Synthesis and preclinical evaluation of novel 18F-vancomycin-based tracers for the detection of bacterial infections using positron emission tomography.

INTRODUCTION: Bacterial infections are a major problem in medicine, and the rapid and accurate detection of such infections is essential for optimal patient outcome. Bacterial infections can be diagnosed by nuclear imaging, but most currently available modalities are unable to discriminate infection from sterile inflammation. Bacteria-targeted positron emission tomography (PET) tracers have the potential to overcome this hurdle. In the present study, we compared three 18F-labelled PET tracers based on the clinically applied antibiotic vancomycin for targeted imaging of Gram-positive bacteria. METHODS: [18F]FB-NHS and [18F]BODIPY-FL-NHS were conjugated to vancomycin. The resulting conjugates, together with our previously developed [18F]PQ-VE1-vancomycin, were tested for stability, lipophilicity, selective binding to Gram-positive bacteria, antimicrobial activity and biodistribution. For the first time, the pharmacokinetic properties of all three tracers were compared in healthy animals to identify potential binding sites. RESULTS: [18F]FB-vancomycin, [18F]BODIPY-FL-vancomycin, and [18F]PQ-VE1-vancomycin were successfully synthesized with radiochemical yields of 11.7%, 2.6%, and 0.8%, respectively. [18F]FB-vancomycin exhibited poor in vitro and in vivo stability and, accordingly, no bacterial binding. In contrast, [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin showed strong and specific binding to Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which was outcompeted by unlabeled vancomycin only at concentrations exceeding clinically relevant vancomycin blood levels. Biodistribution showed renal clearance of [18F]PQ-VE1-vancomycin and [18F]BODIPY-FL-vancomycin with low non-specific accumulation in muscles, fat and bones. CONCLUSION: Here we present the synthesis and first evaluation of the vancomycin-based PET tracers [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin for image-guided detection of Gram-positive bacteria. Our study paves the way towards real-time bacteria-targeted diagnosis of soft tissue and implant-associated infections that are oftentimes caused by Gram-positive bacteria, even after prophylactic treatment with vancomycin.

Targeted optical fluorescence imaging: a meta-narrative review and future perspectives.

PURPOSE: The aim of this review is to give an overview of the current status of targeted optical fluorescence imaging in the field of oncology, cardiovascular, infectious and inflammatory diseases to further promote clinical translation. METHODS: A meta-narrative approach was taken to systematically describe the relevant literature. Consecutively, each field was assigned a developmental stage regarding the clinical implementation of optical fluorescence imaging. RESULTS: Optical fluorescence imaging is leaning towards clinical implementation in gastrointestinal and head and neck cancers, closely followed by pulmonary, neuro, breast and gynaecological oncology. In cardiovascular and infectious disease, optical imaging is in a less advanced/proof of concept stage. CONCLUSION: Targeted optical fluorescence imaging is rapidly evolving and expanding into the clinic, especially in the field of oncology. However, the imaging modality still has to overcome some major challenges before it can be part of the standard of care in the clinic, such as the provision of pivotal trial data. Intensive multidisciplinary (pre-)clinical joined forces are essential to overcome the delivery of such compelling phase III registration trial data and subsequent regulatory approval and reimbursement hurdles to advance clinical implementation of targeted optical fluorescence imaging as part of standard practice.

A light-responsive liposomal agent for MRI contrast enhancement and monitoring of cargo delivery.

Medical magnetic resonance imaging (MRI) produces high-resolution anatomical images of the human body, but has limited capacity to provide useful molecular information. The light-responsive, liposomal MRI contrast agent described herein could be used to provide an intrinsic theranostic aspect to MRI and enable tracking the distribution and cargo release of drug delivery systems upon light-triggered activation.

Tavipec in acute rhinosinusitis: a multi-centre, doubleblind, randomized, placebo-controlled, clinical trial.

BACKGROUND: This randomized clinical trial was designed to evaluate the efficacy and safety of Tavipec® (Spicae aetheroleum), a phytomedicine obtained by steam distillation of the flowering tops of Lavandula latifolia, as compared to placebo in adult patients suffering from acute viral rhinosinusitis. METHODOLOGY: Patients with acute viral rhinosinusitis were randomly assigned to treatment with 2 capsules Tavipec® 150 mg or placebo thrice daily over a period of 7 days in a double-blind, parallel-group design. No additional treatment was admitted. The efficacy endpoints comprised the improvement of the main rhinosinusitis symptoms as per Major Symptom Score (MSS) and Sino-Nasal Outcome Test (SNOT-22) as well as of quality of life (QoL) by global assessment scale, evaluated at baseline, day 5 and day 8, respectively. RESULTS: 288 patients were enrolled and randomized to treatment. At day 8 the patients in the Tavipec® group had a significantly lower MSS compared to placebo and the impact of rhinosinusitis symptoms on QoL was significantly reduced. A significantly higher proportion of Tavipec® treated patients experienced a change in SNOT-22 score greater than or equal to 10 points at day 5 or day 8. No new safety signals were identified. CONCLUSIONS: The treatment with Tavipec® effectively reduced the symptoms of acute rhinosinusitis in adult patients.

