Definitions of remission in psoriasis: a systematic literature review from the National Psoriasis Foundation.

Psoriasis studies increasingly employ outcomes that indicate complete disease resolution, yet remission and cure are poorly defined for psoriasis. We conducted a systematic literature review to identify definitions of psoriasis remission and cure reported in the literature. Medline, EMBASE, and The Cochrane Central Register of Controlled Trials databases were searched on July 22, 2020, for full-text studies providing definitions for psoriasis remission/cure. Definitions were analysed descriptively for endpoint, time-frame, on/off treatment, patient-reported outcomes, and disease domains. We identified 106 studies that provided 41 unique remission definitions. Most definitions included endpoints based on Psoriasis Area and Severity Index (PASI), such as PASI75 (n = 16 studies), PASI90 (n = 10), PASI100 (n = 10), and PASI of 0 (n = 3), and descriptive endpoints related to 'skin clearance' (n = 18). Few definitions specified time-frame, on/off treatment or other psoriasis-related disease domains. One small consensus-initiative defined drug-free remission for plaque psoriasis by BSA of 0 without any therapy for at least 12 months. While there is no cure for psoriasis, seven studies defined psoriasis cure using similar endpoints to those used to define remission. We identified a variety of definitions of psoriasis remission. These results will inform the development of consensus-based definitions for psoriasis remission to support efforts to improve research and clinical outcomes.

Development of a peptide-based bifunctional chelator conjugated to a cytotoxic drug for the treatment of melanotic melanoma.

The cytotoxic drug gemcitabine (GEM) has been conjugated to receptor-binding peptides to target melanoma tumors. A hexapeptide having a Lys-Gly-His-Lys sequence (pep-1), an octapeptide with an Arg-Gly-Asp-Lys-Gly-His-Lys sequence (pep-2), a GEM-conjugated Lys-Gly-His-Lys peptide (GEM-pep-3) and a GEM-conjugated Asp-Gly-Arg peptide (GEM-pep-4) were synthesized and characterized. In vitro uptake of fluorescently labeled GEM-pep-3 and GEM-pep-4 on B16F10 cells was investigated. Fluorescence microscopy studies demonstrated significant uptake of GEM-pep-3 in the B16F10 mouse melanoma cell line. The peptides and GEM-coupled peptides were radiolabeled with [99mTc(CO)3(H2O)3]+ and examined for in vitro cell binding in the B16F10 melanoma cell line and in vivo biodistribution and scintigraphic studies in a B16F10 melanoma tumor-bearing mice model. In vitro cellular uptake studies and biological evaluation confirmed significant deposition of GEM-pep-3 at the melanoma tumor site. The MTT assay depicted higher cytotoxic behaviour of GEM-pep-3 than free GEM. A considerable amount of cell apoptosis was also observed in B16F10 cells. Finally, the in vivo therapeutic efficacy study revealed a significant decrease in tumor growth in the GEM-pep-3-treated animal model. These studies reveal enough potentiality of GEM-pep-3 to treat melanoma and underline the need for further evaluation.

Apigenin loaded nanoparticle delayed development of hepatocellular carcinoma in rats.

Hepatocellular carcinoma (HCC) is one of the major causes of cancer related death globally. Apigenin, a dietary flavonoid, possesses anti-tumor activity against HCC cells in-vitro. Development, physicochemical characterization of apigenin loaded nanoparticles (ApNp), biodistribution pattern and pharmacokinetic parameters of apigenin upon intravenous administration of ApNp, and effect of ApNp treatment in rats with HCC were investigated. Apigenin loaded nanoparticles had a sustained drug release pattern and successfully reached the hepatic cancer cells in-vitro as well as in liver of carcinogenic animals. ApNp predominantly delayed the progress of HCC in chemical induced hepatocarcinogenesis in rats. Quantification of apigenin by liquid chromatography-mass spectroscopy (LC-MS/MS) showed that apigenin availability significantly increased in blood and liver upon ApNp treatment. Apigenin loaded nanoparticle delivery substantially controlled the severity of hepatocellular carcinoma and could be a future hope for lingering the survival in hepatic cancer patients.

