DIABETIC NEPHROPATHY IN PREGNANT WOMEN WITH TYPE 1 DIABETES (MULTIPLE CASES REVIEW AND DISCUSSION).

Pregnancy in women with pre-existing diabetes is associated with a doubled, or even up to four-fold increased risk of preeclampsia, preterm delivery, and perinatal mortality compared to the risk observed in a background population. Diabetic nephropathy (DN) is a progressive disease that affects about one third of diabetic patients and is among the most frequent causes of the end stage renal disease (ESRD) worldwide. In the random population, it is present in up to 7% of women with type 1 diabetes mellitus (T1DM), and it represents the most common chronic kidney disease occurring in graviditas, complicating between 2.5% and 5% of T1DM pregnancies. Although maternal and perinatal morbidity and mortality rates in the pregnancies complicated with DN have declined over time, pregnancy related health complications are still more common in women with DN compared to those observed among diabetic women without DN. The adequate pre-pregnancy counseling and a tailored approach to the treatment of women with DN during the pregnancy are crucial for an avoidance of the adverse maternal and fetal outcomes. This paper is highlighting the impact of DN on maternal and fetal outcomes in women with T1DM, through presentation of the cases from a real-world clinical practice.

Aggressiveness in depression: a neglected symptom possibly associated with bipolarity and mixed features.

OBJECTIVE: To evaluate aggressiveness during a major depressive episode (MDE) and its relationship with bipolar disorder (BD) in a post hoc analysis of the BRIDGE-II-MIX study. METHOD: A total of 2811 individuals were enrolled in this multicenter cross-sectional study. MDE patients with (MDE-A, n = 399) and without aggressiveness (MDE-N, n = 2412) were compared through chi-square test or Student's t-test. A stepwise backward logistic regression model was performed. RESULTS: MDE-A group was more frequently associated with BD (P < 0.001), while aggressiveness was negatively correlated with unipolar depression (P < 0.001). At the logistic regression, aggressiveness was associated with the age at first depressive episode (P < 0.001); the severity of mania (P = 0.03); the diagnosis of BD (P = 0.001); comorbid borderline personality disorder (BPD) (P < 0.001) but not substance abuse (P = 0.63); no current psychiatric treatment (P < 0.001); psychotic symptoms (P = 0.007); the marked social/occupational impairment (P = 0.002). The variable most significantly associated with aggressiveness was the presence of DSM-5 mixed features (P < 0.001, OR = 3.815). After the exclusion of BPD, the variable of lifetime suicide attempts became significant (P = 0.013, OR = 1.405). CONCLUSION: Aggressiveness seems to be significantly associated with bipolar spectrum disorders, independently from BPD and substance abuse. Aggressiveness should be considered as a diagnostic criterion for the mixed features specifier and a target of tailored treatment strategy.

Resonant dynamic Stark shift as a tool in strong-field quantum control: calculation and application for selective multiphoton ionization of sodium.

A method for determining the resonant dynamic Stark shift (RDSS), based on wave-packet calculations of the populations of quantum states, is presented. It is almost insensitive to variations of the laser pulse profile, and this feature ensures generality in applications. This method is used to determine an RDSS data set for 3s → nl (n ≤ 6) transitions in sodium induced by laser pulses with peak intensities up to 7.9 × 1012 W cm-2 and wavelengths in the range from 455.6 to 1139 nm. The data are applied to analyze the photoelectron spectra (electron yield versus excess energy) of the sodium atom interacting with 800 nm laser radiation. Substructures observed in the experimentally measured spectra are successfully reproduced and related to the resonantly enhanced multiphoton ionization via specific (P and F) intermediate states.

PECAM-1 gene polymorphism (rs668) and subclinical markers of carotid atherosclerosis in patients with type 2 diabetes mellitus.

