Memory technology-a primer for material scientists.

From our own experience, we know that there is a gap to bridge between the scientists focused on basic material research and their counterparts in a close-to-application community focused on identifying and solving final technological and engineering challenges. In this review, we try to provide an easy-to-grasp introduction to the field of memory technology for materials scientists. An understanding of the big picture is vital, so we first provide an overview of the development and architecture of memories as part of a computer and call attention to some basic limitations that all memories are subject to. As any new technology has to compete with mature existing solutions on the market, today's mainstream memories are explained, and the need for future solutions is highlighted. The most prominent contenders in the field of emerging memories are introduced and major challenges on their way to commercialization are elucidated. Based on these discussions, we derive some predictions for the memory market to conclude the paper.

Photochemical regeneration of flavoenzymes - An Old Yellow Enzyme case-study.

Direct, NAD(P)H-independent regeneration of Old Yellow Enzymes represents an interesting approach for simplified reaction schemes for the stereoselective reduction of conjugated C=C-double bonds. Simply by illuminating the reaction mixtures with blue light in the presence of sacrificial electron donors enables to circumvent the costly and unstable nicotinamide cofactors and a corresponding regeneration system. In the present study, we characterise the parameters determining the efficiency of this approach and outline the current limitations. Particularly, the photolability of the flavin photocatalyst and the (flavin-containing) biocatalyst represent the major limitation en route to preparative application.

Ferrocene-containing tetrahydropyrazolopyrazolones: Antioxidant and antimicrobial activity.

A series of ferrocenes which contain dinitrogen-fused pyrazolidinone ring were synthesized from acryloylferrocene (4) and N,N'­cyclic azomethine imines (3). Novel 5­aryl­6­ferrocenoyltetrahydropyrazolo[1,2­a]pyrazol­1(5H)-ones were obtained as mixtures of two diastereoisomers (trans and cis) which were separated and isolated as pure substances. Ortho-substituted N,N'­cyclic azomethine imines 5-oxo-2-(2,4,6-trimethylbenzylidene)pyrazolidin-2-ium-1-ide (3e) and 2-(2-methoxybenzylidene)-5-oxopyrazolidin-2-ium-1-ide (3f) reacted stereoselectively affording only trans-6-ferrocenoyl-5-mesityltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one (5e) and 6-ferrocenoyl-5-(2-methoxyphenyl)tetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one (5f). Ferrocenyl derivatives were screened for in vitro antioxidant and antifungal activities and excellent DPPH and ABTS radicals scavenging activity was observed with majority of tested 5­aryl­6­ferrocenoyltetrahydropyrazolo[1,2­a]pyrazol­1(5H)-ones. Several tested compounds showed selective scavenging properties neutralizing ABTS•+ radical cations in contrast to inactivity toward DPPH radicals. Trans-5-aryl-6-ferrocenoyltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-ones 5b, 5c, 5d, 5j as well as cis-6-ferrocenoyl-5-(p-tolyl)tetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one (6d) displayed fungal growth inhibition at low concentration against C. albicans and/or A. brasiliensis. Molecular docking studies revealed that the cis-6-ferrocenoyl-5-(4-nitrophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one (6l) and cis-6-ferrocenoyl-5-(naphthalen-2-yl)tetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one (6n) have potential to become lead molecules in drug discovery process.

The effect of metformin on TSH levels in euthyroid and hypothyroid newly diagnosed diabetes mellitus type 2 patients.

INTRODUCTION: Metformin is the first-line oral hypoglycemic agent in the treatment of type 2 diabetes mellitus with a number of positive effects. The aim of the study was to determine the effect of metformin on TSH levels in euthyroid and hypothyroid newly diagnosed diabetes mellitus type 2 patients. MATERIAL AND METHODS: The study included 255 newly diagnosed diabetes mellitus type 2 drug naive patients, 170 euthyroid patinets, group A, 85 hypothiroid patients, group B, and 80 euthyroid DM type 2 patients on metformin therapy for more than 5 years, group C. Patients in groups A and B began metformin treatment with a dose of 2000 mg/day. We assessed baseline TSH, FT3, FT4 levels and TPOab, in groups A , B and C, and 6 months after initiation of metformin therapy in groups A and B. RESULTS: There were no differences in FT3 and FT4 levels after 6 months of metformin treatment in all groups. TSH level in Group A showed some reduction after 6 months of metformin therapy, not statistically significant. The only statistically significant change in Group A is the change of TSH level after 6 months in TPOAb positive patients. There was statiscically significant decrease in TSH level after 6 months in group B. There were no significant differences of basal TSH, FT3 and FT4 levels in groups A and B compared to group C. CONCLUSION: The results show that metformin has TSH lowering effect in patients with type 2 DM and hypothyreoidism, but also in euthyroid TPOab positive, levothyroxine naive patients. We have shown that the TSH lowering effect of metformin is not dependent on long term metformin therapy (Tab. 2, Ref. 18).

