A single-centre experience with octreotide in the treatment of different hypersecretory syndromes in patients with functional gastroenteropancreatic neuroendocrine tumors

The aim of this research was to assess the clinical and biochemical efficacy of the octreotide in the treatment of patients with various functional gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The study included 14 patients treated with octreotide for 6 months. They were diagnosed with VIPoma, glucagonoma, gastrinoma, medullary thyroid carcinoma (solitary and as a part of MEN-II syndrome), pancreatic carcinoids (solitary and as a part of multiple endocrine neoplasia type-1 syndrome-MEN-1 syndrome) and midgut carcinoids. The patients presented with Verner-Morrison, glucagonoma, Zollinger Ellison and carcinoid syndrome respectively. All had a metastatic disease at the time of diagnosis and a positive octreoscan finding. Initially elevated chromogranin A (CgA) levels were detected in 11 (78.6%) and elevated 5-hydroxyindolacetic acid (5-HIAA) levels in 8 (57.1%) patients. Symptomatic efficacy assessments were made by diarrhea reductions during treatment course, and laboratory efficacy was assessed through changes in 5-HIAA and CgA levels. Assessments were made initially and following 6 months of therapy. Median urinary 5-HIAA and the number of stools decreased significantly (p = 0.016 and p = 0.009 respectively, p < 0.05) while CgA levels had the decreasing tendency but not statistically significant (p = 0.14). There was a positive correlation between the 5-HIAA reduction and the decrease in stool number at baseline and during treatment course (p < 0.05). No correlation was observed between 5-HIAA and CgA levels and also there was no correlation between CgA reduction and symptomatic improvement. The results prove octreotide to be effective in reducing symptoms and biochemical markers associated with hypersecretory syndromes of GEP-NETs.     

Regiochemistry of epoxide ring opening in methyl 2,3-anhydro-4-azido-4-deoxy-alpha- and beta-L-lyxopyranosides

Methyl 2,3-anhydro-4-O-methanesulfonyl-alpha-d-ribopyranoside (12) was prepared through a new six-step sequence starting from d-arabinose. Chemical behaviour of 12 was further studied under solvolytic conditions and in the presence of azide anion as a nucleophile. Factors governing the regiochemistry of epoxide ring opening are briefly discussed.     

Calcium and dairy product modulation of lipid utilization and energy expenditure

Objective: The purpose of this study was to investigate the impact of dietary calcium or dairy product intake on total energy expenditure (TEE), fat oxidation, and thermic effect of a meal (TEM) during a weight loss trial. Methods and Procedures: The intervention included a prescribed 500‐kcal deficit diet in a randomized placebo‐controlled calcium or dairy product intervention employing twenty‐four 18 to 31‐year‐old (22.2 ± 3.1 years, mean ± s.d.) overweight women (75.5 ± 9.6 kg). TEM and fat oxidation were measured using respiratory gas exchange after a meal challenge, and TEE was measured by doubly labeled water. Fat mass (FM) and lean mass (fat‐free mass (FFM)) were measured by dual‐energy X‐ray absorptiometry. Subjects were randomized into one of these three intervention groups: (i) placebo (<800 mg/day calcium intake); (ii) 900 mg/day calcium supplement; (iii) three servings of dairy products/day to achieve an additional 900 mg/day. Results: There were no group effects observed in change in TEE; however, a group effect was observed for fat oxidation after adjusting for FFM (P = 0.02). The treatment effect was due to an increase in fat oxidation in the calcium‐supplemented group of 1.5 ± 0.6 g/h, P = 0.02. Baseline 25‐hydroxyvitamin D (25OHD) was positively correlated with TEM (R = 0.31, P = 0.004), and trended toward a correlation with fat oxidation (P = 0.06), independent of group assignment. Finally, the change in log parathyroid hormone (PTH) was positively correlated with the change in trunk FM (R = 0.27, P = 0.03). Discussion: These results support that calcium intake increases fat oxidation, but does not change TEE and that adequate vitamin D status may enhance TEM and fat oxidation.     