The platelet endothelial cell adhesion molecule 1 (PECAM-1) plays an important role in many inflammatory processes, including the development of atherosclerosis. Polymorphism rs668 of the PECAM-1 gene (373C/G) is functional, and it was reported to be associated with increased serum levels of PECAM-1. We investigated the association between the rs668 polymorphism of PECAM-1 and subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). Five hundred and ninety-five T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Geno-typing of the PECAM-1 gene polymorphism (rs668) was performed using KASPar assays. The control examinations were performed 3.8 ± 0.5 years after the initial examination. Higher CIMT was found in patients with T2DM in comparison with subjects without T2DM. Statistically sig-nificantly faster progression of the atherosclerotic markers was shown in subjects with T2DM in comparison with the control group. When adjusted to other risk factors, the rs668 GG genotype was associated with an increased risk of carotid plaques in subjects with T2DM. We concluded that our study demonstrated a minor effect of the rs668 PECAM-1 on markers of carotid atherosclerosis in subjects with T2DM.

Clinical implications of predominant polarity and the polarity index in bipolar disorder: a naturalistic study.

OBJECTIVE: Predominant polarity (PP) is an important variable in maintenance treatment of bipolar disorder (BD). This study aimed at determining the role of polarity index (PI), a metric indicating antimanic versus antidepressive prophylactic potential of drugs, in clinical decision-making. METHOD: Two hundred and fifty-seven of 604 (43%) of patients with BD-I or II fulfilled criteria for manic (MPP) or depressive PP (DPP). The PI, representing the ratio of number needed to treat (NNT) for depression prevention to NNT for mania prevention, was calculated for patients' current treatment. MPP and DPP groups were compared regarding sociodemographic, clinical and therapeutic characteristics. RESULTS: One hundred and forty-three patients (55.6%) fulfilled criteria for DPP and 114 (44.4%) for MPP. Total PI, Antipsychotics' PI, and mood stabilizers PI were higher, indicating a stronger antimanic action, in MPP. MPP presented higher prevalence of BD-I, male gender, younger age, age at onset and at first hospitalization, more hospitalizations, primary substance misuse, and psychotic symptoms. DP correlated with BD-II, depressive onset, primary life events, melancholia, and suicide attempts. CONCLUSION: The results confirm the usefulness of the PI. In this large sample, clinical differences among these groups justify differential treatment approach. The PI appears to be a useful operationalization of what clinicians do for maintenance therapy in BD.

Risk factors for suicide in schizophrenia: systematic review and clinical recommendations.

OBJECTIVE: To identify risk factors associated with suicide of patients with schizophrenia and provide clinical recommendations, which integrate research findings into a consensus based on clinical experience and evidence. METHOD: A task force formed of experts and clinicians iteratively developed consensus through serial revisions using the Delphi method. Initial survey items were based on systematic literature review published up to June 2013. RESULTS: Various risk factors were reported to be implicated in suicide in schizophrenia. Our findings indicate that suicide risk in schizophrenia is mainly related to affective symptoms, history of a suicide attempt and number of psychiatric admissions. Other risk factors identified are given by younger age, closeness to illness onset, older age at illness onset, male sex, substance abuse and period during or following psychiatric discharge. Integrating the evidence and the experience of the task force members, a consensus was reached on 14 clinical recommendations. CONCLUSION: Identification of risk factors for suicide in individuals diagnosed with schizophrenia is imperative to improve clinical management and develop strategies to reduce the incidence of suicide in this population. This study provides the critical overview of available data and clinical recommendations on recognition and management of the above-mentioned risk factors.

Clinical, dermoscopic and histopathologic features of genital and extragenital lichen sclerosus.

BACKGROUND: Little is currently known about the dermoscopic patterns of genital and extragenital lichen sclerosus (LS). In order to evaluate and compare the dermoscopic and histopathologic patterns of genital and extragenital lichen sclerosus, a retrospective analysis of clinical, dermoscopic and histopathologic features of genital and extragenital LS, collected between March 2010 and December 2011 at four dermatology clinics in Greece, Italy, Serbia and Uruguay was performed. OBSERVATIONS: A total of 29 lesions from 14 (mean age 62.8 years) and 12 (mean age 53.5 years) patients with genital and extragenital LS, respectively were analyzed. Mean duration of disease was 3.5 years for genital and 1.8 years for extragenital LS. White-yellowish structureless areas were seen in all cases of genital and extragenital LS; however linear vessels occurred at higher frequency in genital than in extragenital lesions (85.7% vs. 33.3%, respectively). Extragenital LS revealed two different time-related patterns: keratotic plugs were more prevalent in lesions with short duration (<2 years), whereas longer persisting lesions appeared atrophic and revealed fine chrysalis structures. CONCLUSIONS: Our morphologic study provides novel insights into the morphologic diversity of LS at different body sites and different stages of progression.