Controlling the activity of quorum sensing autoinducers with light.

Bacteria use a communication system, called quorum sensing (QS), to organize into communities and synchronize gene expression to promote virulence and secure survival. Here we report on a proof-of-principle for externally interfering with this bacterial communication system, using light. By employing photoswitchable small molecules, we were able to photocontrol the QS-related bioluminescence in an Escherichia coli reporter strain, and the expression of target QS genes and pyocyanin production in Pseudomonas aeruginosa.

Basal serum tryptase level correlates with severity of hymenoptera sting and age.

BACKGROUND: Increased serum tryptase has been linked to the severity of the reaction after Hymenoptera stings. The aim of the study was to measure basal tryptase levels in patients with Hymenoptera venom allergy and investigate the possible correlation between these levels and the severity of sting reaction. METHODS: One hundred nine patients were included in the study. Sixty-three were wasp venom-allergic and 46 were honey bee venom-allergic. Basal serum tryptase levels were measured by UniCAP. RESULTS: Basal serum tryptase levels were elevated in 12 (11%) of the 109 patients. Levels were 5.14 pg/L (3.62-5.84), 5.3 microg/L (2.94-6.54), 5.18 microg/L (3.71-6.25), and 6.98 microg/L (4.78-12.6), for patients with sting reactions of grade I, II, III and IV (as classified by Mueller), respectively. Basal serum tryptase levels correlated significantly with the sting reaction severity (r = 0.2752; P = .004) and with age (r = 0.2906; P = .002). Sting reaction severity also correlated with age (r = 0.3654; P = .001). CONCLUSIONS: Basal serum tryptase levels were found to be elevated in 11% of venom allergic patients and correlated significantly with both sting reaction severity and age.

Assessment and prevalence of depression in women 45-55 years of age visiting gynecological clinics in Poland: screening for depression among midlife gynecologic patients.

The aims of the Polish survey were to assess efficacy of screening for depression in gynecological practice and to estimate prevalence of depressive disorders in midlife women visiting gynecologists. The study included 2262 female outpatients aged 45-55, who were screened by 120 gynecologists throughout Poland. Patients completed the Beck's Depression Inventory (BDI) and were assessed by gynecologists to verify the presence of symptoms of a current Depressive Episode according to ICD-10 diagnostic criteria. Patients who obtained a score of 12 points or more on the BDI were referred for psychiatric evaluation, including the modified version of Mini International Neuropsychiatric Interview (MINI). The study showed that gynecologists in Poland are able to perform screenings for depression effectively in outpatient settings. Results also suggested that about 19% of women aged 45 to 55 years visiting gynecologists may suffer from depressive disorders.

Frequency of three BRCA1 gene founder mutations in breast/ovarian cancer families from the Pomerania-Kujawy region of Poland.

A group of 63 families from the Pomerania-Kujawy region were analyzed for three BRCA1 gene Polish founder mutations, 5382insC, 300T>G, and 4153delA, because of breast (BrCa) and/or ovarian cancer (OvCa) history. The analysis was carried out by multiplex polymerase chain reaction method. BRCA1 mutation was revealed in nine (14%) families: in three (33%) of hereditary BrCa and OvCa families, in three (8%) of hereditary BrCa families, and in three (21%) of hereditary OvCa families. According to risk criteria, it was revealed in 45% of high-risk families with more than three cancers, 13% of moderate-risk families with two cancers, and 8% of families with sporadic OvCa. In six families, the mutation was found in a proband with BrCa or OvCa and in three families, the mutation was found in a healthy proband, first-degree relative of a patient deceased of BrCa or OvCa. 5382insC frameshift mutation accounted for 67% and 300T>G missense mutation for 33% of all identified familial mutations. 4153delA frameshift mutation was not found in analyzed sample of families. 5382insC mutation was found in 9% and 300T>G in 5% of all investigated families, and in 27 and 18%, respectively, of high-risk families. This underlines the importance of applying strict inclusion criteria to analyze mutation frequency in hereditary BrCa/OvCa families.

Polish consensus: procedure in case of estrogen deficiency in women after breast cancer therapy.

