Towards Cancer Nanoradiopharmaceuticals-Radioisotope Nanocarrier System for Prostate Cancer Theranostics Based on Radiation-Synthesized Polymer Nanogels.

Despite the tremendous development of oncology, prostate cancer remains a debilitating malignancy. One of the most promising approaches to addressing this issue is to exploit the advancements of nanomedicine in combination with well-established nuclear medicine and radiotherapy. Following this idea, we have developed a radioisotope nanocarrier platform of electron-beam-synthesized nanogels based on poly(acrylic acid). We have developed a functionalization protocol, showing the very high (>97%) efficiency of the conjugation in targeting a ligand-bombesin derivative. This engineered peptide can bind gastrin-releasing peptide receptors overexpressed in prostate cancer cells; moreover, it bears a radioisotope-chelating moiety. Our nanoplatform exhibits very promising performance in vitro; the radiolabeled nanocarriers maintained high radiochemical purity of >90% in both the labeling buffer and human serum for up to 14 days. The application of the targeted nanocarrier allowed also effective and specific uptake in PC-3 prostate cancer cells, up to almost 30% after 4 h, which is a statistically significant improvement in comparison to carrier-free radiolabeled peptides. Although our system requires further studies for more promising results in vivo, our study represents a vital advancement in radionanomedicine-one of many steps that will lead to effective therapy for castration-resistant prostate cancer.

Development of the 99mTc-Labelled SST2 Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study.

Broad availability and cost-effectiveness of 99Mo/99mTc generators worldwide support the use, and thus the development, of novel 99mTc-labelled radiopharmaceuticals. In recent years, preclinical and clinical developments for neuroendocrine neoplasms patient management focused on somatostatin receptor subtype 2 (SST2) antagonists, mainly due to their superiority in SST2-tumour targeting and improved diagnostic sensitivity over agonists. The goal of this work was to provide a reliable method for facile preparation of a 99mTc-labelled SST2 antagonist, [99mTc]Tc-TECANT-1, in a hospital radiopharmacy setting, suitable for a multi-centre clinical trial. To ensure successful and reproducible on-site preparation of the radiopharmaceutical for human use shortly before administration, a freeze-dried three-vial kit was developed. The final composition of the kit was established based on the radiolabelling results obtained during the optimisation process, in which variables such as precursor content, pH and buffer, as well as kit formulations, were tested. Finally, the prepared GMP-grade batches met all predefined specification parameters together with long-term kit stability and stability of the product [99mTc]Tc-TECANT-1. Furthermore, the selected precursor content complies with micro-dosing, based on an extended single-dose toxicity study, where histopathology NOEL was established at 0.5 mg/kg BW, being more than 1000 times higher than the planned human dose of 20 µg. In conclusion, [99mTc]Tc-TECANT-1 is suitable to be advanced into a first-in-human clinical trial.

Next-generation sequencing testing in children with epilepsy reveals novel clinical, diagnostic and therapeutic implications.

Introduction: Epilepsy is one of the commonest diseases in children, characterized by extensive phenotypic and genetic heterogeneity. This study was conducted to determine the diagnostic utility and to identify novel clinical and therapeutic implications of genetic testing in pediatric patients with epilepsy. Methods: Large multigene panel and/or exome sequencing was performed in 127 unrelated Polish and Ukrainian patients with suspected monogenic epilepsy. Diagnostic yields were presented for five phenotypic subgroups, distinguished by seizure type, electroencephalographic abnormalities, anti-seizure treatment response, and neurodevelopmental deficits. Results: A definite molecular diagnosis was established in 46 out of 127 cases (36%). Alterations in six genes were detected in more than one patient: SCN1A, MECP2, KCNT1, KCNA2, PCDH19, SLC6A1, STXBP1, and TPP1, accounting for 48% of positive cases. 4/46 cases (8.7%) were mosaic for the variant. Although the highest rates of positive diagnoses were identified in children with developmental delay and generalized seizures (17/41, 41%) and in developmental end epileptic encephalopathies (16/40, 40%), a monogenic etiology was also frequently detected in patients with solely focal seizures (10/28, 36%). Molecular diagnosis directly influenced anti-seizure management in 15/46 cases. Conclusion: This study demonstrates the high diagnostic and therapeutic utility of large panel testing in childhood epilepsies irrespective of seizure types. Copy number variations and somatic mosaic variants are important disease-causing factors, pointing the need for comprehensive genetic testing in all unexplained cases. Pleiotropy is a common phenomenon contributing to the growing phenotypic complexity of single-gene epilepsies.

