Interaction between the amino and carbonyl groups in copoly(2-dimethylaminoethyl methacrylate/N-phenylmaleimide)

Interactions between the carbonyl and amino groups in copolymers of 2-dimethylaminoethyl methacrylate with N-phenylmaleimide are reported. The existence of interactions ensues from potentiometric measurements and UV-VIS spectra. Interactions in these copolymers result in the formation of energetically very advantageous chromophores, reflected in an intense red colour of the substances obtained.     

Effects of Alendronate and Calcitonin on Bone Mineral Density in Postmenopausal Osteoporotic Women. An Observational Study

Objective: Alendronate and calcitonin are antiresorptive drugs that were used for the treatment of postmenopausal osteoporosis and were shown to increase bone mineral density (BMD). However, the effect of both drugs in daily clinical practice may differ from that observed in clinical trials.Method: About 50 postmenopausal osteoporotic women were observed during their first year of treatment. Among them, 32 patients used alendronate and 18 used calcitonin. Lumbar spine and femoral neck BMD were measured by dual energy X-ray absorptiometry (DXA) at baseline and after 1 year of therapy. Biochemical markers (B-ALP – bone-specific alkaline phosphatase, OTC – osteocalcin and DPD/UCr – deoxypyridinoline/creatinine ratio) of bone metabolism were measured at baseline and 6 months later. Patient compliance was assumed by tablet counting and verified at interview. Each patient was further questioned about her attitude towards the treatment, as well as her dairy product intake, physical activity, use of other medications, smoking and social status.Main outcome measure: (1) Annual percent change in BMD in lumbar spine and femoral neck after the one-year treatment with either alendronate or calcitonin. (2) The change in biochemical markers of bone turnover.Results: The lumbar spine BMD significantly increased by 7.0% (P < 0.001), the femoral neck BMD by 4.3% (P < 0.01). OTC, B-ALP and DPD/UCr decreased significantly during the therapy with alendronate. Compliance with therapy was 79% (95% CI 68–90%). In the calcitonin-treated group, the lumbar spine BMD significantly increased by 3.1 % (P < 0.05), while the femoral neck BMD remained unchanged. OTC, B-ALP and DPD/UCr did not change significantly during the treatment with calcitonin. Compliance with calcitonin therapy was 87% (95% CI 63–110%). The annual change of BMD in both treatment groups was independent on all questioned factors.Conclusion: In daily practice, alendronate enhanced significantly BMD both in lumbar spine and femoral neck. Calcitonin showed increase only in the lumbar spine BMD.     

Architectural switch in plant photosynthetic membranes induced by light stress

Unavoidable side reactions of photosynthetic energy conversion can damage the water-splitting photosystem II (PSII) holocomplex embedded in the thylakoid membrane system inside chloroplasts. Plant survival is crucially dependent on an efficient molecular repair of damaged PSII realized by a multistep repair cycle. The PSII repair cycle requires a brisk lateral protein traffic between stacked grana thylakoids and unstacked stroma lamellae that is challenged by the tight stacking and low protein mobility in grana. We demonstrated that high light stress induced two main structural changes that work synergistically to improve the accessibility between damaged PSII in grana and its repair machinery in stroma lamellae: lateral shrinkage of grana diameter and increased protein mobility in grana thylakoids. It follows that high light stress triggers an architectural switch of the thylakoid network that is advantageous for swift protein repair. Studies of the thylakoid kinase mutant stn8 and the double mutant stn7/8 demonstrate the central role of protein phosphorylation for the structural alterations. These findings are based on the elaboration of mathematical tools for analyzing confocal laser-scanning microscopic images to study changes in the sophisticated thylakoid architecture in intact protoplasts.     

De novo mutations of GCK,HNF1A and HNF4A may be more frequent in MODY than previously assumed

Aims/hypothesis

MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A).

Methods

Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing.

Results

Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo.

Conclusions/interpretation

In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.     

Hydrophobic sodium fluoride‐based nanocrystals doped with lanthanide ions: assessment of in vitro toxicity to human blood lymphocytes and phagocytes