Women surviving breast cancer in the postmenopausal period suffer from hormonal alternations with adverse effect on mental status and functioning of a number of organs and systems. Two thirds of these women had menopause before the diagnosis of breast cancer. In the remaining one-third ovarian failure is natural or induced by chemotherapy. Doctors cautiously approach the use of estrogen therapy in this group of patients. Their fears are not unsupported bearing in mind known epidemiological data exist linking breast cancer with the use of hormonal therapy. The purpose of this review is to evaluate current data on hormonal use and breast cancer risk.

Charge-reduced nano electrospray ionization combined with differential mobility analysis of peptides, proteins, glycoproteins, noncovalent protein complexes and viruses.

This study explores the potential of a novel electrospray-based method, termed gas-phase electrophoretic mobility molecular analysis (GEMMA), allowing the molecular mass determination of peptides, proteins and noncovalent biocomplexes up to 2 MDa (dimer of immunglobulin M). The macromolecular ions were formed by nano electrospray ionization (ESI) in the 'cone jet' mode. The multiple charged state of the monodisperse droplets/ions generated was reduced by means of bipolar ionized air (generated by an alpha-particle source) to yield exclusively singly charged positive and negative ions as well as neutrals. These ions are separated subsequently at atmospheric pressure using a nano differential mobility analyzer according to their electrophoretic mobility in air. Finally, the ions are detected using a standard condensation particle counter. Data were expressed as electrophoretic mobility diameters by applying the Millikan equation. The measured electrophoretic mobility diameters, or Millikan diameters, of 32 well-defined proteins were plotted against their molecular weights in the range 3.5 to 1920 kDa and exhibited an excellent squared correlation coefficient (r(2) = 0.999). This finding allowed the exact molecular weight determination of large (glyco)proteins and noncovalent biocomplexes by means of this new technique with a mass accuracy of +/-5.6% up to 2 MDa at the femtomole level. From the molecular masses of the weakly bound, large protein complexes thus obtained, the binding stoichiometry of the intact complex and the complex stability as a function of pH, for example, can be derived. Examples of specific protein complexes, such as the avidin or catalase homo-tetramer, are used to illustrate the potential of the technique for characterization of high-mass biospecific complexes. A discussion of current and future applications of charge-reduced nano ESI GEMMA, such as chemical reaction monitoring (reduction process of immunglobulin G) or size determination of an intact virus, a supramolecular complex, and monitoring of partial dissociation of a human rhinoviruses, is provided.

[Application of IVF in women with endometriosis]. / Zastosowanie IVF u pacjentek z endometrioza.

Application of IVF at women with endometriosis after pharmacological and surgical therapy hold out hopes to possession of child. Endometriosis occurs three times more often in the patients with primary sterility than in patients with secondary sterility. The presence of a small endometriosis does not reduce the success of the IVF therapy. The women with endometriosis who undergo IVF treatment have similar prospect in compensate with women with tubal sterility. IVF improve fertility in women with mild or minimal endometriosis. But at women after IVF the presence of endometriomas is associated with increased rates of early pregnancy losses. Women with endometriosis marking often antinuclear antibodies and antiphospholipid antibodies than women without endometriosis. To evaluate the 15% of infertile women have endometriosis.

[Evaluation of incidence of Chlamydia trachomatis infections among the group of infertile women diagnosed by laparoscopy, and based on properties of Chlamydia trachomatis in the cervical canal, peritoneal fluid and ovarian cyst puncture]. / Ocena czestosci wystepowania infekcji wywolywanych przez Chlamydia Trachomatis, u nieplodnych kobiet diagnozowanych laparoskopowo, na podstawie obecnosci Chlamydii Trachomatis w szyjce macicy, plynie z wolnej jamy otrzewnowej, punktatów torbieli jajnika.

The number of 75 patients who underwent diagnostic et operative laparoscopy was analysed. The percentage of infection cases caused by Chlamydia Trachomatis was 9.33% investigations proved correlation between fallopian tube factor and infection. It seems that pelvic infection not always undergoes with infection of uterine cervix.

[Concentrations of MMP-1, TIMP-1, MMP-1/TIMP-1 and I CTP complexes in follicular fluid as related to fertilization rate in women treated with in-vitro fertilization]. / Stezenie MMP-1, TIMP-1, kompleksów MMP-1/TIMP-1 i I CTP w plynie pecherzykowym w odniesieniu do wskaznika zaplodnienia komórek jajowych u kobiet leczonych metoda zaplodnienia pozaustrojowego.

