Radiolabeling and Preliminary Evaluation of Ga-68 Labeled NODAGA-Ubiquicidin Fragments for Prospective Infection Imaging

Purpose

The present work was aimed at the development of prospective positron emission tomography (PET) agents for infection imaging. Towards this aim, ubiquicidin (UBI) fragments conjugated with the macrocyclic NODAGA chelator were radiolabeled with Ga-68 and evaluated.

Procedures

Conformations of custom synthesized NODAGA-UBI (29–41) and NODAGA-UBI (31–38) conjugates were compared with UBI (29–41) by circular dichroism (CD) spectroscopy. Optimization of labeling of NODAGA conjugates of UBI peptides with Ga-68 was performed and quality control analysis was carried out by chromatography techniques. In vitro uptake of [⁶⁸Ga] NODAGA-UBI (29–41) and [⁶⁸Ga]NODAGA-UBI (31–38) was studied in Staphylococcus aureus cells. In vivo distribution of [⁶⁸Ga]GaCl₃ and [⁶⁸Ga]NODAGA-UBI complexes was performed in normal Swiss mice.

Results

Conformations of NODAGA-UBI (29–41) and NODAGA-UBI (31–38) conjugates were found to be similar to UBI (29–41). NODAGA-UBI conjugates could be consistently labeled with Ga-68 in high radiochemical yields (>95 %) with high radiochemical purity (>95 %). [⁶⁸Ga]NODAGA-UBI (29–41) and [⁶⁸Ga]NODAGA-UBI (31–38) complexes showed retention time of 14 and 14.5 min, respectively, by HPLC radiochromatogram. Specific uptake of [⁶⁸Ga]NODAGA-UBI fragments was observed in S.aureus cells. Greater than 64 % of the injected dose was cleared via the renal route at 1 h post injection, and no significant uptake in vital organs of mice was observed with both the agents.

Conclusion

This is the first report on Ga-68 labeled NODAGA-UBI fragments for infection imaging and the agents hold tremendous prospect in PET imaging.

     

Management of locally advanced prostate cancer: a European consensus

This report summarises the findings of a European Consensus Group review of current standards of care in locally advanced prostate cancer defined as (a) untreated cancer extending clinically beyond the prostatic capsule in patients with no evidence of lymph node invasion or distant metastases, and (b) residual disease remaining after local treatment with positive surgical margins, seminal vesicle invasion, persistent prostate-specific antigen (PSA) and/or secondary PSA relapse. There was no overall consensus as to the standard of care in clinically apparent locally advanced prostate cancer. It was agreed, however, that hormonal therapy (e.g. with a gonadotrophin releasing hormone analogue [GnRHa]) represents a valid treatment in these patients. Treatment practices and regimens vary considerably between European countries, but GnRHa is widely used, either alone or in combination with antiandrogens. Hormonal therapy alone is a valid option, though the optimal modality, timing and duration of treatment remain to be defined. Adjuvant therapy with a GnRHa has been shown to improve survival in patients undergoing external beam radiotherapy. It is a viable option after prostatectomy in patients with persistent or secondary relapsing PSA. It was determined that optimal treatment will be different according to PSA, clinical staging and Gleason score, and the treatment of locally advanced disease should be individually tailored after discussion between physician and patient. In many instances, patients prefer and expect some form of treatment in preference to watchful waiting. Treatment nomograms such as the Kattan nomograms provide precise, comprehensive and invaluable tools for everyday use and may be used to predict outcomes and guide treatment decisions.     

The natriuretic peptides and their role in disorders of right heart dysfunction and pulmonary hypertension

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are increased in conditions with cardiac ventricular volume and pressure overload. The general physiological and potential therapeutic roles of natriuretic peptides in respiratory disease, right ventricular (RV) dysfunction, and pulmonary arterial hypertension (PAH) are reviewed. BNP levels can be used to differentiate between dyspneic patients with a pure respiratory defect and those with RV dysfunction. BNP levels also correlate with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with PAH (atrial septal defect, chronic thromboembolic disease, and scleroderma). BNP is a predictor of mortality in patients with primary pulmonary hypertension (PPH). These are important clinical implications in that a noninvasive blood test may be used to identify high-risk patients for more invasive procedures such as cardiac catheterization. BNP or NT-proBNP measurements may also be used to guide therapy (e.g., pulmonary vasorelaxants) in PAH since upregulation of the natriuretic peptide pathway has been shown to reduce cardiac hypertrophy and PAH. Additionally, there may be therapeutic potential via recombinant BNP or neutral endopeptidase inhibitors in RV dysfunction and PAH.     