Biphasic insulin aspart 30: better glycemic control than with premixed human insulin 30 in obese patients with Type 2 diabetes.

AIM: This 3-month study compared the effect on overall glycemic control of adding biphasic insulin aspart 30 (BIAsp30) and premixed human insulin 30/70 (BHI30) to metformin (met) in insulin-naïve, obese patients (30 males/20 females) with Type 2 diabetes (T2DM). MATERIAL/SUBJECTS: At baseline, patients had a mean age of 58.7 yr, glycated hemoglobin (HbA1c) 9.5%, and body mass index 34+/-2 kg/m2. Patients received either twice-daily BIAsp30 (no.=20) or twice-daily BHI30 (no.=30), and continued to receive maximal doses (2000 mg) of met for the duration of the study, but sulphonylurea oral antidiabetic drugs were discontinued. Primary efficacy endpoint was the change in HbA1c in both groups at study end. Safety endpoints included hypoglycemic episodes and weight gain. RESULTS: Both groups reduced HbA1c by end of trial: BIAsp30 + met by 2.5% [2.16-2.86%; 95% confidence interval (CI)]; BHI30 + met by 1.18% (0.98- 1.39%; 95% CI), giving a significantly better HbA1c reduction with BIAsp30 + met (1.33%; p<0.05). Post-prandial plasma glucose decreased in both groups, by 6.38 mmol/l in patients treated with BIAsp30 + met, and by 4.34 mmol/l in those treated with BHI30 + met (p<0.05). Fasting plasma glucose also decreased in both groups, with a slightly larger decrease seen in BIAsp30 patients than in BHI30 patients (7.36 mmol/l at end of study vs 7.82 mmol/l; p=ns). Subjects treated with BIAsp30 gained less weight than those receiving BHI30 (0.3+/-0.1 kg vs 1.2+/-0.4 kg). There was no significant difference in the frequency or number of hypoglycemic episodes between groups. CONCLUSIONS: Adding BIAsp30 to met in obese patients with T2DM results in better glycemic control and less weight gain than adding BHI30.

Demyelinating events in early multiple sclerosis have inherent severity and recovery.

BACKGROUND: It is unclear whether the severity of and recovery from the initial demyelinating event (IDE) are recapitulated in subsequent multiple sclerosis (MS) relapses. We sought to identify the factors associated with relapse severity and recovery and to evaluate whether events have inherent severity or recovery. METHODS: Patients seen at the UCSF MS Clinic within 1 year of disease onset were identified from a prospective database. Ordinal logistic regression was used to analyze predictors of three-level categorizations of event severity and recovery. RESULTS: We identified 330 patients with MS or clinically isolated syndrome; 152 had a second event and 63 had a third event. Nonwhite and younger patients were at an increased risk of more severe demyelinating events. A severe prior event predicted a substantial increase in the odds of being above any given severity cutoff for a severe subsequent event (for second event severity, odds ratio [OR] = 5.62, 95% confidence interval [CI] [2.39, 13.26], p < 0.0001; for third event severity, OR = 6.74, 95% CI [1.67, 27.18], p = 0.007). Similarly, poor recovery of the IDE predicted poor second event recovery (OR = 5.28, 95% CI [1.95, 14.25], p = 0.001), while fair or poor second event recovery predicted about a 5- or 13-fold increase in the odds of poor third event recovery. A more severe event also predicted a substantial increase in the odds of poor recovery. CONCLUSIONS: Patients with severe presentation and poor recovery at disease onset continue on a similar trajectory with subsequent demyelinating events. Whether genetic or other biologic factors are responsible for this pattern remains to be determined.