OBJECTIVES: Metalloproteinases and their inhibitors appear to control connective tissue remodelling during follicular rupture. The aim of the study was to establish if oocytes fertilisation rate after ovulation induction depends on the concentrations of MMP-1, its inhibitor TIMP-1, MMP-1/TIMP-1 complex and I CTP in follicular fluid (FF). MATERIAL AND METHODS: FF were collected from 37 infertile patients undergoing ovulation induction using either short or long protocol. FF was obtained 36 hours after administration of hCG (Pregnyl). The level of MMP-1, TIMP-1, MMP-1/TIMP-1 complex were measured using ELISA kits and I CTP, E2, FSH, LH, using RIA assay kits. RESULTS: Statistically significant (p < 0.05) difference was found in TIMP-1, E2, and FSH concentration, being higher in the group with more than 75% fertilisation rate: TIMP-1 728.8 + 100.1 ng/ml vs 666.3 + 94.5 ng/ml; E2 477.3 +/- 160.0 ng/ml vs 368.0 +/- 190.0 ng/ml and FSH 7.27 +/- 1.45 mIU/ml vs 6.24 +/- 1.6 mIU/ml. CONCLUSIONS: Statistically significant increase in TIMP-1 concentration observed among patients with fertilisation rate above 75% indicates an important role of this substance in ovulation process.

Blood selenium and glutathione peroxidases in miscarriage.

OBJECTIVE: To investigate the selenium glutathione and glutathione peroxidase (glutathione-Px) levels in blood in women who experience miscarriage. DESIGN: An observational study. PARTICIPANTS: Forty women with miscarriage occurring in the first and second trimesters. METHODS: Concentrations were measured in whole blood and plasma. Glutathione was measured in red cells and glutathione-Px activity was measured in the red cells and plasma. The results were compared with 36 women in the same period of viable pregnancy and 28 age-matched, healthy, non-pregnant controls. RESULTS: The selenium concentrations in whole blood and plasma of women following abortion were the same as in viable pregnancy, but were significantly lower compared with controls. The glutathione levels were significantly higher in women with miscarriage compared with viable pregnancies and with non-pregnant women. Red cell and plasma glutathione-Px activities of women who had had a miscarriage were significantly lower than in both normal pregnancies and the control group. CONCLUSION: The decreased activities of the antioxidant enzymes, red cell and plasma glutathione-Px, may play an important role in the aetrology of spontaneous abortion.

[Evaluation of cGMP plasma concentration in women in normal pregnancy and labor]. / Ocena stezenia CGMP w osoczu krwi kobiet w przebiegu ciazy prawidlowej i poczatku fizjologicznego porodu.

UNLABELLED: Aim of our study was evaluation of cGMP plasma concentration in women in course normal pregnancy and labour. The investigations were performed in Department of Obstetrics and Gynaecology Medical Academy in Bydgoszcz. Following groups of patients were examined. 1. 12 non-pregnant women 2. 59 women with normal pregnancy 3. 31 women at term with spontaneous uterus contractions. RESULTS: 1. low concentrations cGMP in plasma in non-pregnant women in course of menstruation cycle 2, low concentration cGMP in the first half of pregnancy--with gradual increase from 25 to 33 gestation week and with rapid increase in last 7 weeks of pregnancy, 3.--significant higher cGMP concentration at term in relation to values observed in early pregnancy and to the period between 28 and 37 weeks of gestation 4. significant higher cGMP plasma concentration in women in labour in relation to cGMP concentrations at term without uterus contractions.

The level of typical biomarker of oxidative stress 8-hydroxy-2'-deoxyguanosine is higher in uterine myomas than in control tissues and correlates with the size of the tumor.

The results of this work show a higher level of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a typical biomarker of oxidative stress, in uterine myoma tissues than in their respective tumor-free tissues. The level of this modified base was elevated in uterine tissues of premenopausal women when compared with postmenopausal ones. We have also found the correlation between the size of the tumor and the amount of 8-OH-dG. These results suggest that estrogen-produced 8-OH-dG may be one of the factors responsible for the formation of the myoma, and it may contribute to malignant transformation of myoma cells.

[The influence of delivery methods for twins on obstetric results]. / Wplyw sposobu prowadzenia porodu blizniaczego na wyniki poloznicze.

The analysis covered 100 twin gestations over the years 1996-1998 in the material of Gynecology and Obstetrics Clinic in Bydgoszcz. The authors estimated the relations between the mode of delivery and presentations of the twins. Abnormal foetal presentation occurred in 68 pregnancies (68%), and was more often in the second twin (61.8%). The highest percentage of cesarean sections (29%) we have observed in the case of an abnormal presentation of the first twin. The condition of the twins in their first minute after the birth was estimated according to the birth weight, the gestational age, and the mode of surgical procedures performed. Better condition after the birth of the second twin with the birth weight above 1000 g comparing to the first twin was established in cesarean sections, not in other obstetrical procedures. There was no essential difference between the mortality rate of the first and the second twin. Early diagnosis of the twin pregnancy using USG helps us to choose a suitable management during pregnancy and an optimal mode of delivery.