Exploring the Potential of (99m)Tc(CO)3-Labeled Triazolyl Peptides for Tumor Diagnosis.

In recent years the authors have reported on (99m)Tc(CO)3-labeled peptides that serve as carriers for biomolecules or radiopharmaceuticals to the tumors. In continuation of that work they report the synthesis of a pentapeptide (Met-Phe-Phe-Gly-His; pep-1), a hexapeptide (Met-Phe-Phe-Asp-Gly-His; pep-2), and a tetrapeptide (Asp-Gly-Arg-His; pep-3) and the attachment of 3-amino-1,2,4-triazole to the ß carboxylic function of the aspartic acid unit of pep-2 and pep-3. The pharmacophores were radiolabeled in high yields with [(99m)Tc(CO)3(H2O)3](+) metal aqua ion, characterized for their stability in serum and saline, as well as in His solution, and found to be substantially stable. B16F10 cell line binding studies showed favorable uptake and internalization. In vivo behavior of the radiolabeled triazolyl peptides was assessed in mice bearing induced tumor. The (99m)Tc(CO)3-triazolyl pep-3 demonstrated rapid urinary clearance and comparatively better tumor uptake. Imaging studies showed visualization of the tumor using (99m)Tc(CO)3-triazolyl pep-3, but due to high abdominal background, low delineation occurred. Based on the results further experiments will be carried out for targeting tumor with triazolyl peptides.

Synthesis and evaluation of technetium-99m-labeled bioreductive pharmacophores conjugated with amino acids and peptides for tumor imaging.

Development of molecular imaging agents to target tumor has become a major trend in nuclear medicine. With the aim to develop new potential 99mTc-radiopharmaceuticals for targeting tumor, we have synthesized 5-nitroimidazolyl amino acids and RGD-coupled 2-nitroimidazoles. Technetium-99m radiolabeling with high radiochemical purity (>90%) was achieved for all the compounds. The radiolabeled complexes exhibited substantial in vitro stability in saline, serum, and histidine solution (10(-2) m). Cell binding studies in EAC and B16F10 cell lines also revealed rapid and comparatively high cellular internalization. Among all the compounds studied, the binding of 99mTc(CO)3-5 to B16F10 cells was moderately inhibited by the competitive peptide c[RGDfV], suggesting specificity of the radioligand toward αvß3 receptor. However, no significant displacement of bound radioligand was observed when the binding of the 99mTc-labeled complexes to above cells was challenged with excess competitive peptide. Fluorescent microscopy study provided direct evidence of intracellular localization of 5(6)-carboxyfluorescein-labeled 2-nitroimidazolyl-RGD-peptide in αvß3-positive B16F10 mouse melanoma cell line. The ligands caused only 8-13% of hemolysis toward rat erythrocytes at concentrations as high as 100 µm. Imaging and biodistribution studies were performed in Swiss albino mice bearing induced tumor. 99mTc-1 and 99mTc(CO)3-5 demonstrated a very favorable in vivo profile. Selective uptake and retention in tumor with encouraging tumor/muscle and tumor/blood ratio and significant cellular uptake of fluorescence-labeled-2-nitroimidazolyl RGD indicate the great potentiality of the pharmacophore for further evaluation as potential molecular imaging agent in cancer diagnosis.

Synthesis, characterization, and biological evaluation of (99m) Tc(CO)3 -labeled peptides for potential use as tumor targeted radiopharmaceuticals.