In vitro immunotoxicity of hydrophobic sodium fluoride‐based nanocrystals (NCs) doped with lanthanide ions was examined in this study. Although there is already a significant amount of optical and structural data on NaYF₄ NCs, data on safety assessment are missing. Therefore, peripheral whole blood from human volunteers was used to evaluate the effect of 25 and 30 nm hydrophobic NaYF₄ NCs dissolved in cyclohexane (CH) on lymphocytes, and of 10 nm NaYF₄ NCs on phagocytes. In the concentration range 0.12–75 µg cm^?2 (0.17–106 µg ml^?1), both 25 and 30nm NaYF₄ NCs did not induce cytotoxicity when measured as incorporation of [³H]‐thymidine into DNA. Assessment of lymphocyte function showed significant suppression of the proliferative activity of T‐lymphocytes and T‐dependent B‐cell response in peripheral blood cultures (n = 7) stimulated in vitro with mitogens phytohemagglutinin (PHA) and pokeweed (PWM) (PHA > PWM). No clear dose–response effect was observed. Phagocytic activity and respiratory burst of leukocytes (n = 5–8) were generally less affected. A dose‐dependent suppression of phagocytic activity of granulocytes in cultures treated with 25 nm NCs was observed (vs. medium control). A decrease in phagocytic activity of monocytes was found in cells exposed to higher doses of 10 and 30 nm NCs. The respiratory burst of phagocytes was significantly decreased by exposure to the middle dose of 30 nm NCs only. In conclusion, our results demonstrate immunotoxic effects of hydrophobic NaYF₄ NCs doped with lanthanide ions to lymphocytes and to lesser extent to phagocytes. Further research needs to be done, particularly faze transfer of hydrophobic NCs to hydrophilic ones, to eliminate the solvent effect. Copyright © 2014 John Wiley & Sons, Ltd.     

Berberine in Human Oncogenic Herpesvirus Infections and Their Linked Cancers

Human herpesviruses are known to induce a broad spectrum of diseases, ranging from common cold sores to cancer, and infections with some types of these viruses, known as human oncogenic herpesviruses (HOHVs), can cause cancer. Challenges with viral latency, recurrent infections, and drug resistance have generated the need for finding new drugs with the ability to overcome these barriers. Berberine (BBR), a naturally occurring alkaloid, is known for its multiple biological activities, including antiviral and anticancer effects. This paper comprehensively compiles all studies that have featured anti-HOHV properties of BBR along with promising preventive effects against the associated cancers. The mechanisms and pathways induced by BBR via targeting the herpesvirus life cycle and the pathogenesis of the linked malignancies are reviewed. Approaches to enhance the therapeutic efficacy of BBR and its use in clinical practice as an anti-herpesvirus drug are also discussed.     

Haloperidol affects coupling between QT and RR intervals in guinea pig isolated heart

Prolonged QT interval is an independent risk factor for development of ventricular arrhythmias. Haloperidol is one of the drugs inducing QT prolongation. Previous studies showed that haloperidol affects not only QT duration but also heart rate (RR interval). The present work focused on relationship between QT and RR and its changes under acute and chronic haloperidol administration. The study included 14 male guinea pigs divided into control and haloperidol-treated group. After 21-days administration of haloperidol or vehiculum, electrograms in isolated hearts were recorded. QT/RR and dQT/dRR coupling were calculated. Chronic haloperidol administration significantly decreases the coupling between QT and RR. Acute haloperidol exposure significantly decreases the dQT/dRR coupling in both treated and untreated guinea pig hearts. Flatter QT/RR relationship reveals a lack of QT adaptation to increased heart rate. It should be emphasized that in such situation ECG recording will not show significant QT prolongation evaluated according to clinical rules. However, if QT interval does not adapt to increased heart rate sufficiently, the risk of ventricular arrhythmias may be increased despite practically normal QT interval length. The results are supported by findings in biochemical analyses, which proved eligibility of the used model.     

Second cancers in MPN: Survival analysis from an international study

One out of ten patients with Philadelphia-negative myeloproliferative neoplasms (MPN) develop a second cancer (SC): in such patients we aimed at assessing the survival impact of SC itself and of MPN-specific therapies. Data were therefore extracted from an international nested case-control study, recruiting 798 patients with SC diagnosed concurrently or after the MPN. Overall, 2995 person-years (PYs) were accumulated and mortality rate (MR) since SC diagnosis was 5.9 (5.1-6.9) deaths for every 100 PYs. A “poor prognosis” SC (stomach, esophagus, liver, pancreas, lung, ovary, head-and-neck or nervous system, osteosarcomas, multiple myeloma, aggressive lymphoma, acute leukemia) was reported in 26.3% of the patients and was the cause of death in 65% of them (MR 11.0/100 PYs). In contrast, patients with a “non-poor prognosis” SC (NPPSC) incurred a MR of 4.6/100 PYs: 31% of the deaths were attributed to SC and 15% to MPN evolution. At multivariable analysis, death after SC diagnosis was independently predicted (HR and 95% CI) by patient age greater than 70 years (2.68; 1.88-3.81), the SC prognostic group (2.57; 1.86-3.55), SC relapse (1.53; 10.6-2.21), MPN evolution (2.72; 1.84-4.02), anemia at SC diagnosis (2.32; 1.49-3.59), exposure to hydroxyurea (1.89; 1.26-2.85) and to ruxolitinib (3.63; 1.97-6.71). Aspirin was protective for patients with a NPPSC (0.60; 0.38-0.95). In conclusion, SC is a relevant cause of death competing with MPN evolution. Prospective data are awaited to confirm the role of cytoreductive and anti-platelet drugs in modulating patient survival after the occurrence of a SC.