Evaluation of a panel of 28 biomarkers for the non-invasive diagnosis of endometriosis.

BACKGROUND: At present, the only way to conclusively diagnose endometriosis is laparoscopic inspection, preferably with histological confirmation. This contributes to the delay in the diagnosis of endometriosis which is 6-11 years. So far non-invasive diagnostic approaches such as ultrasound (US), MRI or blood tests do not have sufficient diagnostic power. Our aim was to develop and validate a non-invasive diagnostic test with a high sensitivity (80% or more) for symptomatic endometriosis patients, without US evidence of endometriosis, since this is the group most in need of a non-invasive test. METHODS: A total of 28 inflammatory and non-inflammatory plasma biomarkers were measured in 353 EDTA plasma samples collected at surgery from 121 controls without endometriosis at laparoscopy and from 232 women with endometriosis (minimal-mild n = 148; moderate-severe n = 84), including 175 women without preoperative US evidence of endometriosis. Surgery was done during menstrual (n = 83), follicular (n = 135) and luteal (n = 135) phases of the menstrual cycle. For analysis, the data were randomly divided into an independent training (n = 235) and a test (n = 118) data set. Statistical analysis was done using univariate and multivariate (logistic regression and least squares support vector machines (LS-SVM) approaches in training- and test data set separately to validate our findings. RESULTS: In the training set, two models of four biomarkers (Model 1: annexin V, VEGF, CA-125 and glycodelin; Model 2: annexin V, VEGF, CA-125 and sICAM-1) analysed in plasma, obtained during the menstrual phase, could predict US-negative endometriosis with a high sensitivity (81-90%) and an acceptable specificity (68-81%). The same two models predicted US-negative endometriosis in the independent validation test set with a high sensitivity (82%) and an acceptable specificity (63-75%). CONCLUSIONS: In plasma samples obtained during menstruation, multivariate analysis of four biomarkers (annexin V, VEGF, CA-125 and sICAM-1/or glycodelin) enabled the diagnosis of endometriosis undetectable by US with a sensitivity of 81-90% and a specificity of 63-81% in independent training- and test data set. The next step is to apply these models for preoperative prediction of endometriosis in an independent set of patients with infertility and/or pain without US evidence of endometriosis, scheduled for laparoscopy.

Neurocognitive impairment and psychosocial functioning in bipolar II disorder.

OBJECTIVE: There is a growing body of evidence on neurocognitive impairment in euthymic bipolar patients, but this issue has been studied mostly in bipolar I disorder, data on bipolar II (BD-II) are scant and discrepant. The two aims of this study were to ascertain whether strictly defined euthymic BD-II patients would present neurocognitive disturbances and to evaluate their impact on functional outcome. METHOD: Forty-three BD-II patients and 42 demographically and educationally matched healthy subjects were assessed with a comprehensive neuropsychological test battery and with the Social and Occupational Functioning Assessment Scale (SOFAS). The euthymia criteria were reduced (Hamilton Rating Scale for Depression score ≤6 and a Young Mania Rating Scale score ≤6) to minimize the influence of subdepressive symptomatology on cognition and functioning. RESULTS: BD-II patients showed a significantly lower performance on several measures of attention, learning and verbal memory, and executive function compared with healthy controls. The presence of subthreshold depressive symptomatology and one measure related to executive function (Trail Making Test, part B) was the variables that best predicted psychosocial functioning measured with the SOFAS. CONCLUSION: This report provides further evidence that euthymic BD-II patients present cognitive impairment which may impact psychosocial functioning.