During the past decade, several peptides containing Arg-Gly-Asp sequence have been conjugated with different chelating agents for labeling with various radionuclides for the diagnosis of tumor development. In this study, we report the synthesis of two tetrapeptides (Asp-Gly-Arg-His and Asp-Gly-Arg-Cys) and one hexapeptide [Asp-Gly-Arg-D-Tyr-Lys-His] by changing the amino acid sequence of the Arg-Gly-Asp motif. Peptide synthesis was initiated from aspartic acid. Aspartic acid placed at C-terminal end of the peptide chain can be conjugated with different drug molecules facilitating their transport to the site of action. The peptides were synthesized in excellent yield and labeled using freshly prepared [(99m) Tc(CO)3 (H2 O)3 ](+) intermediate. A complexation yield of over 97% was achieved under mild conditions even at low ligand concentrations of 10(-2)  m. Radiolabeled peptides were characterized by HPLC and were found to be substantially stable in saline, in His solution as well as in rat serum and tissue (kidney, liver) homogenates. Internalization studies using Ehrlich ascites carcinoma cell line showed rapid and significant internalization (30-35% at 30 min of incubation attaining maximum value of about 40-60% after 2-4 h incubation). A good percentage of quick internalization was also observed in αv ß3 -receptor-positive B16F10 mouse melanoma cell line (14-16% after 30 min of incubation and 25-30% after 2-4 h incubation). Imaging and biodistribution studies were performed in Swiss albino mice bearing Ehrlich ascites tumor in right thigh. Radiolabeled peptides exhibited fast blood clearance and rapid elimination through the urinary systems. (99m) Tc(CO)3 -tetra-Pep2 exhibited remarkable localization at tumor site (1.15%, 1.17%, and 1.37% ID/g at 2, 4, and 6 h p.i., respectively) which could be due to slow clearance of the radiolabeled peptide from blood in comparison with the other two radiolabeled peptides. However, (99m) Tc(CO)3 -hexa-Pep exhibited the highest tumor to muscle and tumor to blood ratios among the three. The preliminary results with these amino acid-based peptides are encouraging enough to carry out further experiments for targeting tumor.

What is the clinical significance of pulmonary hypertension in acute respiratory distress syndrome? A review.

Elevated pulmonary arterial pressures appear to be a prominent feature of the acute respiratory distress syndrome (ARDS). Current clinical guidelines for the management of ARDS do not specifically address treatment of pulmonary hypertension or associated right ventricular dysfunction because the clinical significance of this entity remains unclear. Interpretation of elevated pulmonary arterial pressures, pulmonary vascular resistance, and transpulmonary gradient as well as signs of right ventricular dysfunction is confounded by the effects of positive pressure ventilation. There does not appear to be a consistent relationship between the diagnosis of pulmonary hypertension or right ventricular failure and mortality in patients with ARDS, but it is unclear if right ventricular failure contributes to the mortality risk per se or if the underlying cause of pulmonary hypertension, including intravascular micro and macro thrombosis, are simply markers for systemic dysregulation of coagulation and fibrinolysis that may lead to multiorgan failure in ARDS. While studies of pulmonary vasodilator therapies have not shown a mortality benefit in ARDS, such trials have targeted improved oxygenation rather than improved pulmonary hemodynamics so that the possible contribution of improved right ventricular function to better outcomes has not been directly tested in large trials. Future studies are needed to determine if treatment of pulmonary hypertension and associated right ventricular dysfunction will affect mortality in patients with ARDS.

Left atrial myocardial function in either physiological or pathological left ventricular hypertrophy: a two-dimensional speckle strain study.

