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.

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.

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.

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.

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.

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.

Racial differences in the presentation and surgical management of breast cancer.

BACKGROUND: African American women are seen with more advanced breast cancers, are less likely to be treated with breast-conserving surgery, and generally have poorer prognoses than white women. There are a myriad of potential causes for these phenomena. The purpose of this study was to measure racial differences in the surgical treatment of breast cancer among women with comparable health care access and delivery. METHODS: The Breast Cancer Registry of the Department of Surgery at Henry Ford Hospital was accessed for all patients between January 1, 1990, and December 31, 1997 for whom data on race, tumor characteristics, stage, and treatment specifics were available. Socioeconomic information was collected with use of 1990 census block data. Proportions of women who received each treatment were compared for African Americans and whites with use of the relative risk (RR) and 95% confidence intervals (CI). We used multiple logistic regression to obtain estimates of the relative risk, controlling for potential confounding factors. RESULTS: Of the 1699 patients in the database, 1250 had sufficient information for analysis. A total of 8.7% of African American women were diagnosed with late-stage disease (i.e., stage III or IV) compared with 7.9% of whites. Nevertheless, African American women had a lower frequency of stage I disease (30.5% vs 36.2%) and a higher frequency of stage II disease (36.8% vs 31.4%). Overall and adjusted risk estimates for age, tumor stage, marital status, median income, and type of insurance revealed no substantive or statistically significant differences between African American and white patients. The adjusted RR for local excision was 1.39 (95% CI 0.78 to 2.49), for lumpectomy and axillary dissection RR 0.92 (95% CI 0.66 to 1.29), for simple mastectomy RR 0.84 (95% CI 0.41 to 1.72), and for modified radical mastectomy RR 1.00 (95% CI 0.73 to 1.36). CONCLUSIONS: In this setting of equal access to health care, African American women still have higher frequencies of stage II disease, although the frequencies for late-stage disease are similar. Nevertheless, no surgical differences were found in this population, even after the effects of socioeconomic indicators and stage at diagnosis were controlled for Survival differences between African American and white women are unlikely to be explained by differences in treatment.

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.

IgG, IgA, IgM and IgE serum levels in asthmatic patients sensitive to house dust and mite allergens after two-year specific immunotherapy.

The investigations were carried out on 36 atopic asthma patients treated with a specific allergen vaccine--Allpyral. The serum immunoglobulin levels, specific IgE blocking antibodies were determined by various immunological methods. It was shown that a marked rise in the IgG level appeared after 6 months of therapy and maintained during the whole period of observation. This higher IgG level was often correlated with an increase in blocking antibody titer. IgE serum revealed a higher value after 6 months, but on prolongation of the immunotherapy the total IgE level decreased not statistically significantly. The specific IgE antibody showed a tendency to fall after 2-year hyposensitization. The most marked changes in the behaviour of specific IgE and blocking antibodies were observed in the patients with clinical improvement.

The effect of short-term immunotherapy with Pollinex on anti-IgE and antigen-induced histamine release from sensitive human basophils.

Anti-IgE and antigen-induced histamine release from basophils isolated from 30 atopic patients sensitive to grass pollen allergens was evaluated. The studies were made before and after short-term immunotherapy with glutaraldehyde-pollen-tyrosine adsorbate (Pollinex). It was shown, that after immunotherapy a significant drop in anti-IgE and specific antigen-induced histamine release from isolated basophils occurs. The investigations confirm that the diminution of the target cell sensitivity and releasability may be one of the effects of specific immunotherapy.

Blood histamine level and histamine content in the lung tissue in immediate immunological reactions in human and experimental animals.

The blood histamine level was determined in 66 patients with bronchial asthma and 25 guinea-pigs in whom the asthma attacks were induced by histamine or ovoalbumin inhalation after previous immunization of the animals. At the same time, histamine content of the lung tissue of the guinea-pigs was determined. It was found that in both humans and animals the level of blood histamine during immediate allergic reactions rises significantly. The extent of this rise depends on intensity of the reaction and time of determination. In asymptomatic period the blood histamine level did not differ from that of the control groups. Histamine concentration in the lung tissue of many of the animals increased during asthma attack but not in all cases was this increase correlated to the rise in blood histamine level. The reasons for these changes are discussed.

Histamine level in the blood and in the lung tissue during anaphylactic reaction in guinea-pigs treated with hydrocortisone and sodium cromoglycate.

The effect of hydrocortisone and disodium cromoglycate (Intal) on histamine release during immediate allergic reaction in experimental animals was studied. Histamine level in the blood and lung tissue was determined before antigen challenge during experimental asthma and after administration of hydrocortisone or Intal. The investigations revealed some differences in the histamine content in the blood and lung tissue depending on the time of the drug administration in relation to the antigen challenge and to the period of treatment.

Anaphylactic histamine release during inhibition of the proteolytic and kinin-forming system in experimental animals.

The experiments were carried out on immunized guinea-pigs. Histamine concentration in the blood and the lung tissue, the plasma prekallikrein and kininogen levels, kininase and fibrinolytic activity were determined. The examinations were made before antigen challenge, during anaphylactic reaction and after pharmacological inhibition of proteolysis. As protease inhibitors--Trasylol and EACA were used. The inhibition of the kinin and fibrinolytic systems by Trasylol and EACA did not markedly affect the allergic symptoms and did not change the high level of blood and lung tissue histamine. These experiments suggest that activation of the kinin system is not essential for the initiation of the immediate response but is the consequence of immunological release of histamine and other mediators.