[99mTc]Tc-PSMA-T4-Novel SPECT Tracer for Metastatic PCa: From Bench to Clinic.

Despite significant advances in nuclear medicine for diagnosing and treating prostate cancer (PCa), research into new ligands with increasingly better biological properties is still ongoing. Prostate-specific membrane antigen (PSMA) ligands show great potential as radioisotope carriers for the diagnosis and therapy of patients with metastatic PCa. PSMA is expressed in most types of prostate cancer, and its expression is increased in poorly differentiated, metastatic, and hormone-refractory cancers; therefore, it may be a valuable target for the development of radiopharmaceuticals and radioligands, such as urea PSMA inhibitors, for the precise diagnosis, staging, and treatment of prostate cancer. Four developed PSMA-HYNIC inhibitors for technetium-99m labeling and subsequent diagnosis were subjected to preclinical in vitro and in vivo studies to evaluate and compare their diagnostic properties. Among the studied compounds, the PSMA-T4 (Glu-CO-Lys-L-Trp-4-Amc-HYNIC) inhibitor showed the best biological properties for the diagnosis of PCa metastases. [99mTc]Tc-PSMA-T4 also showed effectiveness in single-photon emission computed tomography (SPECT) studies in humans, and soon, its usefulness will be extensively evaluated in phase 2/3 clinical trials.

Does the Number of Bifunctional Chelators Conjugated to a mAb Affect the Biological Activity of Its Radio-Labeled Counterpart? Discussion Using the Example of mAb against CD-20 Labeled with 90Y or 177Lu.

There has been considerable interest in developing a monoclonal antibody (mAb) against-CD-20 (for example, Rituximab) modified by bifunctional chelating agents (BCA) for non-Hodgkin's lymphoma radioimmunotherapy. Therefore, many researchers have modified this monoclonal antibody by attaching different BCA moieties and evaluated their biological activities in terms of in vitro study and in vivo study in healthy and tumor xenografted rodents. This mini-perspective reviews the in vitro studies, the immunoreactivity and physiological distribution studies: organ-to-blood and the tumor-to-organ ratio of conjugates with different numbers of chelators per mAb. We set up a null hypothesis that states there is no statistical significance between the biological activity of monoclonal antibody (Rituximab) and the number of conjugated bifunctional chelators. Overall, we have concluded that there is no strong evidence for this hypothesis. However, the literature data should be questioned due to the potential lack of uniform study methodology.

Reflex seizures in rare monogenic epilepsies.

Reflex seizures (RSs) are epileptic events consistently induced by specific triggers. They occur in epilepsies of varied etiologies and are often accompanied by spontaneous seizures. The genetic background of RSs is heterogeneous and polygenic or multifactorial inheritance is suspected in the majority of cases. Although causative single-gene variants are rarely identified, the number of genes associated with RSs is gradually increasing. In this article, we describe individuals presenting reflex seizures as predominant epileptic events in whom we identified pathogenic and likely pathogenic variants in CACNA1A, GNAO1, and NOVA2 genes. In addition, we summarize rare monogenic epilepsies associated with RSs. The presence of RSs in our patients expands the phenotypic spectrum of the diseases and contributes to our knowledge of the underlying monogenic defects in reflex seizures.

The PURPLE N study: objective and perceived nutritional status in children and adolescents with cerebral palsy.