Are bipolar II patients cognitively impaired? A systematic review.

BACKGROUND: There is evidence that bipolar disorder (BD) is associated with significant neurocognitive deficits and this occurs in individuals with BD type I (BD I) and with BD type II (BD II). Only a few studies have focused on cognitive impairment in BD II. The aim of this study was to describe the pattern of cognitive impairment in patients with BD II, in order to identify specific cognitive deficits that distinguish BD II from BD I patients as well as from healthy subjects. METHOD: We performed a systematic review of the literature of neuropsychological studies of BD II published between 1980 and July 2009. Fourteen articles fulfilled the inclusion criteria and were included in this review. RESULTS: Main cognitive deficits found in BD II include working memory and some measures of executive functions (inhibitory control) and approximately half of the studies also detected verbal memory impairment. CONCLUSIONS: There are subtle differences between the two subtypes regarding cognition. This may suggest neurobiological differences between the two subgroups which will be helpful in order to determine cognitive endophenotypes in BD subtypes.

Effects of conventional versus biocompatible peritoneal dialysis solutions on peritoneal and systemic inflammation, malnutrition and atherosclerosis in CAPD patients.

BACKGROUND: Chronic inflammation, malnutrition and atherosclerosis (MIA syndrome) are important predictors of high mortality in continuous ambulatory peritoneal dialysis (CAPD) patients. We aimed to evaluate the effects of PD solutions (standard vs. biocompatible) on some parameters of MIA syndrome in patients undergoing CAPD. METHODS: 42 stable patients who were on CAPD at least 2.5 years participated in this cross-sectional study. Patients who had severe anemia (Hb < 10 g/l), immunomodulatory therapy, peritonitis or any inflammatory conditions for at least 3 months before the analysis, malignant disease and acute exacerbation of heart failure, were excluded. 21 (50%) patients were treated with standard PD solutions (CAPDP-1), while the remaining 21 (50% of patients) were treated with biocompatible PD solutions (neutral solutions with lower level of glucose degradation products and lower concentration of calcium, CAPDP-2). All patients underwent echocardiography and B-mode ultrasonography of common carotid arteries together with assessments of nutrition status and parameters of systemic and local inflammation. RESULTS: There were no significant differences between the groups concerning age, gender, underlying disease, residual renal function, peritoneal transport characteristics, comorbidity or therapy applied. Patients from group CAPDP-2 had a significantly lower serum level of hs-CRP (3.7 ± 2.6 mg/l vs. 6.3 ± 4.5 mg/l; p = 0.023) and significantly better nutritional status confirmed by mid-arm circumference (p = 0.015), mid-arm muscle circumference (p = 0.002) and subjective global assessment (14.28% of patients in CAPDP-2 vs. 71% of patients in CAPDP-1 were malnourished; p = 0.000). Group CAPD-2 had less frequent left ventricular hypertrophy (p = 0.039), thinner intima-media thickness (p = 0.005), smaller carotid narrowing (p = 0.000) and fewer calcified plaques of common carotide arteries (p = 0.003). No significant difference between the CAPDP groups was observed in serum and effluent levels of inflammatory cytokines (IL-1, IL-6 and TNF-α) and CA-125 effluent level. Logistic regression analysis did not confirm that biocompatibility of PD solutions was an independent predictor of any parameter of MIA syndrome. CONCLUSIONS: According to the present study and logistic regression analysis, the effect of biocompatible CAPD solutions on parameters of malnutrition, inflammation and atherosclerosis have to be confirmed by well-designed and controlled studies in a higher number of patients.

Systolic right ventricular adaptive changes in athletes as predictors of the maximal functional capacity: a pulsed tissue Doppler study.