2-(3-Amino-3-deoxy-beta-D-xylofuranosyl)thiazole-4-carboxamide: a new tiazofurin analogue with potent antitumour activity

A new tiazofurin analogue, 2-(3-amino-3-deoxy-beta-d-xylofuranosyl)thiazole-4-carboxamide (3), was synthesized starting from d-glucose and evaluated for its in vitro antiproliferative activity against a panel of human tumour cell lines. Compound 3 exhibited the most powerful cytotoxicity against K562 cells, being approximately 100-fold more potent than tiazofurin. This analogue was also active against Jurkat, HT-29 and HeLa malignant cells, with respective IC(50) values being ca. 2-, 27- and 17-fold lower than those observed for tiazofurin. Remarkably, compound 3 did not exhibit any significant cytotoxicity towards normal foetal lung MRC-5 cell line.     

The validity of ESIN method of osteosynthesis compared to other active surgical methods of treatment of diaphyseal fractures of long bones in children and adolescents

We investigated the relationship of efficiency in the application of the ESIN method of intramedullary osteosynthesis and other active surgical methods in the treatment of diaphyseal fractures of long bones in children and adolescents. The study comprised 100 subjects treated by elastic stable intramedullary osteosynthesis (ESIN - group A) and 50 subjects in whom other active surgical methods were applied (group B). The following criteria of efficiency of treatment were applied: 1. length of perioperative hospitalization, 2. time elapsed since the operation until the beginning of loading of the traumatized extremity, 3. time elapsed since the operation until the full loading of the extremity, i.e. until the recovery of the fracture, 4. incidence of complications, 5. number of post-operative outpatient clinical visits until the recovery of the fracture and 6. overall number of X-ray images of the fractured bone since the accident until the coalescence of the fracture. The results obtained in both groups were compared. 1. The length of perioperative hospitalization is shorter in patients in whom ESIN method was applied. The difference between arithmetic means was 4.45 days and is statistically significant (p < 0.001). 2. The time between the operation until the beginning of loading of the extremity is shorter in patients subjected to ESIN method of osteosynthesis, the difference of mean values being 23.49 days and is statistically significant (p < 0.001). 3. The time between the operation until the full loading of the extremity is shorter in patients subjected to ESIN method of osteosynthesis, the difference being 16.6 days and is statistically significant (p < 0.001). 4. The number of complications in patients treated by the ESIN method of osteosynthesis is not statistically different from that in group B (chi2 = 0.25, p = 0.62). 5. In postoperative period there were fewer outpatient controls in patients to whom ESIN method of osteosynthesis was applied, and the difference is statistically significant (Z = 7.69, p < 0.001). 6. Likewise, the overall number of X-ray controls was lesser (Z = 8.06, p < 0.001). The results of examining the above parameters point to a greater efficiency of treating diaphyseal fractures of long bones in children and adolescents by the ESIN method of osteosynthesis, compared to other active surgical methods.     

ObStruct: A Method to Objectively Analyse Factors Driving Population Structure Using Bayesian Ancestry Profiles

Bayesian inference methods are extensively used to detect the presence of population structure given genetic data. The primary output of software implementing these methods are ancestry profiles of sampled individuals. While these profiles robustly partition the data into subgroups, currently there is no objective method to determine whether the fixed factor of interest (e.g. geographic origin) correlates with inferred subgroups or not, and if so, which populations are driving this correlation. We present ObStruct, a novel tool to objectively analyse the nature of structure revealed in Bayesian ancestry profiles using established statistical methods. ObStruct evaluates the extent of structural similarity between sampled and inferred populations, tests the significance of population differentiation, provides information on the contribution of sampled and inferred populations to the observed structure and crucially determines whether the predetermined factor of interest correlates with inferred population structure. Analyses of simulated and experimental data highlight ObStruct''s ability to objectively assess the nature of structure in populations. We show the method is capable of capturing an increase in the level of structure with increasing time since divergence between simulated populations. Further, we applied the method to a highly structured dataset of 1,484 humans from seven continents and a less structured dataset of 179 Saccharomyces cerevisiae from three regions in New Zealand. Our results show that ObStruct provides an objective metric to classify the degree, drivers and significance of inferred structure, as well as providing novel insights into the relationships between sampled populations, and adds a final step to the pipeline for population structure analyses.     