PURPOSE: To obtain information on characteristics, management, current objective nutritional status and perception of nutritional status of children with cerebral palsy (CP) from healthcare professionals (HCPs) and caregivers. MATERIALS AND METHODS: A detailed survey of several items on eight main topics (general characteristics, motor function, comorbidities, therapies, anthropometry, feeding mode and problems and perceived nutritional status) was developed and tested for the study. Correlation between nutritional status and Gross Motor Function Classification System (GMFCS) levels was assessed using continuous variables (Z-scores for weight-for-age, height-for-age, weight-for-height, and body mass index-for-age), and categorical variables (being malnourished, stunted, or wasted). HCP and caregiver perceptions of the child's nutritional status as well as agreement between perceived and objective nutritional status and agreement between perceived nutritional status and concerns about the nutritional status were analyzed. RESULTS: Data were available for 497 participants from eight European countries. Poorer nutritional status was associated with higher (more severe) GMFCS levels. There was minimal agreement between perceived and objective nutritional status, both for HCPs and caregivers. Agreement between HCP and caregiver perceptions of the child's nutritional status was weak (weighted kappa 0.56). However, the concerns about the nutritional status of the child were in line with the perceived nutritional status. CONCLUSIONS: The risk of poor nutritional status is associated with more severe disability in children and adolescents with CP. There is a mismatch between HCP and caregiver perceptions of participants' nutritional status as well as between subjective and objective nutritional status. Our data warrant the use of a simple and objective screening tool in daily practice to determine nutritional status in children and adolescents with CP. Clinical trial registration: ClinicalTrials.gov Identifier: NCT03499288 (https://clinicaltrials.gov/ct2/show/NCT03499288). IMPLICATIONS FOR REHABILITATIONUse of the ESPGHAN recommendations and simple screening tools in daily practice is needed to improve nutritional care for individuals with CP.Attention should be paid to the differences in the perception of nutritional status of individuals with CP between professionals and caregivers to improve appropriate referral for nutritional support.Objective measures rather than the professional's perception need to be used to define the nutritional status of individuals with CP.

Impact of DOTA-Chelators on the Antitumor Activity of 177Lu-DOTA-Rituximab Preparations in Lymphoma Tumor-Bearing Mice.

Background: This work aimed to evaluate the influence of two chelators: DOTA(SCN) and DOTA(NHS) on radioimmunotherapy using 177Lu-DOTA-Rituximab preparations in murine lymphoma xenograft models. Subsequently, based on animal data, the organ radiation-absorbed doses were extrapolated to humans (adult male). Materials and Methods: Therapeutic efficacy of 177Lu-DOTA-Rituximab was evaluated in male nude mice bearing either Raji (B lymphocyte, CD20+) and Jurkat (T lymphocyte, CD20) xenografts, utilizing an anti-CD20 antibody-Rituximab conjugate with either DOTA(SCN) or DOTA(NHS). The DOTA-Rituximab conjugates were prepared in the form of freeze-dried kits. Results: All radioimmunoconjugates were obtained with high radiolabeling yield (radiochemical purity, RCP > 95%) and specific activity of ca. 0.5 GBq/mg. Therapeutic effects of 177Lu-DOTA-Rituximab were observed in animals regardless whether DOTA(SCN) or DOTA(NHS) were used for conjugation. Importantly, therapy involving 177Lu-DOTA-Rituximab was more effective than use of Rituximab alone. Conclusions: The degree of antitumor efficacy was dependent on the type of applied bifunctional chelators conjugated to mAb. However, this difference was not statistically significant. Dosimetry calculations showed that the absorbed radiation doses extrapolated to humans were very low for osteogenic cells regardless of the conjugates. Organs like the liver and spleen, treated with 177Lu-DOTA(SCN)-Rituximab, showed similar radiation absorbed doses when compared with 177Lu-DOTA(NHS)-Rituximab.

Single, very low dose (0.03 mg) of recombinant human thyrotropin (rhTSH) effectively increases radioiodine uptake in the I-131 treatment of large nontoxic multinodular goiter.

