Phase 1 Study of THR-687, a Novel, Highly Potent Integrin Antagonist for the Treatment of Diabetic Macular Edema.

Purpose: To evaluate the safety and preliminary efficacy of THR-687 in patients with center-involved diabetic macular edema (DME). Design: Phase 1, open-label, multicenter, 3 + 3 dose-escalation study with 3-month follow-up. Participants: Patients 18 years of age or older with visual impairment resulting from DME. Methods: Single intravitreal injection of THR-687 (0.4 mg, 1.0 mg, or 2.5 mg). Main Outcome Measures: The primary outcome measure was the incidence of dose-limiting toxicities (DLTs). The secondary outcome measure was the incidence of adverse events (AEs), including the occurrence of laboratory abnormalities. Exploratory outcome measures included changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST), assessments of ischemia and leakage on fluorescein angiography, and THR-687 levels in plasma. Results: Twelve patients were treated: 3 patients received 0.4 mg of THR-687, 3 patients received 1.0 mg of THR-687, and 6 patients received 2.5 mg of THR-687. Most patients were men (9/12 patients). Their mean age was 57.8 years. No DLTs or serious AEs were reported at any of the dose levels tested. Overall, 9 AEs in the study eye were reported for 5 of 12 patients. Of those, 4 AEs in 3 of 12 patients were deemed treatment related by the investigator, all of which were mild, started on the day of the injection, and had resolved within 28 days without treatment. Overall, mean gains from baseline in BCVA were observed at all study visits with a rapid onset (7.2 Early Treatment Diabetic Retinopathy Study [ETDRS] letters at day 7) and a durability up to the end of the study (8.3 ETDRS letters at month 3). A mean decrease in CST was observed up to month 1. Overall, the mean BCVA gains and CST decreases were highest at the highest THR-687 dose level tested. THR-687 was undetectable in plasma at 7 days after the injection. Conclusions: At all dose levels tested, a single intravitreal injection of THR-687 was safe and well tolerated. Preliminary efficacy was observed by a rapid gain in BCVA with 3 months' durability and a decrease in CST up to 1 month after the injection.

[Breast conservative surgery after neoadjuvant oncologic treatment for breast carcinoma at the 1st Department of Surgery, 1st Faculty of Medicine of Charles University and General Teaching Hospital in Prague over a ten-year period (20042013)]. / Prs setrící výkony po neadjuvantní onkologické lécbe pro karcinom na I. chirurgické klinice 1. LF UK a VFN v Praze v období deseti let (2004-2013).

INTRODUCTION: Since the first breast conservative surgery following neoadjuvant oncotherapy performed in the 1990s, there has been a shift in indications, diagnostic, surgical and oncotherapeutic procedures. The aim of the study is to present the results of the comprehensive treatment of patients with breast conservative surgery performed after neoadjuvant oncologic treatment for breast cancer at our department of surgery. METHOD: A retrospective study involving 96 patients operated on at our department between 2004 and 2013. The median follow-up time is 6 years and 8 months after the diagnosis. RESULTS: Breast recurrence was found in 2 (2.1%) cases. No axillary recurrence occurred. A total of 8 (8.3%) patients with generalized carcinoma of the breast died. Total remission was achieved in 81 (84.4%) patients. 76 (79.2%) patients survive in the CR. CONCLUSIONS: The results of the studies mentioned below as well as our results have shown that BCS after neoadjuvant oncologic therapy is safe and effective in appropriately selected patients.Key words: breast cancer neoadjuvant therapy - breast-conserving surgery - recurrence -cosmetic outcome.

Changes in Liver Ganglioside Metabolism in Obstructive Cholestasis - the Role of Oxidative Stress.

Bile acids have been implicated in cholestatic liver damage, primarily due to their detergent effect on membranes and induction of oxidative stress. Gangliosides can counteract these harmful effects by increasing the rigidity of the cytoplasmic membrane. Induction of haem oxygenase (HMOX) has been shown to protect the liver from increased oxidative stress. The aim of this study was to determine the changes in the synthesis and distribution of liver gangliosides following bile duct ligation (BDL), and to assess the effects of HMOX both on cholestatic liver injury and ganglioside metabolism. Compared to controls, BDL resulted in a significant increase in total as well as complex gangliosides and mRNA expression of corresponding glycosyltransferases ST3GalV, ST8SiaI and B3GalTIV. A marked shift of GM1 ganglioside from the intracellular compartment to the cytoplasmic membrane was observed following BDL. Induction of oxidative stress by HMOX inhibition resulted in a further increase of these changes, while HMOX induction prevented this effect. Compared to BDL alone, HMOX inhibition in combination with BDL significantly increased the amount of bile infarcts, while HMOX activation decreased ductular proliferation. We have demonstrated that cholestasis is accompanied by significant changes in the distribution and synthesis of liver gangliosides. HMOX induction results in attenuation of the cholestatic pattern of liver gangliosides, while HMOX inhibition leads to the opposite effect.

