Molecular requirements involving the human platelet protease-activated receptor-4 mechanism of activation by peptide analogues of its tethered-ligand.

Thrombin is the most potent agonist of human platelets and its effects are primarily mediated through the protease-activated receptors (PARs)-1 and -4. Although PAR-1 has higher affinity for thrombin than PAR-4, both receptors contribute to thrombin-mediated actions on platelets. Recently, a potent and selective PAR-1 antagonist (vorapaxar) was approved for clinical use in selected patients. In contrast, despite the fact that several PAR-4 antagonists have been developed, few of them have been tested in clinical trials. The aim of the present study was to elucidate the molecular requirements involving the PAR-4 mechanism of activation by peptide analogues of its tethered-ligand. Eight synthetic PAR-4 tethered-ligand peptide analogues were synthesized and studied for their agonistic/antagonistic potency and selectivity toward human washed platelet aggregation, using light transmittance aggregometry. In addition, in silico studies were conducted to describe the receptor-peptide interactions that are developed following PAR-4 exposure to the above analogues. To provide a first structure-activity relationship rationale on the bioactivity profiles recorded for the studied analogues, molecular docking was applied in a homology model of PAR-4, derived using the crystal structure of PAR-1. The following peptide analogues were synthesized: AYPGKF-NH2 (1), GYPGKF-NH2 (2), Ac-AYPGKF-NH2 (3), trans-cinnamoyl-AYPGKF-NH2 (4), YPGKF-NH2 (5), Ac-YPGKF-NH2 (6), trans-cinnamoyl-YPGKF-NH2 (7), and caffeoyl-YPGKF-NH2 (8). Peptide (1) is a selective PAR-4 agonist inducing platelet aggregation with an IC50 value of 26.2 µM. Substitution of Ala-1 with Gly-1 resulted in peptide (2), which significantly reduces the agonistic potency of peptide (1) by 25-fold. Importantly, substitution of Ala-1 with trans-cinnamoyl-1 resulted in peptide (7), which completely abolishes the agonistic activity of peptide (1) and renders it with a potent antagonistic activity toward peptide (1)-induced platelet aggregation. All other peptides tested were inactive. Tyr-2, residue, along with its neighboring environment was a key determinant in the PAR-4 recognition mode. When the neighboring residues to Tyr-2 provided an optimum spatial ability for the ligand to enter into the binding site of the transmembrane receptor, a biological response was propagated. These results were compared with the predicted binding poses of small molecule antagonists of PAR-4, denoted as YD-3, ML-354, and BMS-986120. π-π stacking interaction with Tyr-183 appears to be critical and common for both small molecules antagonists and the peptide trans-cinnamoyl-YPGKF-NH2. Conclusively, the lipophilicity, size, and aromatic nature of the residue preceding Tyr-2 are determining factors on whether a human platelet PAR-4 tethered-ligand peptide analogue will exert an agonistic or antagonistic activity.

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders.

As B cells differentiate into antibody-secreting cells (ASCs), short-lived plasmablasts (SLPBs) are produced by a primary extrafollicular response, followed by the generation of memory B cells and long-lived plasma cells (LLPCs) in germinal centers (GCs). Generation of IgG4 antibodies is T helper type 2 (Th2) and IL-4, -13, and -10-driven and can occur parallel to IgE, in response to chronic stimulation by allergens and helminths. Although IgG4 antibodies are non-crosslinking and have limited ability to mobilize complement and cellular cytotoxicity, when self-tolerance is lost, they can disrupt ligand-receptor binding and cause a wide range of autoimmune disorders including neurological autoimmunity. In myasthenia gravis with predominantly IgG4 autoantibodies against muscle-specific kinase (MuSK), it has been observed that one-time CD20+ B cell depletion with rituximab commonly leads to long-term remission and a marked reduction in autoantibody titer, pointing to a short-lived nature of autoantibody-secreting cells. This is also observed in other predominantly IgG4 autoantibody-mediated neurological disorders, such as chronic inflammatory demyelinating polyneuropathy and autoimmune encephalitis with autoantibodies against the Ranvier paranode and juxtaparanode, respectively, and extends beyond neurological autoimmunity as well. Although IgG1 autoantibody-mediated neurological disorders can also respond well to rituximab induction therapy in combination with an autoantibody titer drop, remission tends to be less long-lasting and cases where titers are refractory tend to occur more often than in IgG4 autoimmunity. Moreover, presence of GC-like structures in the thymus of myasthenic patients with predominantly IgG1 autoantibodies against the acetylcholine receptor and in ovarian teratomas of autoimmune encephalitis patients with predominantly IgG1 autoantibodies against the N-methyl-d-aspartate receptor (NMDAR) confers increased the ability to generate LLPCs. Here, we review available information on the short-and long-lived nature of ASCs in IgG1 and IgG4 autoantibody-mediated neurological disorders and highlight common mechanisms as well as differences, all of which can inform therapeutic strategies and personalized medical approaches.

A modification of the Bjork flap in tracheostomies for head and neck cancer patients.

The etymology of the word tracheotomy derives from two Ancient Greek words: the word trachea (Greek τραχɛία tracheía) and the word stoma (Greek στóµα stóma) meaning "mouth," and refers to the making of an opening. It is believed that an early tracheostomy was performed by the Greek physician Asclepiades of Bithynia, in order to treat upper airway obstruction. A secure airway in the intraoperative and early postoperative period is of paramount importance for a number patients undergoing head and neck cancer surgery. We describe a modification of the Bjork flap used in tracheostomies for head and neck cancer patients, which allows tracheal outline reconstitution and significantly decreases the risk of respiratory obstruction and clinically evident tracheal stenosis, as our results have shown, at least five years after the last patient was discharged.