BACKGROUND: Radioiodine therapy (RIT) in patients with large nontoxic multinodular goiter (MNG) recently becomes more common method in comparison to surgery (especially in elderly patients and with contraindications because of severe chronic diseases other systems). Repeatedly low thyroid radioactive iodine uptake (RAIU) decreases effectiveness of RIT or makes it impossible. The recombinant human thyrotropin can increase RAIU and improve the results of RIT. THE AIM OF THE STUDY: was to assess the influence of a single very low dose (0.03 mg) of rhTSH on RAIU and thyroid function in euthyroid (MNG-EU) and subclinical hyperthyroid (MNG-SC) patients with a large multinodular goiter. MATERIAL AND METHODS: 40 patients (14 male, 26 female, age 57-80 yr) with large non-toxic MNG over 80 grams and with baseline RAIU < 40% were included into the double-blind randomized study and divided into two groups: rhTSH-group and control group. First group received the single intramuscular injection of 0.03 mg rhTSH and the second received placebo. The RAIU were measured 24 and 48 hours after the rhTSH and then all the patients were administered therapeutic doses of I-131. TSH and free thyroxine levels were measured at 1st and 2nd day after the injection of rhTSH and later, at 4 and 8 weeks after the RIT. RESULTS: The mean RAIU increased significantly from 30.44 ± 7.4% to 77.22 ± 8.7% (p < 0.001). There were no statistically significant differences in RAIU between euthyroid (MNG-EU) and subclinically hyperthyroid (MNG-SC) patients. The peak of serum TSH was noticed 24 hours after rhTSH injection and in MNG-EU patients it has remained within normal range, similarly as fT4. In the MNG-SC group the administration of rhTSH resulted in a significant increase in the TSH values after 24 hours, whose mean level slightly exceeded the upper limit of the normal range with normalization at 48 hours. 8 weeks after the RIT, the TSH and fT4 levels did not exceed the normal range and did not differ in a statistically significant way. CONCLUSIONS: Even the single very low dose of rhTSH increases the values of RAIU in significant way, in euthyroid and subclinically hyperthyroid patients. The administration of rhTSH is well-tolerated. Neoadjuvant administration of a low dose (0.03 mg) of rhTSH before I-131 seems to be an optimal method of management which may increase the effectiveness of RIT and decrease the exposure of the patients to absorbed doses of ionizing radiation.

Radioiodine therapy for Graves' disease - retrospective analysis of efficacy factors.

INTRODUCTION: Radioiodine ((131)I) isotope therapy is the method of choice in the treatment of Graves' disease relapse. The efficiency of this method is dependent on many factors; therefore, the present paper aims to identify the parameters that have a crucial impact on the efficacy of radioiodine therapy for Graves' disease. MATERIAL AND METHODS: The authors performed a retrospective analysis of the medical documentation of 700 Graves' disease sufferers treated with (131)I. The patients were divided into three groups depending on the thyroid-absorbed dose of (131)I: group I - 100 Gy, II - 150 Gy, and III - 200 Gy. The authors assessed the influence of gender, age, presence of orbitopathy, TRab titres, thyroid mass, iodine uptake after 24 and 48 hours, and the absorbed dose on the treatment efficacy at one year post-(131)I administration. RESULTS: The volume of thyroid gland (P < 0.002) and the thyroid-absorbed dose (P < 0.001) were the only factors that had a significant impact on the outcome of the treatment. The likelihood of hyperthyroidism persisting (odds ratio: 3.71, 95% confidence interval: 2.4-5.87) was greatest in patients from group I. In group II, with thyroid volume amounting both to 25 mL and to 25-50 mL, the percentage of hyperthyroidism was lowest (1 and 0%). However, with thyroid volume > 50 mL, the percentage of hyperthyroidism was lowest in group III (10%). CONCLUSIONS: The absorbed dose of (131)I and the volume of the thyroid gland are two parameters that have a significant influence on the efficacy of radioiodine therapy for Graves' disease. 150 Gy is the optimal dose for glands < 50 mL. A goitre > 50 mL requires an absorbed dose of 200 Gy in order to minimise the risk of recurrent hyperthyroidism.

Parathyroid gland function after radioiodine ((131)I) therapy for toxic and non-toxic goitre.

INTRODUCTION: The therapeutic effect of radioactive iodine ((131)I) on benign goitre consists of the emission of tissue-destructive beta-radiation. Since the range of beta (131)I radiation in tissue can reach 2.4 mm, it can affect the adjacent parathyroid glands. The purpose of this paper is to assess parathyroid function in patients with toxic and non-toxic goitres, up to five years following (131)I therapy. MATERIAL AND METHODS: The study sample consisted of 325 patients with benign goitres (220 with toxic nodular goitre (TNG), 25 with non-toxic nodular goitre (NTNG), and 80 with Graves' disease (GD) treated with (131)I. The therapeutic activity of (131)I for each patient was calculated using Marinelli's formula. The serum levels of fT3, fT4, TSH, iPTH and Ca(2+), Ca and phosphates were determined one week before (131)I administration, as well as every two months up to a year following the therapy, and then after three and five years post-treatment. RESULTS: After two months following the administration of (131)I, all the treated patients showed a statistically significant above normal increase in iPTH concentrations (amounting to a value almost twice the norm in patients with TNG), which remained stable up to ten months after treatment, to return to normal level in the following months. In all the patients, Ca(2+), Ca, phosphates concentration remained within normal range throughout the course of the study. The concentrations of fT3 and fT4 quickly returned to normal after (131)I administration, and remained within normal range until the completion of the study. CONCLUSION: Radioiodine treatment of benign thyroid disorders results in transient (up to ten months after (131)I administration) hyperparathyroidism. The condition does not influence the level of calcium and phosphates concentration in any significant way.