Reactive oxygen species accelerate degradation of anion exchange membranes based on polyphenylene oxide in alkaline environments.

Anion exchange membranes (AEM) based on polyphenylene oxide (PPO) suffered quaternary-ammonium-cation-site degradation in alkaline environments. Surprisingly, the degradation rate was considerably faster in the presence of molecular oxygen. We postulated that the AEM cation-site catalyzes the reduction of dioxygen by hydroxide ions to yield the superoxide anion radical and the highly reactive hydroxyl free radical. We substantiated our hypothesis by using a phosphorous-containing spin trap (5-diisopropoxy-phosphoryl-5-methyl-1-pyrroline-N-oxide) to detect the adducts for both free radicals in situ using (31)P-NMR spectroscopy.

Protective effects of inhaled carbon monoxide in endotoxin-induced cholestasis is dependent on its kinetics.

Carbon monoxide (CO), a product of heme oxygenase (HMOX), has many beneficial biological functions and is a promising therapeutic agent for many pathological conditions. However, the kinetics of inhaled CO and its protective role in endotoxin-induced cholestasis is not fully known. Thus, our objective was to characterize the kinetics of inhaled CO and then investigate its use in early phase experimental endotoxin-induced cholestasis. Female Wistar rats were randomly divided into 4 groups: CON (control), LPS (lipopolysaccharide, 6 mg/kg), CO (250 ppm COx1h), and CO + LPS. Rats were sacrificed at 0-12 h after LPS administration. Tissues and blood were collected for liver injury markers and tissue CO distribution measurements. Livers were harvested for measurements of Hmox activity, Hmox1 mRNA expression, cytokines (IL10, IL6, TNF), and bile lipid and pigment transporters. Half-lives of CO in spleen, blood, heart, brain, kidney, liver, and lungs were 2.4 ± 1.5, 2.3 ± 0.8, 1.8 ± 1.6, 1.5 ± 1.2, 1.1 ± 1.1, 0.6 ± 0.3, 0.6 ± 0.2 h, respectively. CO treatment increased liver IL10 mRNA and decreased TNF expression 1 h after LPS treatment and prevented the down-regulation of bile acid and bilirubin hepatic transporters (Slc10a1, Abcb11, and Abcc2, p < 0.05), an effect closely related to the kinetics. The protective effect of CO against cholestatic liver injury persisted even 12 h after CO exposure, as shown by attenuation of serum cholestatic markers in CO-treated animals. CO exposure substantially attenuated endotoxin-induced cholestatic liver injury and was directly related to the kinetics of inhaled CO. This data underscores the importance of the kinetics of inhaled CO for the proper design of experimental and clinical studies of using CO as a treatment strategy.

Influence of test site and baseline temperature on orofacial thermal thresholds.

AIMS: To investigate thermal thresholds of selected orofacial sites, determine if there is a relationship between thermal thresholds at each site, and analyze the influence of two different baseline temperatures on thermal thresholds at the tongue tip. METHODS: Thirty healthy men (mean age, 26 years) participated. Cold detection (CDT), warm detection (WDT), cold pain (CPT), and heat pain (HPT) thresholds were measured bilaterally at five orofacial sites (mentum, lower lip, cheek, forehead, and tongue tip). Relations between thermal thresholds at each test site were assessed. Thermal sensitivity of the tongue tip was compared at two different baseline temperatures (32°C and 36°C). One-way ANOVA, Turkey post-hoc test, paired t test and Pearson's correlation were used for statistical analyses. RESULTS: There was a significant difference for CDT, WDT, and HPT between test sites (ANOVA, P < .001) but no significant difference for CPT (P = .634). Subjects sensitive to cooling were sensitive to warming at the mentum (r = 0.379), tongue tip (r = 0.610), and cheek (r = 0.431) but not at the other test sites. There was a strong negative correlation between CPT and HPT at all test sites. There was no significant difference for CDT and WDT at the baseline temperature of 36°C (paired t test, P = .660), but there was a significant difference at the baseline temperature of 32°C (P < .001). There were no significant differences between CPTs at the two different baseline temperatures (P = .773), while a significant difference existed between HPTs (P = .034). CONCLUSION: Thermal thresholds varied between the orofacial test sites, and baseline temperature affected thermal sensitivity of the tongue. Subjects who were relatively sensitive to cold tended to be more sensitive to heat.