BACKGROUND: Atrial function is an integral part of cardiac function that is often neglected. The presence of left ventricule hypertrophy (LVH) due to arterial hypertension may impair atrial function. However, it has also been suggested that physical training attenuates the age-associated impairment of diastolic filling. This study investigated whether mechanical dysfunction in the left atrium (LA) is present in patients with either physiological or pathological LVH, using two-dimensional strain rate imaging (2D strain echocardiography; 2DSE). METHODS: Standard echocardiography, exercise stress echo and 2DSE of the left atrium were performed in 40 patients with arterial hypertension, 45 age-matched elite athletes (>40 years) and 25 healthy sedentary controls. Atrial longitudinal strain was performed from the apical views for the basal segments of the LA septum, lateral wall and roof. RESULTS: LV mass index and ejection fraction were comparable between patients with either physiological or pathological LVH. Elite athletes showed increased LV end-diastolic diameter, end-diastolic volume and stroke volume, whereas circumferential end-systolic stress was higher in patients with hypertension. LA diameter and maximum volume were increased but similar between the two groups of patients with LVH. LA active emptying volume and fraction were both higher in patients with hypertension. Conversely, peak systolic myocardial atrial strain was significantly reduced in patients with pathological LVH compared with controls and athletes for all the analysed atrial segments (p<0.0001). Using multivariate analysis, LV end-diastolic volume/body surface area (BSA) (beta coefficient 0.52; p<0.0001) and LV mass (beta = 0.48; p<0.001) in athletes emerged as the only independent determinants of LA lateral wall peak systolic strain. In contrast, in patients with hypertension, an independent negative association of LA lateral wall peak systolic strain with both LV mass (beta = -0.42; p<0.001) and circumferential end-systolic stress (beta = -0.43; p<0.001) was found. In addition, in the overall population of patients with LVH, LA lateral wall systolic strain (beta = 0.49; p<0.0001) was a powerful independent predictor of maximum workload during exercise testing. CONCLUSIONS: 2DSE represents a promising, non-invasive, simple and reproducible technique to assess LA myocardial function in patients with either physiological or pathological LVH. LA myocardial deformation is impaired in patients with hypertension compared with age-matched sedentary controls and elite athletes, and is closely associated with functional capacity during effort.

Prognostic value of intra-left ventricular electromechanical asynchrony in patients with mild hypertrophic cardiomyopathy compared with power athletes.

OBJECTIVES: We sought to assess the indexes of myocardial activation delay, using Doppler myocardial imaging (DMI), as potential diagnostic tools and predictors of cardiac events in patients with hypertrophic cardiomyopathy (HCM) compared with power athletes. BACKGROUND: the distribution and magnitude of left ventricular (LV) hypertrophy are not uniform in patients with HCM, which results in heterogeneity of regional LV systolic function. METHODS: The study population comprised 70 young patients with HCM (mean (SD) age 29.4 (5.9) years) with mild septal hypertrophy (15-19 mm) and 85 age and sex matched athletes with septal thickness >12 mm, followed up for 44.4 (10.8) months. Using pulsed DMI, myocardial peak velocities, systolic time intervals, and myocardial intraventricular and interventricular systolic delays were measured in six different basal myocardial segments. RESULTS: DMI analysis showed in HCM lower myocardial both systolic and early diastolic peak velocities of all the segments. Patients with HCM also showed significant interventricular and intraventricular delay (p<0.0001), whereas athletes showed homogeneous systolic activation of the ventricular walls. During the follow up, seven sudden deaths occurred in the HCM group, while no cardiovascular event was observed in the group of athletes. In patients with HCM, intraventricular delay on DMI was the most powerful independent predictor of sudden cardiac death (p<0.0001). An intraventricular delay >45 ms identified with high sensitivity and specificity patients with HCM at higher risk of ventricular tachycardia and cardiac events (test accuracy 90.6%). CONCLUSIONS: DMI may be a valid supporting tool for the differential diagnosis between HCM and "athlete's heart". In patients with HCM, DMI indexes of intraventricular delay may provide additional information for selecting subgroups of patients with HCM at increased risk of ventricular arrhythmias and sudden cardiac death at follow up. Accordingly, such patients may benefit from early intensive treatment and survey. MINIABSTRACT: Doppler myocardial imaging may represent a valid supporting tool for the differential diagnosis between mild hypertrophic cardiomyopathy (HCM) and "athlete's heart". In patients with HCM, DMI indexes of intraventricular delay may provide additional information for selecting subgroups of patients with HCM at increased risk of ventricular arrhythmias and sudden cardiac death at follow up.

Preparation of 99mTc-labelled conjugates of ouabagenin and their biological evaluation in animal models.

BACKGROUND: Ouabagenin and its 1,19-acetonide were conjugated with nitrilotriacetic acid (NTA) and diethylenetriaminepentaacetic acid (DTPA) through their respective anhydrides. METHODS: The reaction mixtures were exhaustively purified by silica gel column chromatography and preparative high-performance liquid chromatography to furnish the ligands in good purity and moderate yield. These ligands were labelled with 99mTc to produce four chelates in 90-95% yield. Of these chelates the 99mTc-oubagenin-NTA conjugate and the corresponding acetonide exhibited appreciable myocardial uptake with respect to that of other vicinal organs in a guinea-pig model. However, all these 99mTc chelates exhibited poor heart-to-blood ratios, which could be attributed to the absence of a 3beta sugar residue in this molecule. CONCLUSION: The result is in agreement with that previously reported in connection with radioiodinated digoxin and digoxigenin derivatives.