Meckel’s diverticulum with benign stricture: A very rare cause of intestinal obstruction

We report a very rare case of Meckel’s diverticulum with benign stricture presenting as recurrent small bowel obstruction in a malnourished young adult female. Extensive preoperative investigations were unable to diagnose the cause of recurrent obstruction. Segmental small bowel resection with attached diverticulum was performed.     

Screen media time usage of 12-16 year-old Spanish school adolescents: Effects of personal and socioeconomic factors, season and type of day

This study examined screen media time usage (SMTU) and its association with personal and socioeconomic factors, as well as the effect of season and type of day, in a Spanish sample of 12-16 year-old school adolescents (N=323). The research design was a cross-sectional survey, in which an interviewer-administered recall questionnaire was used. Statistical analyses included repeated measures analyses of variance, analysis of covariance and structural equation models. Results showed an average of 2.52h per day of total SMTU and partial times of 1.73h per day in TV viewing, 0.27h per day in computer/videogames, and 0.52h per day in mobile use. Four significant predictors of SMTU emerged. Firstly, the type of school was associated with the three media of our study, particularly students from state/public school spent more time on them than their private schools counterparts. Secondly, older adolescents (14-16 years old) were more likely to use computer/videogame and mobile phone than younger adolescents. Thirdly, the more accessibility to household technology the more probable computer/videogames and mobile phone were used. Finally, boys spent significantly more time in mobile phone than girls. Additionally, results revealed that adolescents seemed to consume more TV and computer/videogames in autumn than in winter, and more TV and mobile phones on weekends than on weekdays, especially among state school students. Findings from this study contribute to the existing knowledge on adolescents' SMTU patterns that can be transferred to families and policies.     

How successful is the conservative management of pelvi‐ureteric junction obstruction in adults?

OBJECTIVE

To assess the conservative management of pelvi‐ureteric junction obstruction (PUJO), according to severity, accepted in paediatric urology but rarely reported in adults.

PATIENTS AND METHODS

A series of 23 patients (median age 58 years, 17 men and six women) with asymptomatic or minimally symptomatic PUJO were managed conservatively. The patients’ age, preference and comorbidities were considered. The diagnosis of PUJO was based on intravenous urography and isotopic renography. After stringently reviewing the renograms based on relative renal function (RRF) and output efficiency (OE), 15 patients had an OE consistent with definitive PUJO. One patient had no further imaging due to associated comorbidities. Ten patients had right PUJO, three left and one with bilateral PUJO, with unilateral conservative management. The follow‐up included annual renography and clinical consultation. Laparoscopic pyeloplasty was considered for patients with a >10% loss of RRF and/or <40% RRF during the follow‐up.

RESULTS

Overall, 14 of 15 patients had renograms during the follow‐up. The mean RRF of the affected kidney at diagnosis was 48.6% which marginally decreased to 46.7% after a median (range) follow‐up of 44 (23–75) months. The RRF of 11 patients remained stable and in three decreased significantly (median 11% RRF), requiring pyeloplasty. None of the patients became symptomatic throughout the follow‐up.

CONCLUSION

In asymptomatic adults the conservative management of PUJO appears to be safe during a short‐ to medium‐term follow‐up. We recommend that patients are regularly followed with renography and seen promptly should they become symptomatic. A longer follow‐up is needed in a larger group to confirm these findings.     

Post traumatic pituitary apoplexy with contiguous intra cerebral hematoma operated through endonasal route—a case report

Pituitary apoplexy is a clinical syndrome occurring as a consequence of fulminant expansion of pituitary tumor due to massive infarction, necrosis, and hemorrhage. Its association with head injury is rare and only few reports are available. Shear forces on stalk and arterial vasospasm have been proposed to be the possible reasons. The clinical picture is characterized by sudden onset headache, visual symptoms, multiple cranial nerves involvement, meningismus, altered mental status, and hormonal dysfunction. Transsphenoidal decompression is the standard treatment but suprasellar and widespread extension of hematoma may need intracranial approach. We are reporting a rare association of head injury with pituitary apoplexy, where endonasal surgery proved to be a simple useful approach to evacuate contiguous intra-cerebral hematoma with excision of apoplectic pituitary adenoma.     