Iodine isotope ¹³¹I therapy for toxic nodular goitre: treatment efficacy parameters.

BACKGROUND: When planning radioactive iodine therapy, it frequently happens, both in Poland and world-wide, that inadequate attention is paid to such easily measurable parameter sas: 1) the serum concentration of thyrotropin (TSH) before administering radioiodine, which is a key factor for extranodular(non-autonomous) iodine uptake of the thyroid gland, 2) thyroid gland iodine uptake, and 3) the effective half-life of 131I (Teff.). The aim of the study is to evaluate the impact of the above factors on the efficacy of 131I treatment in hyperthyroid patients. METHODS: The material consisted of 4140 patients: 2190 with autonomous toxic nodules (ATN) and 1950 with toxic multinodular goitres (TMG). The patients were prepared for treatment in such a way that the concentration of TSH did not exceed 0.1 mU/land Teff.< 5 days. The therapeutic activity of 131I was calculated using Marinelli's formula. The selection of absorbed dose value was determined by the degree of suppression of extranodulart issue. Monitoring was performed every eight weeks. RESULTS: At one year after 131I administration showed that a euthyroid status was achieved in 94%, hypothyroidism was seen observed in 3%, while persistence or recurrence of hyperthyroidism in 3% of ATN patients and, respectively, 89%, 4% and 7% of TMG patients. CONCLUSIONS: Patients with toxic nodular goitre who are to be treated with radioiodine should have the lowest possible serum concentration of TSH. The suppression of extranodular determines the optimal value of absorbed dose for Marinelli's formula.

Bone scan in metabolic bone diseases. Review.

Metabolic bone disease encompasses a number of disorders that tend to present a generalized involvement of the whole skeleton. The disorders are mostly related to increased bone turnover and increased uptake of radiolabelled diphosphonate. Skeletal uptake of 99mTc-labelled diphosphonate depends primarily upon osteoblastic activity, and to a lesser extent, skeletal vascularity. A bone scan image therefore presents a functional display of total skeletal metabolism and has valuable role to play in the assessment of patients with metabolic bone disorders. However, the bone scan appearances in metabolic bone disease are often non-specific, and their recognition depends on increased tracer uptake throughout the whole skeleton. It is the presence of local lesions, as in metastatic disease, that makes a bone scan appearance obviously abnormal. In the early stages, there will be difficulty in evaluating the bone scans from many patients with metabolic bone disease. However, in the more severe cases scan appearances can be quite striking and virtually diagnostic.

The influence of non-radioactive iodine (127I) on the outcome of radioiodine (131I) therapy in patients with Graves' disease and toxic nodular goitre.

BACKGROUND: The aim of the study was to achieve an effective target dose in the thyroid by increasing the effective half-life (Teff) of (131)I by use of iodide ((127)I) two days after (131)I therapy in patients with hyperthyroidism with low Teff. MATERIAL AND METHODS: The study was carried out in two groups. Group A - 41 patients, and Group B - 14 patients, all the patients were with hyperthyroidism with Teff less than 3 days qualified for (131)I therapy. Only group A patients received 600 µg of iodide a day for 3 days, two days after (131)I therapy. Radioiodine uptake (RAIU) after 24 and 48 hours, thyroid scintiscan and ultrasonography were done before and after 12 months of (131)I therapy. RESULTS: In group A a significant increase was seen in the Teff (5 days on average) resulting in an increase in the energy target dose by 28% and 37%, in patients with Graves' disease (GD) and toxic nodular goitre (TNG), respectively. After one year of therapy 50% of GD and 93% of TNG patients achieved euthyroidism; 28% of GD and 3% of TNG patients were in hypothyroidism. In Group B, all the patients had radioiodine treatment failure and received a second therapeutic dose of (131)I. CONCLUSIONS: Administration of (127)I after (131)I treatment can lead to an increase in its effective half-life. This will also increase the absorbed energy dose in thyroid tissue, thereby improving therapeutic outcome without administration of a higher or second dose of (131)I. This may minimize whole-body exposure to radiation and reduces the cost of treatment.