Phase I and pharmacological study of an oxaliplatin and carboplatin combination in advanced malignancies.

BACKGROUND: Phase I and pharmacokinetic study to determine the maximal tolerated dose and the recommended dose, as well as the optimal sequence of a carboplatin/oxaliplatin combination delivered every 3 weeks. PATIENTS AND METHODS: Patients received either carboplatin [area under the curve (AUC)-based individually calculated dose (starting dose AUC 4 mg.min/ml), 1 h intravenous (i.v.) infusion] followed by oxaliplatin (110 mg/m(2), 2 h i.v. infusion), every 3 weeks, or the reverse sequence. RESULTS: Sixteen patients were included and only one dose level was assessed. In group A, 10 patients received 23 cycles of carboplatin followed by oxaliplatin. In group B, 6 patients received 20 cycles with the reverse sequence. Delayed recovery from hematological toxicities was treatment-limiting, with mainly moderate thrombocytopenia and neutropenia as dose-limiting toxicities for group A (5 of 10 patients for each) and thrombocytopenia for group B (3 of 6 patients). No febrile neutropenia or grade 3/4 non-hematological toxicity occurred. Pharmacokinetic analysis showed similar mean total platinum AUCs for the two groups: 37.2 +/- 13.7 and 33.6 +/- 9.9 mg.h/l, respectively. One complete response and two partial responses (World Health Organization-International Union Against Cancer criteria, response rate 18.8%) were seen in ovarian, Fallopian and neuroendocrine carcinomas, respectively. CONCLUSIONS: This platinum combination appears feasible and active at the dose of AUC 4 mg.min/ml for carboplatin (Chatelut formula) and oxaliplatin 110 mg/m(2); however, it does not allow a significant increase in platinum dose-intensity delivery.

[Eighty years of Japanese immigration in Brazil]. / Ochenta anos de inmigracion japonesa en el Brasil.

"Japanese emigration to Brazil started in 1908 with some eight hundred subsidized contract workers for coffee plantations. Hard conditions made many of them flee, and the paulista government suppressed subsidies for these projects; however, the Japanese emigration to Brazil kept on under Japanese subsidies from 1925 until 1934 when Brazil imposed immigration quotas unfavorable to Japanese immigration. International circumstances in the late 1930s and local prohibition on the use of the Japanese language in Brazil caused many immigrants to return to Japan between 1939-1941. Emigration to Brazil restarted as diplomatic relations between Japan and Brazil were reestablished in 1952 but decreased in the late 1960s. Subsequent economic evolution in both countries caused Japanese emigrants in Brazil and their [descendants] to initiate dekasegui [labor] migration from Brazil to Japan as from the late 1980s." (SUMMARY IN ENG)

D-2 dopamine receptors inhibit release of aspartate and glutamate in rat retina.

Release of endogenous Asp, Glu and gamma-aminobutyric acid (GABA) has been investigated using synaptosomes prepared from rat retina. Exposure in superfusion to a depolarizing concentration of KCl (30 mM) evoked overflow of Asp and Glu, which were almost entirely Ca-dependent. However, 70% of the GABA release was Ca-independent. Dopamine (DA) almost completely inhibited the K(+)-evoked release of Asp and Glu in a concentration-dependent manner, but the release of GABA was only partly inhibited. The potencies of DA (IC50) to Asp and Glu release were 12 and 30 nM, respectively. A selective D-2 receptor antagonist, S-sulpiride, counteracted the DA-induced inhibition of Asp and Glu release, but a selective D-1 antagonist, SCH 23390, showed no effect. The data suggest that D-2 dopamine receptors located on the Asp and Glu neurons in rat retina may inhibit the release of these excitatory amino acids.