AIM: The aim of this study was to extend the analysis of the systolic right ventricular (RV) adaptation to combined endurance and strength training, to assess the utility of tissue Doppler imaging in detecting the degree of these changes and to find independent RV predictors of the maximal functional capacity. METHODS: Standard Doppler and TDI were used to assess cardiac parameters at rest in 37 elite male athletes (16 wrestlers, 21 water polo players) and 20 sedentary subjects of similar age. Progressive maximal test on treadmill was used to assess VO2max. The obtained parameters were adjusted for HR, FFM, and BSA. RESULTS: Wrestlers showed higher VO2max than controls, but lesser than water polo players. RV diameter was larger in athletes. Right atrial pressure (RVE/e) was higher in water polo players than in other groups. Systolic function assessed by tricuspid annular plane systolic excursion (TAPSE) and RVs' was the highest in wrestlers. Global RV systolic parameters myocardial performance index (MPI) and preejection time/ejection time index (PET/ET) were similar. On multivariate analysis systolic parameters were independent predictors of VO2max only in wrestlers: RVs' (beta=3.18, P=0.001) and RV ET (beta=2.32, P=0.001). RVE/e` correlated with RVs' (r=-0.57, P=0.000). TAPSE correlated with RV ET (r=0.32, P=0.015) and RVs` (beta=0.28, P=0.033). CONCLUSION: Systolic function assessed by TAPSE and RVs` has more improved in less endurance athletes. RVs`and TDI ejection time predict VO2max in wrestlers, and possibly in other athletes with lesser right atrial pressure. TDI enables quantifying RV adaptation degree in athletes, but complementary to M-mode technique.

Nonsteroidal anti-inflammatory drugs: as inappropriate pharmacotherapy in the elderly?

Nonsteroidal anti-inflammatory drugs (NSAID) are one of the most used groups of drugs in elderly population. The aim of this study was to establish the frequency of reported disorders while using NSAID in elderly patients. A multi-centric study was conducted with a standard questionnaire for all geriatrician outpatients who were using NSAID. It has been found that out of 421 patients, 320 reported some kind of disorder; 287 of them used other drugs beside NSAID, 33 used only NSAID during the study. It has been concluded that frequency of reported disorders was significantly higher among patients who used another drug beside NSAID, and statistically most frequent reported disorders were gastrointestinal.

Association between cardiac high-energy phosphate metabolism and whole body metabolism in healthy female adults.

Decline in cardiac high-energy phosphate metabolism [phosphocreatine-to-ATP (PCr/ATP) ratio] and whole body metabolism increase the risk of heart failure and metabolic diseases. The aim of the present study was to assess the relationship between PCr/ATP ratio and measures of body metabolic function. A total of 35 healthy women (56+/-14.0 years of age) underwent cardiac 31P magnetic resonance spectroscopy to assess PCr/ATP ratio - an index of cardiac high-energy phosphate metabolism. Fasting and 2-hour glucose levels were assessed using oral glucose tolerance test. Indirect calorimetry was performed to determine oxygen consumption and resting metabolic rate. There were no significant relationships between PCr/ATP ratio and resting metabolic rate (r=-0.09, p=0.62), oxygen consumption (r=-0.11, p=0.54), fasting glucose levels (r=-0.31, p=0.07), and 2-hour plasma glucose (r=-0.10, p=0.58). Adjusted analysis for covariates including age, body mass index, fat mass, and physical activity, had no significant influence on the relationship between PCr/ATP ratio and body metabolism. In conclusion, the lack of relationship between cardiac PCr/ATP ratio, glucose control and metabolic rate may suggest that overall metabolic function does not influence cardiac high-energy phosphate metabolism.

Similarity of cytochrome c oxidases in different organisms.

Most of biological oxygen reduction is catalyzed by the heme-copper oxygen reductases. These enzymes are redox-driven proton pumps that take part in generating the proton gradient in both prokaryotes and mitochondria that drives synthesis of ATP. The enzymes have been divided into three evolutionarily-related groups: the A-, B-, and C-families. Recent comparative studies suggest that all oxygen reductases perform the same chemistry for oxygen reduction and comprise the same essential elements of the proton pumping mechanism, such as the proton loading and kinetic gating sites, which, however, appear to be different in different families. All species of the A-family, however, demonstrate remarkable similarity of the central processing unit of the enzyme, as revealed by their recent crystal structures. Here we demonstrate that cytochrome c oxidases (CcO) of such diverse organisms as a mammal (bovine heart mitochondrial CcO), photosynthetic bacteria (Rhodobacter sphaeroides CcO), and soil bacteria (Paracoccus denitrificans CcO) are not only structurally similar, but almost identical in microscopic electrostatics and thermodynamics properties of their key amino-acids. By using pK(a) calculations of some of the key residues of the catalytic site, D- and K- proton input, and putative proton output channels of these three different enzymes, we demonstrate that the microscopic properties of key residues are almost identical, which strongly suggests the same mechanism in these species. The quantitative precision with which the microscopic physical properties of these enzymes have remained constant despite different evolutionary routes undertaken is striking.