Chromosomal alterations in mini organ cultures of human oropharyngeal mucosa cells caused by hydrogen peroxide.

BACKGROUND: Oxidative stress is a known exogenous risk factor for carcinogenesis in the head and neck. In addition to exogenous risk factors, the development of head and neck cancer is based on genetic alterations and individual mutagen sensitivity. DNA damage caused by reactive oxygen species (ROS) is not uniformly distributed over the DNA, as certain chromosomes and genes are more likely to be damaged than others. The ability to repair damaged DNA sufficiently is a necessity in order to prevent carcinogenesis. The DNA-damaging effect of ROS, the specific sites of chromosomal changes and DNA repair in those regions require further investigation. MATERIALS AND METHODS: In order to evaluate DNA damage in macroscopically healthy mucosal tissue of 37 patients with (15) and without cancer (22) of the oropharynx, four different chromosomes (chromosomes 3, 5, 8 and 11) involved in carcinogenesis of the oropharynx were examined. After incubation with H(2)O(2), comet FISH was applied to assess DNA damage of these chromosomes. The extent of DNA repair was evaluated in the same samples after a 24-hour repair period. RESULTS: H(2)O(2) caused significant DNA damage in oropharyngeal mucosal cells of patients with and without carcinoma. DNA fragmentation of all chromosomes investigated in the two groups was comparable. No differences were observed between mutagen sensitivity of patients suffering from cancer of the oropharynx and those without malignancy for any of the observed chromosomes. On the other hand, chromosomal DNA damage of these specific chromosomes was significantly higher than the average DNA fragmentation of the entire DNA in both groups. DNA repair led to a significant decrease in DNA damage in all groups. Controls tend to have a better DNA repair in all of the analysed chromosomes. However, these differences were not significant. CONCLUSION: The increased chromosomal DNA fragmentation in comparison to that of the entire DNA indicates the contribution of the investigated chromosomes to carcinogenesis in the oropharynx. DNA repair in those chromosomes might play a role in carcinogenesis of the oropharynx, but further investigations are warranted.

[Nephrology of love]. / Nefrologia milosci.

The article presents different aspects of the connection between human heart and kidneys. This connection is evident in the symbolism of the Old Testament of the Bible, organ donation as the manifestation of the love of our neighbor, endocrinological and sexual dysfunction, and finally in searching for biological determinants of finer feelings. In the Old Testament tradition kidneys were thought to be human spirit's dwelling. Moreover, the simultaneous studying of kidneys and heart meant profound understanding of the matter. Nowadays, it is also possible to find the Biblical love of our neighbor, for instance among kidney donors. What is more, every nephrologist should treat his patients with love and dedication, which makes it easier for him to understand their problems, especially these concerning sexual dysfunction. Sexual dysfunction occurs among men and women equally and specialists, apart from using many different methods, have to deal with the consequences of renal failure mainly by means of transplantation.

Inverse potassium hydride: a theoretical study.

Results of an experimental study on the unusual "inverse" charge state (H(+)Na(-)) in salts where the H(+) ion is sequestered, combined with our earlier theoretical calculations on an unsequestered model compound (Me(3)N-H(+)...Na(-)), prompted us to further investigate such systems. In particular, we examined Et(3)N-H(+)...K(-) because considerations of the proton affinity of the amine and of the metal-hydride bond strength suggested that this ion-pair complex might be more stable to proton abstraction than was Me(3)N-H(+)...Na(-). In the present work, the ground-state potential energy surface of the Et(3)N-H(+)...K(-) ion pair was examined using second-order Møller-Plesset perturbation theory and 6-311++G basis sets. We found Et(3)N-H(+)...K(-) to be metastable to dissociation with a barrier of 8 kcal mol(-1) (computed at the CCSD(T) level of theory). This barrier indeed is substantially larger than that found earlier for (Me(3)N-H(+)...Na(-)) and suggests that unsequestered inverse-charged H(+)M(-) ion-pair salts may offer a reasonable route to creating high-energy materials if a means for synthesizing them in the laboratory can be designed.

Coulomb-assisted dissociative electron attachment: application to a model peptide.