Concomitant replacement of the dilated ascending aorta during aortic valve replacement; does it increase the perioperative morbidity and mortality risks?

BACKGROUND: Concerns of increased surgical risks with ascending aortic replacement have led surgeons to manage post-stenotic aortic dilatation more conservatively during aortic valve replacement (AVR). The present study aimed to assess the prognostic implications and surgical risks of replacing the dilated aorta during AVR. METHODS: Between January 1999 and March 2010, 134 patients who received surgery for aortic stenosis and post-stenotic dilatation (aorta size ≥40 mm) were included in the present study. AVR was performed in 92 patients (AVR group) while aortic valve and ascending aorta replacement (AVR + aorta group) were performed in 42 patients. Overall survival was compared between the two groups using Cox proportional hazard model after adjustment with inverse-probability-of-treatment weighting. RESULTS: The mean follow-up duration was 3.5 ± 3 years. There were no significant differences in the operative mortality and morbidity between the two groups. The late cardiac deaths were also not significantly different between the two groups (p = 1.00). In the AVR group, the ascending aortic expansion rate which was 0.18 mm/year over a mean follow-up duration of 2.3 ± 2.2 years by echocardiography showed a positive correlation with time (r = 0.3, p = 0.08). A relatively greater aortic expansion rate was identified as a risk factor for late mortality (p = 0.015, HR 1.08 (CI: 1.02 to 1.15). CONCLUSIONS: Concomitant replacement of the dilated ascending aorta during AVR did not increase the immediate postoperative morbidity or mortality risks and tended to exert a long-term beneficial effect on the risk of late mortality.

[Outcomes of complex therapy in female patients after breast-saving surgery for breast carcinoma at the 1st Surgical Department 1st Faculty of Medicine, Charles University and General University Hospital in Prague during a ten-year follow up period]. / Výsledky komplexní terapie u pacientek s provedeným prs setrícím výkonem pro karcinom prsu operovaných na I. chirurgické klinice 1. LF UK a VFN.

INTRODUCTION: Good longterm outcomes of complex therapy in operable breast cancer can be achieved mainly due to early diagnosis of the tumor, adequate radicality of surgery and adequate oncotherapy. The following outcome criteria are considered significant: long-term survival rate in complete remission, a number of locoregional recurrences and a number of reoperations or mastectomies required by results of final histological examination, patient satisfaction with a cosmetic result of their breast- saving surgery. Comparison of complex treatment results collected from patients who underwent breast-saving procedures performed for breast cancer at our department of surgery with data reported in literature. MATERIAL AND METHODS: Retrospective analysis of data collected from 106 female patients suffering from invasive breast cancer and ductal carcinoma in situ operated at our surgery department from 1998 until mid-2002. The sample included nine patients who underwent surgery after neoadjuvant oncotherapy. The median follow-up time after surgery was 10 years and 7 months. Reresection was indicated based on the following criteria, set up by the authors: outline margin of less than 1 mm in invasive tumors, and in cases of ductal carcinomas in situ and carcinomatous lymphangiopathy their presence directly within the resection line. RESULTS: The patient group included 13 (12.3%) patients with early reoperations. During the follow up period, locoregional recurrence was recorded in 3 (2.8%) patients. A total of 12 (11.3%) patients with generalized breast carcinoma died, their median survival was 6 years and 4 months. A total of 90 (84.9%) patients are surviving with complete remission of the disease. Thecosmetic outcome was evaluated by patients according to a five-point scale. Out of the total of 77 surviving patients who underwent breast-saving procedures, the authors personally contacted 52 subjects (67.5 %). Out of the total, 45 (86.5 %) subjects evaluated the cosmetic outcome as excellent or very good. CONCLUSION: The survival rate with complete remission and satisfactory cosmetic results is considered to be comparable with the data presented in literature. Considering a small number of early reresections or mastectomis and locoregional recurrences our clinic achieved good outcomes.

Association between thyroid autoimmunity and fibromyalgia.