Saccharomyces eubayanus and Saccharomyces arboricola reside in North Island native New Zealand forests

Saccharomyces is one of the best‐studied microbial genera, but our understanding of the global distributions and evolutionary histories of its members is relatively poor. Recent studies have altered our view of Saccharomyces’ origin, but a lack of sampling from the vast majority of the world precludes a holistic perspective. We evaluate alternate Gondwanan and Far East Asian hypotheses concerning the origin of these yeasts. Being part of Gondwana, and only colonized by humans in the last ～1000 years, New Zealand represents a unique environment for testing these ideas. Genotyping and ribosomal sequencing of samples from North Island native forest parks identified a widespread population of Saccharomyces. Whole genome sequencing identified the presence of S. arboricola and S. eubayanus in New Zealand, which is the first report of S. arboricola outside Far East Asia, and also expands S. eubayanus’ known distribution to include the Oceanic region. Phylogenomic approaches place the S. arboricola population as significantly diverged from the only other sequenced Chinese isolate but indicate that S. eubayanus might be a recent migrant from South America. These data tend to support the Far East Asian origin of the Saccharomyces, but the history of this group is still far from clear.     

Synthesis and antiproliferative activity of two new tiazofurin analogues with 2'-amido functionalities

Two novel tiazofurin analogues 2 and 3 were synthesized starting from d-glucose. The key step of the synthesis was the efficient one-step hydrogen sulfide-mediated conversion of 2-azido-3-O-acyl-ribofuranosyl cyanides to the corresponding 2-amido thiocarboxamides. Compounds 2 and 3 were evaluated for their in vitro antiproliferative activity against certain human tumour cell lines. Remarkably, compound 2 was found to be 570-fold more potent than tiazofurin against MCF-7 cells, while compound 3 showed the most powerful cytotoxicity against HT-29 cancer cells, being almost 100-fold more active than tiazofurin.     

Synthesis and biological evaluation of some novel 4'-thio-L-ribonucleosides with modified nucleobase moieties

1,2,3,5-tetra-O-acetyl-4-thio-beta-L-ribofuranose (13) was synthesized by an improved five-step sequence starting from methyl alpha-D-lyxopyranoside. Compound 13 was then converted to the corresponding L-4'-thionucleosides 4-6 and 19 by a modified Vorbrüggen procedure. All of these nucleoside analogues were tested for their antitumour activity in vitro.     

Enhanced lipid peroxidation and inflammation during heat exposure in rats of different ages: Role of α-tocopherol

To investigate early events possibly related to the development of heat shock, we examined whether inflammatory-(interleukin-6, tumor necrosis factor α and 15-keto-13,14-dihydro-PGF_2α) and peroxidative-(8-iso-PGF_2α and malondialdehyde) markers are altered during acute heat exposure and aging. We also studied the relationships between inflammatory and peroxidative markers in these settings. In order to prevent these reactions developed as a consequence of the conditions mentioned above, we tested the effects of α-tocopherol. Our results demonstrated that 15-keto-13,14-dihydro-PGF_2α and malondialdehyde in the liver were altered during acute heat exposure in the young and middle-aged rats and could be predicted by changes in the levels of circulatory cytokines. Regardless of age, the supplementation with α-tocopherol prevented changes in the plasma cytokine levels and 15-keto-13,14-dihydro-PGF_2α and malondialdehyde levels in the liver, during acute heat exposure. This study notably emphasized the ability of α-tocopherol to prevent different heat induced mechanisms, involved in induction of inflammatory or peroxidative reactions.