Induced resistance in the human non small cell lung carcinoma (NCI-H460) cell line in vitro by anticancer drugs.

Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concentrations of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was observed. Flow cytometry analysis showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the observed 15-fold increase in its mRNA concentration in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance.

Axillary recurrence after modified radical mastectomy.

Optimal management for axillary recurrence is poorly understood. The aim of this study was to evaluate the risk factors for overall survival in the patients with axillary recurrence. Data of 1098 patients were collected from breast cancer registers from Clinic for Oncology Nis between 1990-1995. All patients underwent modified radical mastectomy. Axillary recurence was diganosed in 43 (3.92%) patients. Most patients were presented with a localized, palpable axillary mass 30 (69.77%). Cox multivariate analysis of prognostic factors for breast cancer-specific survival showed that node status HR 4.69 (1.50 to 14.72), tumor size HR 3.18 (0.90 to 11.26) and axillary radiotherapy HR 1.99 (0.69 to 5.75) had statistically significant effect on breast cancer mortality. Log-rank (54.21 p < 0.001) analysis showed significant difference for overall survival among women with a axillary recurrence based on different cancer stages. Tumor size and node status were the most important prognostic factors in women with axillary recurrence.

Monotherapy with metformin: does it improve hypoxia in type 2 diabetic patients?

Metformin reduces blood glucose levels predominantly by inhibiting hepatic gluconeogenesis, although it also may enhance insulin receptor number or activity. The full effects of metformin are still poorly understood. In this study the effects of metformin on plasma xanthine oxidase (XO) activity, thiobarbituric acid-reactive substance (TBARS), lactate and fructosamine concentration as well as erythrocyte antioxidant enzyme activities were investigated in 46 patients with type 2 diabetes mellitus. All parameters were measured simultaneously just before metformin therapy (T0), 1 month (T1) and 2 months (T2) later. Results were compared with placebo and control group. We noted significant decrease in XO activity and in TBARS concentration (p<0.001) during monotherapy with metformin vs. placebo and T0 group. A significant correlation was observed between the activity of XO and the concentration of fructosamine (p<0.001). Erythrocyte glutathione peroxidase showed significantly lower activity in T2 group in comparison with T0 group (p<0.01). It is known that diabetic patients produce more TBARS as a result of enhanced free radical generation the source of which may also be the large amounts of XO produced following the conversion of xanthine dehydrogenase in hypoxic diabetic tissues. Thus, our results indirectly suggest that metformin can reduce toxic tissue damage through the inhibition on XO activity.

8-Cl-cAMP and tiazofurin affect vascular endothelial growth factor production and glial fibrillary acidic protein expression in human glioblastoma cells.

Compounds that could block tumor angiogenesis and induce tumor cell differentiation in malignant gliomas represent a very valuable tool in anticancer treatments. In this paper, we demonstrate that more selective drugs, which interfere with specific cellular targets, could treat glioma more effectively. 8-Cl-cAMP and tiazofurin (TR) are site-specific analogs that selectively inhibit PKAI and IMP dehydrogenase, are directly involved in cell proliferation and apoptosis, and mediate the mitogenic effects of different oncogenes and growth factors. In this study, we have examined influence of 8-Cl-cAMP and TR on the production of an angiogenic factor [vascular endothelial growth factor (VEGF)] by human glioblastoma U251 MG cells, as well as their influence on the expression of a differentiating marker [glial fibrillary acidic protein (GFAP)]. Using a cell proliferation assay, VEGF enzyme-linked immunoassay and GFAP immunocytochemistry we demonstrated the effects of these compounds. Our results demonstrate that 8-Cl-cAMP and TR decrease VEGF production by U251 MG cells, and that under the influence of both agents these cells increase GFAP expression and change their morphology, becoming more differentiated. These findings also suggest that 8-Cl-cAMP and TR may have potential for further investigation of their antiangiogenic and differentiational role in malignant disease such as human gliomas.

Inhibition of cell growth and proliferation in human glioma cells and normal human astrocytes induced by 8-Cl-cAMP and tiazofurin.