Evidence exists that autoimmune thyroiditis is present in a high percentage of fibromyalgia (FM) and associated with the presence of typical symptoms of FM. However, the role of thyroperoxidase antibody (TPO Ab) in the manifestation of FM is still unclear. The goal of this study was to investigate the prevalence of positive TPO Ab in euthyroid FM patients, and whether TPO Ab positivity is associated with the clinical manifestations in euthyroid FM patients.Thyroid assessment was done by free T4, TSH and TPO Ab. The clinical parameters including Fibromyalgia Impact questionnaire (FIQ), pain visual analogical scale (VAS) and tender point counts were evaluated in euthyroid primary FM patients, not associated with autoimmune rheumatic disease. The immunologic tests including rheumatoid factor and antinuclear antibody were measured. We compared the prevalence of positive TPO Ab between FM patients, and healthy control. We also compared clinical and laboratory parameter in FM patients according to the presence of TPO Ab.149 patients of FM, 68 healthy controls were recruited. FM patients showed higher prevalence of positive TPO Ab than healthy controls (28 out of 149 patients, 19%; 5 out of 68 healthy controls, 7%; P=0.04). There was no difference of clinical and laboratory parameters in FM patients between 2 groups subdivided by the presence of TPO Ab.In our study, euthyroid FM patients showed significantly higher prevalence of positive TPO Ab, as compared to age and sex matched healthy control. However, TPO Ab positivity was relatively low and not associated with the clinical manifestations in euthyroid FM patients. This finding support thyroid autoimmunity may influence the development of FM, but the evidence which support that FM is related to autoimmune etiology is not clear, and FM severity may not be affected by the presence of thyroid autoantibody.

Formation of Ag nanostrings induced by lyotropic liquid-crystalline phospholipid multilayer.

Morphological variation of the Ag nanoparticles embedded in a lyotropic phospholipid (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, DOPE) membrane during hydration was investigated. Hydration at 5 °C resulted in transformation of the Ag nanoparticles into a bundle of Ag nanostrings as the Ag nanoparticles conformed to the H(II) phase of the DOPE molecules. Above 30 °C, the nanoparticles quickly coarsened into large polygonal-shaped particles since high mobility of the lipid molecules overwhelmed the tendency for the Ag nanoparticles to order. The result provided an insight into the long-term stability of nanoparticles trapped in different lipid membranes depending on the structural ordering of the molecules.

Human immunodeficiency virus in injecting drug users in Europe following a reported increase of cases in Greece and Romania, 2011.

Greece and Romania reported an increased number of HIV cases among injecting drug users (IDUs) during 2011. Most European countries reported no changes in the rate of newly diagnosed cases of HIV or HIV prevalence in IDUs; however, six countries did report increases and several additional countries reported increases in injecting risk indicators or low coverage of prevention services. These indicate a potential risk for increased HIV transmission and future outbreaks unless adequate prevention is implemented.

Influence of long-term statin use in type 2 diabetic patients on thyroid nodularity in iodine-sufficient area.

Statins have marked beneficial effects on lipid profile, but also have pleiotropic actions. A previous study in an iodine-deficient area suggested that statin use is associated with reduced thyroid volume and nodularity. We performed this study to investigate how long-term statin use in type 2 diabetic patients affects thyroid nodularity in iodine-sufficient area.We recruited euthyroid type 2 diabetic patients, receiving statin therapy continuously for at least 5 years (statin group) and, age and sex matched statin-naive type 2 diabetic patients (control group). Subjects with past history of cancer, thyroid disease or treatment with lithium or amiodarone; family history of thyroid cancer; palpable goiter or thyroid nodule, and/or positive thyroperoxidase antibody were excluded. The prevalence, number, and volume of thyroid nodules, size of thyroid were evaluated in all subjects by high resolution ultrasound.Prevalence of non-palpable thyroid nodules of statin group (n=70) and control group (n=98) were 51 and 53%, respectively. There was no difference of prevalence, number, and volume of non-palpable thyroid nodules and size of thyroid between statin and control group. But, the patients aged between 60 and 65 years from statin group showed lower prevalence of non-palpable thyroid nodules than the patients with same age interval from control group (4 out of 12 patients, 33%, statin group; 19 out of 27 patients, 70%, control group; P=0.04).Long-term statin use in elderly type 2 diabetic patients was associated with lesser prevalence of thyroid nodules in an iodine-sufficient area. Our data might support a possible antiproliferative effect of statins on thyroid in old type 2 diabetic patients. But, the effect was not as strong as that in an iodine-deficient area and further studies with enough numbers of subjects and revised design will be needed.

Prevalence of echocardiographic criteria for the diagnosis of pulmonary hypertension in patients with Graves' disease: before and after antithyroid treatment.