The fragmentation of positively charged gas-phase samples of peptides is used to infer the primary structure of such molecules. In electron capture dissociation (ECD) experiments, very low-energy electrons attach to the sample and rupture bonds to effect the fragmentation. It turns out that ECD fragmentation tends to produce cleavage of very specific types of bonds. In earlier works by this group, it has been suggested that the presence of positive charges produces stabilizing Coulomb potentials that allow low-energy electrons to exothermically attach to sigma orbitals of certain bonds and thus to cleave those bonds. In the present effort, the stabilizing effects of Coulomb potentials due to proximal positive charges are examined for a small model peptide molecule that contains a wide range of bond types. Direct attachment of an electron to the sigma orbitals of eight different bonds as well as indirect sigma bond cleavage, in which an electron first binds to a carbonyl C=O pi orbital, are examined using ab initio methods. It is found that direct attachment to and subsequent cleavage of any of the eight sigma bonds is not likely except for highly positively charged samples. It is also found that attachment to a C=O pi orbital followed by cleavage of the nitrogen-to-alpha-carbon bond is the most likely outcome. Interestingly, this bond cleavage is the one that is seen most commonly in ECD experiments. So, the results presented here seem to offer good insight into one aspect of the ECD process, and they provide a means by which one can estimate (on the basis of a simple Coulomb energy formula) which bonds may be susceptible to cleavage by low-energy electron attachment.

[Subclinical hyperthyrodism, diagnosis and radioiodine therapy]. / Subkliniczna nadczynnosc tarczycy, diagnostyka i leczenie radioizotopowe.

Subclinical hyperthyroidism is a state of increased thyroid function with few or no clinical definitive signs or symptoms of hyperthyroidism. It is characterised by a decrease of serum (TSH) concentration below 0.1 mU/L, when serum levels of total and free thyroxin and triiodothyronin concentration are within normal reference ranges. It is not a rare finding and rates between 0.02% and 11.3% have been reported in different groups. The clinical diagnosis of subclinical hyperthyroidism is very difficult in the absence of the typical symptoms of hyperthyroidism. Therefore the diagnostic evaluation is important, especially with the use of radioisotope scan. In nuclear medicine department we can confirm the provisional diagnosis by the use of thyroid scan. Recent studies reported the effects of subclinical hyperthyroidism on cardiovascular system, skeletal system, cognitive function, on quality of life and life expectancy especially in the elderly patient. Treatment is indicated in the presence of palpitation, or atrial fibrillation, in postmenopausal osteoporosis in women not on hormone replacement therapy, and in elderly patients in whom surgery is contraindicated. According to the opinions of European clinicians and clinician members of the American Thyroid Association, the majority recommend radical treatment for these patients. Radioiodine therapy is considered to be the treatment of choice in most of the patients with nodular goiter.

Inverse sodium hydride: a theoretical study.

A recent experimental investigation in which a salt containing the unusual charge distribution H(+) and Na(-) was synthesized and characterized prompted us to undertake an ab initio theoretical investigation. In the salt synthesized, the H(+) is bound to the nitrogen center of an amine and the Na(-) alkalide is "blocked" from approaching the protonated amine site by steric constraints of a cage structure. Although one expects that the Na(-) would deprotonate an unprotected R(3)N-H(+) cation, we decided to further explore this issue. Using extended atomic orbital basis sets and Møller-Plesset and coupled-cluster treatments of electron correlation, we examined the relative stabilities of the prototype (Me)(3)N + NaH, (Me)(3)N + Na(+) + H(-), (Me)(3)N-H(+) + Na(-), and (Me)(3)N-Na(+) + H(-) as well as the ion pair complexes (Me)(3)N-H(+).Na(-) and (Me)(3)N-Na(+).H(-). The primary focus of this effort was to determine whether the high-energy (Me)(3)N-H(+).Na(-) ion pair, which is the analogue of what the earlier workers termed "inverse sodium hydride", might be stable with respect to proton abstraction under any reasonable solvation conditions (which we treated within the polarized continuum model). Indeed, we find that such ion pairs are metastable (i.e., locally geometrically stable with a barrier to dissociation) for solvents having dielectric constants below approximately 2 but spontaneously decompose into their constituent ions for solvents with higher dielectric constants. We suggest that amines with large proton affinities and/or metals with weaker MH bond strengths should be explored experimentally.