8-Cl-cAMP and tiazofurin (TR) are anti-tumor agents that besides their antiproliferative effect, also induce differentiation of tumor cells. Although, these agents exert a profound effect on the same events of tumor cell life, it is thought that 8-Cl-cAMP and TR act by modulating the signal transduction pathway through distinct mechanisms. We have compared their effect on two human glioma cell lines (U87 MG and U251 MG) and examined if there is selectivity in their action toward normal human astrocytes.

Comparison of the MCNP calculated and measured radiation field quantities near the RB reactor.

The RB experimental reactor has operated at Vinca Institute of Nuclear Sciences since the end of April 1958. In this paper, neutron and gamma-ray spectra and corresponding dose quantities near the reactor, calculated by using the MCNP code, are compared to the measured values during the Third International Intercomparison Experiment on Nuclear Accident Dosimetry carried out at the RB reactor in 1973. Discrepancies in the correlation declared power of the reactor-dose rates are found. Good agreements are obtained between measured and calculated neutron and gamma-ray spectra, and corresponding absorbed doses in air, but only after the reactor declared power is multiplied by a correction factor, determined in this study.

Immunomodulation in vitro. The predictive value of in vitro testing of lung cancer patients' lymphocyte responsiveness to stimulation by Thymex L. A preliminary report.

Eleven lung cancer patients were selected for combined radio and immunotherapy with a thymic agent-Thymex L. The selection criteria included the pre-therapy testing of patients' immunocompetence and the responsiveness of their lymphocytes to the in vitro addition of Thymex L: only patients with a significant degree of immunodepression, whose depressed cellular immunity parameters (the number of total and active T cells and their mitogen-induced lymphoproliferative response) were significantly increased upon this agent's action in vitro, entered the study. The results of the pre-therapy in vitro stimulation correlated with those obtained after completion of radioimmunotherapy: the administration of Thymex L along with radiotherapy seances prevented iatrogenic deterioration of initial depression of general immunocompetence and enabled to overcome it to a certain degree. This indicates that pre-therapy in vitro testing has a true predictive value. However, the initial immune disturbances were not normalized by immunotherapy; the post-therapy testing of the patients' lymphocytes to the addition of Thymex L in vitro showed that these cells possessed a residual potential to respond by a significant increase of the active T cell number and proliferative capacity, suggesting that immunotherapy could be prolonged in order to potentiate cellular immunity in immunodepressed lung cancer patients.

Long-term follow up of patients with dilated heart muscle disease treated with human leucocytic interferon alpha or thymic hormones initial results.

OBJECTIVE: To determine whether giving interferon-alpha or thymomodulin in addition to conventional treatment improves cardiac function in patients with idiopathic myocarditis and idiopathic dilated cardiomyopathy. DESIGN: Single-centre, randomised, open label, parallel group comparison of conventional treatment plus interferon-alpha, conventional treatment plus thymomodulin, and conventional treatment alone. PATIENTS: 38 patients aged 19-54 years (23 men) with biopsy-proven myocarditis or dilated cardiomyopathy. 12 were treated with conventional treatment alone, 13 were treated with interferon-alpha and conventional treatment, and 13 with thymomodulin and conventional treatment. SETTING: Tertiary cardiac referral centre. MAIN OUTCOME MEASURES: Clinical evaluation, echocardiography, and Holter monitoring at baseline, 6 months, and 1 and 2 years. Radionuclide ventriculography at rest and during exercise after 2 years. Endomyocardial biopsy at baseline and after a year if the initial diagnosis was myocarditis. RESULTS: Left ventricular ejection fraction was improved in 21 (81%) of 26 patients after interferon-alpha or thymomodulin administration and in 8 (66%) of 12 conventionally treated patients (P < 0.05) at 2 year follow up. The maximum exercise time was significantly longer at 2-year follow up in patients treated with immunomodulators (mean (SEM) 5.1 (0.6) minutes for interferon-alpha and 5.0 (0.4) minutes for thymomodulin) than in conventionally treated patients (3.3 (0.4) minutes). Left ventricular ejection fraction during exercise (assessed by radionuclide ventriculography) improved in 9 of 12 patients treated with interferon-alpha, 10 of 12 patients treated with thymomodulin, and 3 of 9 conventionally treated patients at 2 year follow up. The electrocardiogram was normal in 21 (88%) of 24 patients after interferon-alpha or thymomodulin treatment and 2 (22%) of 9 conventionally treated patients. At 2 year follow up, 19 (73%) of 26 patients treated with immunomodulators and 4 (25%) of 12 conventionally treated patients had improved their functional class. CONCLUSIONS: The results suggest that treatment of idiopathic myocarditis and/or idiopathic dilated cardiomyopathy with interferon-alpha or thymomodulin induces an earlier and significantly superior clinical improvement than conventional treatment alone.

Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy.

It is becoming increasingly apparent that idiopathic dilated cardiomyopathy (IDC) probably results from an acute viral myocarditis. One reasonable hypothesis is that persistent viral infection causes myocardial destruction leading to left ventricular dilatation and heart failure. The aim of this study was to evaluate the efficacy of interferon-alpha (IFN) and thymomodulin in the treatment of idiopathic myocarditis and IDC. Clinical, immunological, haemodynamic and histological evaluation was performed in 40 patients before inclusion in the study. Patients were randomized into three treatment groups: (a) conventional therapy plus IFN, (b) conventional therapy plus thymomodulin and (c) conventional therapy alone. Two-year follow-up included repeated endomyocardial biopsy, echocardiographic evaluation, treadmill exercise test, Holter monitoring study and radionuclide assessment of left ventricular function during exercise. Left ventricular ejection fraction increased during follow-up in most of the IFN-and thymomodulin-treated patients, and only in a few of conventionally treated patients. Left ventricular reserve was significantly higher at 2-year follow-up in patients treated with immunomodulators. No serious adverse effects were noticed during treatment. Our results suggest that treatment of myocarditis and/or IDC with IFN or thymomodulin induces an earlier and significantly superior clinical improvement than conventional therapy alone.

Long-term follow-up of patients with myocarditis and idiopathic dilated cardiomyopathy after immunomodulatory therapy.

The randomized clinical trial with interferon-alpha (IFN) or thymic hormones versus conventional therapy was conducted in patients with myocarditis and idiopathic dilated cardiomyopathy (IDC). We enrolled 180 patients to receive IFN (3-5 million units per day) for 3 months, thymomodulin (10 mg three times per week) for 2 months, or conventional therapy alone. Patients were followed-up for 7 years after the end of treatment. Left ventricular function, exercise tolerance and survival rate were significantly better at long-term follow-up in patients treated with IFN or thymomodulin, than in conventionally treated patients. These results implicate that immune modulating therapy might represent important contribution in the treatment of myocarditis and IDC.

[Immune complexes in diabetes mellitus]. / Imunski kompleksi u dijabetesu melitusu.

Research in recent years has documented more exactly the genetic and immunopathogenetic basis of insulin-dependent diabetes mellitus. Also, in some genetically susceptible subjects, a triggering event activates both cellular and humoral immunity, with diminishing of b cellular mass. Early intervention to prevent diabetes development as well as to prevent microvascular complications is identification of individuals in whom autoimmunity has been activated. One of the non-specific tests is a screening test for the detection of circulating immune complexes /CIC/ by precipitating tests using polyethylene glycol it was performed in series of healthy, insulin-dependent and non-insulin dependent diabetic subjects. Highly increased precitability was seen in a great percentage of pathological sera. In spite of the non-specific method for immune complexes detection, positive results obtained by PEG method generally presumed that diabetes represent immune complex disease.

Techniques for selection of normal-chromatin sperm preparations.

Various sperm preparation techniques, swim-up and Percoll gradient, and the newly developed Wang's tube system, were evaluated for their ability to recover normal-chromatin sperm. Twenty human semen samples, collected by masturbation, were studied simultaneously with the three methods. Analysis by Acridine orange fluorescence test was performed on all samples. Pretreated semen contains 58 +/- 22% green sperm (fertile/normal). Treatment with Wang's tube system resulted in 99 +/- 1.0% green sperm; Percoll gradient, 78 +/- 11%; and swim-up technique, 72 +/- 15%. It would appear that Wang's tube system yields a high-quality sperm preparation with enough concentration, very active forward progression, and greatly improved sperm morphology, while containing normal-chromatin, double-stranded DNA.