The implications of hypersomnia in the context of major depression: Results from a large, international, observational study.

According to the DSM-5, "reduction in the need for sleep" is the only sleep-related criteria for mixed features in depressive episodes. We aimed at studying the prevalence, clinical correlates and the role of hypersomnia in a sample of acutely depressed patients. Secondarily, we factors significantly increasing the odds of hypersomnia were studied. We conducted a post-hoc analysis of the BRIDGE-II-Mix study. Variables were compared between patients with hypersomnia (SLEEP+) and with insomnia (SLEEP-) with standard bivariate tests. A stepwise backward logistic regression model was performed with SLEEP+ as dependent variable. A total of 2514 subjects were dichotomized into SLEEP+ (n = 423, 16.8%) and SLEEP- (n = 2091, 83.2%). SLEEP+ had significant higher rates of obese BMI (p < 0.001), BD diagnosis (p = 0.027), severe BD (p < 0.001), lifetime suicide attempts (p < 0.001), lower age at first depression (p = 0.004) than SLEEP-. Also, SLEEP+ had significantly poorer response to antidepressants (AD) such as (hypo)manic switches, AD resistance, affective lability, or irritability (all 0<0.005). Moreover, SLEEP+ had significantly higher rates of mixed-state specifiers than SLEEP- (all 0 < 0.006). A significant contribution to hypersomnia in our regression model was driven by metabolic-related features, such as "current bulimia" (OR = 4.21) and "overweight/obese BMI (OR = 1.42)". Globally, hypersomnia is associated with poor outcome in acute depression. Hypersomnia is strongly associated with mixed features and bipolarity. Metabolic aspects could influence the expression of hypersomnia, worsening the overall clinical outcome. Along with commonly used screening tools, detection of hypersomnia has potential, costless discriminative validity in the differential diagnosis unipolar and bipolar depression.

Protein dynamics control of electron transfer in photosynthetic reaction centers from Rps. sulfoviridis.

In the cycle of photosynthetic reaction centers, the initially oxidized special pair of bacteriochlorophyll molecules is subsequently reduced by an electron transferred over a chain of four hemes of the complex. Here, we examine the kinetics of electron transfer between the proximal heme c-559 of the chain and the oxidized special pair in the reaction center from Rps. sulfoviridis in the range of temperatures from 294 to 40 K. The experimental data were obtained for three redox states of the reaction center, in which one, two, or three nearest hemes of the chain are reduced prior to special pair oxidation. The experimental kinetic data are analyzed in terms of a Sumi-Marcus-type model developed in our previous paper,1 in which similar measurements were reported on the reaction centers from Rps. viridis. The model allows us to establish a connection between the observed nonexponential electron-transfer kinetics and the local structural relaxation dynamics of the reaction center protein on the microsecond time scale. The activation energy for relaxation dynamics of the protein medium has been found to be around 0.1 eV for all three redox states, which is in contrast to a value around 0.4-0.6 eV in Rps. viridis.1 The possible nature of the difference between the reaction centers from Rps. viridis and Rps. sulfoviridis, which are believed to be very similar, is discussed. The role of the protein glass transition at low temperatures and that of internal water molecules in the process are analyzed.

Caffeine induces metformin anticancer effect on fibrosarcoma in hamsters.