Unexpected functional consequences of xenogeneic transgene expression in beta-cells of NOD mice

We describe unexpected alterations in the non-obese diabetic (NOD/Lt) mouse model of type 1 diabetes (T1D) following forced beta-cell expression of non-mammalian genes ligated to an insulin promoter sequence. These include the jellyfish green fluorescent protein (GFP), useful for beta-cell identification, and the bacteriophage P1 Cre recombinase, necessary for beta cell-specific ablation of a gene using a Cre-loxP system. Homozygous expression of GFP, driven by the mouse insulin 1 gene promoter (MIP-GFP) in a single transgenic line of NOD mice, produced T1D in postnatal mice that was not associated with insulitis, but rather beta cell-depleted islets. Hemizygous transgene expression suppressed spontaneous autoimmune T1D in females, and produced a male glucose intolerance syndrome associated with age-dependent declines in plasma insulin content. Among lines of transgenic NOD/Lt mice expressing Cre recombinase driven by the rat insulin 2 promoter (RIP-Cre), high, non-mosaic expression correlated with suppressed T1D development. These findings emphasize the need for careful characterization of genetically manipulated NOD mouse stocks to insure that model characteristics have not been compromised.     

Possible involvement of free radicals in the differential neurobehavioral responses to stress in male and female rats

The effect of restraint stress (RS) on neurobehavioral and brain oxidative stress parameters, and their modulation by antioxidants were evaluated in male and cycling female rats. Exposure to RS suppressed both open arm entries and open arm time in the elevated plus maze and these changes were more marked in males than in females. Assay of brain homogenates revealed that the behavioral suppression was associated with similar differential increases in malondialdehye (MDA) and decreases in glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels in males and females. Pretreatment with alpha-tocopherol (25 and 50 mg/kg) and N-acetylcysteine (100 and 200 mg/kg), attenuated the stress induced alteration of behavioral and oxidative stress markers in a consistent manner in both male and female rats. These findings suggest that males may be more susceptible than females to stress induced neurobehavioral changes and free radicals may exert a regulatory influence in such gender dependent responses to stress.     

CpG oligonucleotide as an adjuvant for the treatment of prostate cancer

The use of an adenovirus transduced to express a prostate cancer antigen (PSA) as a vaccine for the treatment of prostate cancer has been shown to be active in the destruction of antigen-expressing prostate tumor cells in a pre-clinical model, using Balb/C or PSA transgenic mice. The destruction of PSA-secreting mouse prostate tumors was observed in Ad/PSA immunized mice in a prophylaxis study with 70% of the mice surviving long term tumor free. This successful immunotherapy was not observed in therapeutic studies in which tumors were established before vaccination and the development of anti-PSA immune response was not as easily generated in PSA transgenic mice. Immunization of conventional and transgenic animals was enhanced by incorporating a collagen matrix into the immunizing injection. Therefore the need to strengthen anti-PSA and anti-prostate cancer immunity was an obvious next step in developing a successful prostate cancer immunotherapy. Because the use of immunostimulatory CpG motifs was shown to enhance immune responses to a wide variety of antigens, our studies incorporated CpG into the Ad/PSA vaccine experimental plans. The results of the subsequent studies demonstrated a dichotomy where Ad/PSA plus CpG enhanced the in vivo destruction of PSA-secreting tumors and the survival of experimental animals, but revealed that the number and in vitro activities of antigen specific CD8+ T cells was decreased as compared to the values observed when the vaccine alone was used for immunization. The dichotomous observations were confirmed using another antigen system, OVA also incorporated into a replication defective adenovirus. Despite the reduction in antigen-specific CD8+ cells after vaccine plus CpG immunization the enhanced destruction of sc and systemic tumors was shown to be mediated entirely by CD8+ T cells. Finally, the reduction of the CD8+ T cells was the result of an observed decrease in the proliferation of the antigen specific cell population.