BACKGROUND: Right-sided heart failure with clinical manifestation is only occasionally seen in patients with Graves' disease (GD). Recent studies revealed that pulmonary hypertension (PHT) detected by echocardiography was not rare in patients with GD. We performed this study to investigate the prevalence of PHT in patients with GD before and after antithyroid treatment, and to assess potential mechanisms from the relationship with clinical and echocardiographic features. SUBJECTS AND METHODS: Serial echocardiographic examinations were performed in 64 patients with newly diagnosed GD before and after antithyroid treatment to measure cardiac factors, such as pulmonary artery systolic pressure (PAPs), cardiac output, total vascular resistance, left ventricular filling pressure and right ventricular (RV) function. PHT was defined as PAPs of at least 35 mmHg. RESULTS: The prevalence of PHT in untreated GD patients was 44% (28 out of 64 patients). The presence of systemic hypertension was associated with PHT, especially with pulmonary venous hypertension. GD patients with PHT showed reduced RV function represented by higher RV myocardial performance index without difference of pulmonary vascular resistance, RV wall thickness and peak systolic velocity of free wall side of tricuspid annulus. Follow-up echocardiography was performed in 20 out of 28 GD patients with PHT, and PHT disappeared in all except one patient. CONCLUSION: PHT is a frequent and reversible complication in patients with GD. Our study suggests that PHT in GD may not be related to underlying autoimmune process and increased pulmonary blood flow from thyrotoxicosis might contributes to the pathogenesis of PHT related to GD.

Positive association between striatal serotonin level and abnormal involuntary movements in chronic L-DOPA-treated hemiparkinsonian rats.

Although l-DOPA represents the standard of care in Parkinson's disease, long-term treatment may be compromised by l-DOPA-induced dyskinesia (LID), with adverse fluctuations in motor responsiveness and progressive loss of control. Here we show that in rats with 6-hydroxydopamine-induced lesions of the median forebrain bundle, LID correlates with 5-HT levels. Rats were treated with l-DOPA (6 mg/kg) and benserazide (15 mg/kg) daily for 3 weeks to induce the development of abnormal involuntary movements (AIMs). After this chronic l-DOPA treatment, the lesion side of the rats displayed significant changes in striatal dopamine (DA) and 5-HT levels. Striatal DA and 5-hydroxytryptamine (5-HT) levels were inversely correlated, and AIMs were strongly positively correlated with DA levels and negatively correlated with 5-HT levels. Axial AIMs were more strongly correlated with DA and 5-HT levels than were the other AIMs subtypes, while locomotive AIMs showed no significant correlation at all. In addition, striatal 5-HT was more strongly (negatively) correlated with the AIMs than striatal DA levels. These results demonstrate that 5-HT contributes to LID and that both striatal DA (positively) and 5-HT (negatively) affect the severity of LID. We suggest that by strategic modification of the serotonin system it may be possible to attenuate the adverse effects of chronic l-DOPA therapy.

Effects of fermented soybean meal on growth performance, diarrheal incidence and immune-response of neonatal calves.

The effects of partial substitution of fermented soybean meal (FSBM) for soybean meal (SBM) on immune-physiological parameters, growth performance and diarrheal incidence in neonatal calves after microbial infection were investigated. Holstein calves (n = 12) were randomly assigned to two dietary treatments: the SBM and the FSBM group. The latter group received a calf starter containing 5% FSBM instead of SBM. In order to evaluate the immunocompetence against microbial infection, all calves were challenged with porcine live vaccine by intramuscular injection at 21 days of age. The incidence and severity of diarrhea were significantly less (P < 0.05) in the FSBM group compared to those in the SBM group at 21 and 42 days of age. Feeding FSBM starter resulted in a higher (P < 0.05) relative amount of bacterial-specific IgA than those on SBM at days 5 and 14 post-microbial infection (DPMI). Viral-specific IgA also increased (P < 0.05) at 5 DPMI in the FSBM group when compared to the SBM group. The average concentration of haptoglobin of calves fed FSBM was generally higher at 3 DPMI. Our results indicate that FSBM plays a role in the alleviation of diarrhea and in the production of immune-related effector cells such as IgA and haptoglobin in calves.

Findings from SHAZ!: a feasibility study of a microcredit and life-skills HIV prevention intervention to reduce risk among adolescent female orphans in Zimbabwe.

This study tested the feasibility of a combined microcredit and life-skills HIV prevention intervention among 50 adolescent female orphans in urban/peri-urban Zimbabwe. Quantitative and qualitative data were collected on intervention delivery, HIV knowledge and behavior, and economic indicators. The study also tested for HIV, HSV-2, and pregnancy. At 6 months, results indicated improvements in knowledge and relationship power. Because of the economic context and lack of adequate support, however, loan repayment and business success was poor. The results suggest that microcredit is not the best livelihood option to reduce risk among adolescent girls in this context.