Quality of life of breast cancer patients with lymphedema.

BACKGROUND: Quality of life has increasingly become an important issue in breast cancer treatment. One of the impetuses for sentinel lymph node biopsy or selective axillary lymph node dissection (ALND) is the assumed decreased incidence of lymphedema compared with standard ALND. This is based on the assumption that ALND is associated with a clinically significant incidence of lymphedema and that this lymphedema decreases the quality of life of these patients. However, few data exist on this issue. This study attempts to define the incidence and effect on quality of life of postoperative lymphedema in breast cancer patients. METHODS: To determine the incidence of postoperative lymphedema, the Breast Cancer Registry at Henry Ford Hospital was accessed to obtain information on all patients who underwent ALND in the management of breast cancer over a 7-year period. The registry is a prospectively gathered data base to include the development of various complications, such as lymphedema. To determine the effects of lymphedema on quality of life, 101 consecutive, unselected patients who underwent breast surgery were asked to complete the SF-36, a generic quality of life instrument. The SF-36 measures eight domains of quality of life. Patients were then divided into three groups: (1) breast surgery without ALND (-ALND), (2) breast surgery with ALND but no lymphedema (-LE), and (3) breast surgery with ALND and lymphedema (+LE). RESULTS: In all, 827 patients with ALND were identified in the registry. Of these, 8.3% developed clinically apparent lymphedema. Patients in -ALND and -LE groups had similar scores in all domains of the SF-36. However, patients in the +LE group had significantly lower scores in the domains of role-emotional and bodily pain. A significantly higher percentage of patients in the +LE group had scores below one standard deviation compared with national norms in the domains of bodily pain (P = 0.005), mental health (P = 0.01), and general health (P = 0.04). CONCLUSIONS: Although postoperative lymphedema occurs in a minority of patients, when it does occur it can produce demonstrable diminutions in quality of life. Therefore, efforts to reduce the incidence of lymphedema, such as sentinel lymph node biopsy or selective ALND, would benefit breast cancer patients.

Cathepsin B in predicting the extent of the cervix carcinoma.

The value of cathepsin B activity in determining the extent of disease was investigated in 106 patients with carcinoma of the cervix uteri and in 20 women with dysplasia of the cervix uteri. The measurements of serum and tumor cathepsin B activity were performed before treatment. The levels of cathepsin B were estimated by direct fluorimetric assay based on the use of 2-Phe-Arg-NMec as a substrate. The results show that the mean serum and tumor activity of this enzyme increase with progression of neoplastic disease and was closely dependent on clinical stage of cervical carcinoma. Also, we found higher serum and tumor levels of cathepsin B activities in patients with clinical early disease (FIGO Stage Ib and IIa) in whom metastases to pelvic lymph nodes were detected than in patients with disease limited to the cervix uteri (p < 0.001, t-test). Enhanced activity of cathepsin B was observed in 64% of patients with cervical carcinoma.

[A case of heterotopic ossification in the parapharyngeal region connected with the C2 vertebra in a 9-year-old girl]. / Przypadek kostnienia pozaszkieletowego okolicy przygardlowej zwiazanego z II kregiem szyjnym u dziewiecioletniej dziewczynki.

A rare case of extraskeletal ossification in the parapharyngeal region related to C2 cervical vertebra was observed in a child, without any history of trauma, inflammation or endocrinological disease. One-step surgical intervention was carried out from the side of the neck and pharynx making possible complete removal of the lesion. The girl was admitted to the hospital with dysphagia and breathing difficulties increasing in the last 6 months. During that time the child was observed in laryngological hospital departments. After the operation Horner syndrome and hypoglossal paresis developed, but presently the child is without symptoms.

[Transfontanellar USG examination using a color Doppler method in the diagnosis and differentiation of vascular changes in the CNS (preliminary report)]. / Badanie USG przezciemiaczkowe z zastosowaniem kolorowego Dopplera w diagnostyce i róznicowaniu zmian naczyniowych OUN (doniesienie wstepne).

In the light of own experiences the diagnostic possibilities are presented of using Doppler ultrasonography with transfontanellar projection in the diagnosis and differentiation of vascular changes. Colour Doppler USG makes possible recording and measurement of blood flow in the vessels and may be specially useful in cases of central nervous lesions. The paper is supplemented with a videographic record of Galen's vein aneurysm imaged by Doppler USG.

[Radioimmunological and serological assay of urinary excretion of the luteinizing hormone in women with amenorrhea]. / Radioimmunologiczna i serologiczna ocena wydalania hormonu luteinizujacego w moczu kobiet z brakiem krwawien miesiecznych

PIP: 6 women with amenorrhea were treated with menopausal gonadotropin over the course of 60 days. The urinary excretion of luteinizing hormone (LH) was evaluated by means of radioimmunological and serological tests. These observations showed substantive differences in the concentration of LH between those patients with primary and those with secondary amenorrhea. Those with primary amenorrhea showed an increase in the content of LH in the form of an ovulation peak after the 1st injection of Biogonadyl (human chorionic gonadotropin; HCG). Those with secondary amenorrhea showed a urinary LH increase only some hours after the administration of HCG. This thought to prove that ovulation may be induced without the participation of HCG, but rather as an effect of the menopausal gonadotropin (Menogonadyl). The ratio established was 1:1 for follicle stimulating hormone: LH. Radiological examination of the women with secondary amenorrhea showed several days of persistently high levels of LH. In 4 of the cases the corpus luteum appeared during the course of treatment.^ieng