of both groups dropped out). On this third head-up tilt test, 19 (59%) of 32 tilt trained patients and 18 (60%) of 30 controls still had a positive test. Treated patients performed a mean number of 15 +/- 7 sessions (median 16) and only 11 patients (34%) did all the programmed sessions. Only 1 patient (3%) discontinued treatment because of intolerance, while all other patients did not perform tilt training adequately, because of poor compliance. Thus, in our study tilt training was not effective in reducing tilt testing positivity rate in patients with neurally mediated syncope. Because of poor compliance, tilt training appears to be a feasible treatment only for highly motivated patients, but not for the majority of patients with recurrent neurally mediated syncope.     

Exhaled air temperature in asthmatic children: a mathematical evaluation

Recently, the exhaled breath temperature has been proposed as a potential marker for the evaluation of airway inflammation in asthma. The purpose of this study was to verify the ability to distinguish asthmatics from normal controls by a dedicated detailed mathematical evaluation of the exhaled air curve. Analysis was performed in the different phases of the curve of exhaled temperature, i.e. the rate of temperature increase (Δ e ° T ) and the mean plateau value. Principal components analysis (PCA) and artificial neural networks (ANNs) were used for the evaluation of the data in 90 asthmatic children and in 33 healthy age-matched controls. Both PCA and ANNs showed that a separation between patients and controls can be obtained only by the evaluation of the plateau phase of the curve, which better reflects the periphery of the airway.     

Are Diabetes,Hypertension, and Obesity Independent Risk Factors for Endometrial Polyps?

Study ObjectiveTo investigate whether diabetes, hypertension (HTN), and obesity can be considered risk factors for endometrial polyps (EPs) independently of age and menopausal status.DesignRetrospective analysis (Canadian Task Force classification III).SettingDepartment of Obstetrics and Gynecology of the University of Foggia, Italy.PatientsA total of 353 Caucasian women undergoing office hysteroscopy to assess abnormal uterine bleeding, infertility, cervical polyps, and abnormal sonographic patterns.InterventionsDemographic characteristics and data on diabetes, HTN, and menopausal status were collected and anthropometric parameters were analyzed. Vaginoscopic hysteroscopy was performed with a 5-mm continuous-flow operative office hysteroscope. When present, EPs were treated during the same procedure by means of 5-Fr scissors or electrode.Measurements and Main ResultsIn 134 (38%) of 353 cases, EPs were found. Univariable and multivariable analysis were performed to verify the presence of a statistically significant association among age, menopause, HTN, obesity, diabetes (independent variables), and the presence of EPs. Univariable logistic analysis showed a statistically significant association among age, menopause, HTN, obesity, and the presence of EPs. However, when multivariable logistic regression was performed, all the independent variables, except age, lost statistical significance (OR 1.05, 95% CI 1.02–1.07, p <.001).ConclusionAlthough it appears that EP is a disorder of aging, the significance of diabetes, HTN, and obesity, as well as menopause, on the development of EPs should be reconsidered.     

Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach

Members of the French-American-British Cooperative Leukemia Working Group met to review cases of aplastic anemia, hypocellular myelodysplastic syndrome and hypocellular acute myeloid leukemia. Criteria were proposed and modified following three workshops. Additional input was obtained from another hematopathologist with a special interest in bone marrow histology and immunohistochemistry. Guidelines were recommended based on the workshop results as well as additional studies including selective immunohistochemistry, flow cytometry and cytogenetics.     

Preliminary Experience with a New Sclerosing Foam in the Treatment of Varicose Veins

BACKGROUND: Recently a new method of using a foam sclerosing agent for the treatment of leg veins has been described. We present a pilot study of a new technique for producing the sclerosing foam (Tessari's method) (SFT) and its use in sclerotherapy of major and minor varicosities. OBJECTIVE: A preliminary multicenter experience of sclerotherapy performed by means of this new kind of sclerosing foam made of purified sodium tetradecylsulfate is described. The authors evaluated the safety and efficacy of different doses and concentrations of the drug as well as different methods of preparing the foam in addition, the results of this technique were evaluated. METHODS: Over a 6-week period the three authors performed sclerotherapy or duplex-guided sclerotherapy using SFT, treating 77 patients. The SFT was formed using a three-way stopcock and two syringes, mixing air with liquid sodium tetradecylsulfate to create a foam. Each author used different concentrations (0.1-3%) and doses (2-8 ml) of SFT according to the size and number of the veins. Alternate methods of preparing the foam were examined as well. Seventy percent of the sclerotherapy sessions were performed on either the long or short saphenous veins, recurrent varices, or collaterals. Thirty percent of the treatments were for reticular varices and telangiectases. RESULTS: At 1-month follow-up, the vast majority of treated larger veins were either obliterated or showed a normal state of cephalad blood flow. Results for minor varicosities were good, but with related complications of hyperpigmentation and small areas of cutaneous necrosis. Two patients experienced transient scotomas and one patient developed segmental phlebitis of a collateral vein. The best foam was obtained by mixing one part liquid sodium tetradecylsulfate and four to five parts air, but the duration of the foam product was also related to several other factors. CONCLUSION: This preliminary pilot study demonstrates that the technique of producing sclerosing foam according to Tessari's method (three-way stopcock device) is very promising, especially for larger veins. No serious complications were reported, and further standardization of the method may improve the results and feasibility of this technique. Further studies are needed to validate this new technique.     

Isolated breast relapse after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia

Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone marrow and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT is still controversial.