OBJECTIVE: We investigated the effect of metformin and caffeine on fibrosarcoma in hamsters. MATERIALS AND METHODS: 32 Syrian golden hamsters of both sexes, weighing approximately 100 g, were randomly allocated to 3 experimental and 2 control groups, with a minimum of 6 animals per group. 2 x 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals' back in 4 groups. The first experimental group started peroral treatment with metformin 500 mg/kg daily, the second with caffeine 100 mg/kg daily and the third with a combination of metformin 500 mg/kg and caffeine 100 mg/kg daily, via a gastric probe 3 days before tumor inoculation. After 2 weeks, when the tumors were approximately 2 cm in the control group, all animals were sacrificed. The blood was collected for glucose and other analyses. The tumors were excised and weighed and their diameters were measured. The tumor samples were pathohistologically (HE) and immunohistochemically (Ki-67, CD 31, COX IV, GLUT-1, iNOS) assessed and the main organs toxicologically analyzed, including the control animals that had received metformin and caffeine. Tumor volume was determined using the formula LxS2/2, where L was the longest and S the shortest diameter. Ki-67-positive cells in the tumor samples were quantified. Images were taken and processed by software UTHSCSA Image Tools for Windows Version 3.00. Statistical significances were determined by the Student's t-test. RESULTS: The combination of metformin and caffeine inhibited fibrosarcoma growth in hamsters without toxicity. CONCLUSIONS: Administration of metformin with caffeine might be an effective and safe approach in novel nontoxic adjuvant anticancer treatment.

Neuromodulation of lower limb monoparesis: functional electrical therapy of walking.

After Cerebro-Vascular Accident (CVA), restoration of normal function, such as locomotion, depends on reorganization of existing central nervous system (CNS) circuitry. This capacity for reorganization, generally referred to as plasticity, is thought to underlie many instances of functional recovery after injury as well as learning and memory in the undamaged CNS. Both the reorganization of the supraspinal and spinal circuitry are highly important for the recovery of walking. The neural mechanisms responsible for learning and adapting processes are thought to involve changes both in the efficacy of synaptic function and the pattern of synaptic connections within neural circuits. In the uninjured CNS, these changes occur as a result of alterations in the amount of neural activity within circuits and are, therefore, termed activity-dependent. In this chapter, we will present several therapies of walking that provide effective input for the training of the existing CNS circuitry; thereby, contribute to long term recovery of sensory-motor functions. The focus of this chapter is Functional Electrical Therapy (FET) of walking, that is, the multi-channel electrical stimulation of sensory-motor systems that lead to more normal stance and swing of the paretic leg during the walking exercise.

Effect of metformin on fibrosarcoma in hamsters.

OBJECTIVE: We investigated the effect of metformin on an in vivo solid tumor model of fibrosarcoma in hamsters. MATERIALS AND METHODS: 33 Syrian golden hamsters of both sexes, weighing approximately 100 g, were randomly allocated to 3 experimental and 2 control groups. 2 x 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals' back in 4 groups. The first experimental group (7 animals) started peroral treatment with metformin 500 mg/kg daily via a gastric probe 7 days before tumor inoculation, the second (8 animals) 3 days before inoculation and the third (6 animals) immediately after inoculation. After 2 weeks, when the tumors were approximately 2-3 cm in the control group with tumors (6 hamsters), all animals were sacrificed. The blood was collected for glucose and other analyses. The tumors were excised and weighed and their diameters were measured. The tumor samples were histologically assessed and the main organs toxicologically analyzed, including 6 control animals that had received metformin without tumor inoculation. Tumor volume was determined using the formula Lx S2/2, where L was the longest and S the shortest diameter. Ki-67-positive cells in the tumor samples were quantified; images were taken and processed by software UTHSCSA Image Tools for Windows Version 3.00. Statistical significances of differences in tumor weight, volume, number of Ki-67-positive cells and other parameters were determined by the Student´s t-test. RESULTS: Metformin inhibited fibrosarcoma growth in hamsters without toxicity. The seven-day pretreatment was important for the statistically significant effect. CONCLUSIONS: Administration of metformin as an anti-tumor drug might be an effective and safe therapeutic approach in novel non-toxic therapies for human sarcomas.