Tuberculosis: the great imitator in the head and neck - our experience of 24 cases in 22 years.

This retrospective study covered over two decades, during which an individual head and neck surgeon treated 24 patients with cervicofacial lymphadenitis that was related to both Mycobacterium tuberculosis complex (n=17, made up of M tuberculosis (n=16) and M bovis (n=1)), and non-tuberculous mycobacteria. The seven cases of non-tuberculous mycobacteria were caused by M avium complex (n=3), M malmoense (n=3), and M kansaii (n=1). By using a tailored management approach, at times selective combined surgical and antimycobacterial treatment, he achieved a success rate of 23/24 cases, with only one recurrence and no major complications. The results suggest that patients with tuberculosis confined to the head and neck rarely develop constitutional symptoms, so the absence of such symptoms may not exclude tuberculosis. There was also a good correlation between predictive variables (immune state, inflammatory markers on admission, causative mycobacterium, and the antimycobacterial regimen used) and time spent under follow-up at the head and neck outpatient clinic.

Corpus Hippocraticum: historical source of treatment of craniomaxillofacial trauma.

The works of Hippocrates known in the Western World as the Corpus Hippocraticum have dominated medical thought and surgical practice for centuries. A substantial part of the Hippocratic Collection is dedicated to the description of injuries pertinent to Cranio-maxillofacial surgery and their management. Hippocrates has reached this level of surgical skill despite the limited pre-recorded knowledge and the restriction of post-mortem dissections.

Predictive factors of hospital stay in patients with odontogenic maxillofacial infections: the role of C-reactive protein.

To investigate whether clinical or laboratory variables on admission of patients with odontogenic infections are associated with a severe clinical course and a prolonged hospital stay, we hypothesised that specific factors such as the serum concentration of C-reactive protein (CRP) may act as predictors of the duration of stay. We designed a prospective patient-oriented study that included all those treated for maxillofacial infections of odontogenic origin in the Oral and Maxillofacial Surgery Department of Northampton General Hospital between November 2013 and December 2014. A total of 71 were enrolled. We found that the concentration of CRP was a significant predictor of hospital stay (p=0.01). Its measurement on admission can predict the likely duration of stay of these patients and enable beds to be managed more efficiently.

Graves' disease: a review of surgical indications, management, and complications in a cohort of 59 patients.

An analysis of 59 patients who underwent total thyroidectomy for the treatment of Graves' disease over a 6-year period was conducted in order to assess the current indications and identify any specific factors that may influence the patient's decision to opt for surgical treatment. A comparison of outcomes between the current study and a similar one from Hong Kong was also attempted. Patient preference was the most common reason for opting for surgery over radioactive iodine in both studies. Other indications for surgery, such as Graves' ophthalmopathy, patient refusal for radioactive iodine, large goitre with pressure symptoms, planning for pregnancy, young age, and intolerance to anti-thyroid drugs, were also similar in the two groups. There were no statistically significant differences in laryngeal nerve palsy between the two groups. The rates of permanent hypoparathyroidism in patients in Hong Kong and in the present study were 5.4% and 5.1%, respectively. No patient in either study had recurrent Graves' disease after total thyroidectomy. Our findings confirmed that patient preference is the leading indication for surgery, implicating a continuous misconception of radioactive substances and increasing confidence in surgical outcomes. In experienced hands, the risks of recurrent laryngeal nerve injury and permanent hypoparathyroidism remain minimal.

Treatment of bladder carcinoma with irradiation combined with misonidazole.

One hundred patients suffering from cancer of the bladder were treated by external beam irradiation, 400 cGy twice a week to a total dose of 4800 cGy. One half of the patients were randomized to receive the electron affinic sensitizer agent, misonidazole, at a dose of 1 gr/m2 and a total dose of 12 gr/m2. There was no statistically significant difference in tumor responses and in recurrence--free survival time between the patients who received irradiation and misonidazole as compared to those who received irradiation and placebos.

Dietary lipids and geriatric depression scale score among elders: the EPIC-Greece cohort.

In a prospective epidemiological investigation aiming to identify dietary lipids potentially associated with affective state and depression, 610 healthy men and women aged 60 years or older, participating in the EPIC-Greece cohort and residing in the Attika region had dietary, sociodemographic, anthropometric, medical and lifestyle variables ascertained at enrollment. Six to 13 years later, affective state was evaluated through the 15-point geriatric depression scale (GDS) score along with cognitive function and medical variables. In multivariate linear regression analysis, while adjusting for potential confounders, GDS score was negatively associated with dietary intake of monounsaturated lipids (MUFA) and their main source, olive oil, and positively associated with intake of polyunsaturated lipids (PUFA) and one of their principal sources, seed oils. Intake of calories, total lipids, fish and seafood or saturated lipids did not exhibit significant association with GDS. Potential non-linearities were assessed by quantile multivariate regression analysis: The median GDS score was positively associated with PUFA and seed oils intake, while other lipid groups showed no appreciable associations. The 90th percentile of the GDS score (towards the high end) exhibited significant negative associations with MUFA and olive oil, weaker positive associations with PUFA and seed oils and no appreciable association with other lipid group dietary intakes. We conclude that among Attika elders, lower intake of seed oils and higher intake of olive oil prospectively predict a healthier affective state. Olive oil intake, in particular, predicts a lower chance of scoring in the highest part of the GDS.

Diet, physical activity and cognitive impairment among elders: the EPIC-Greece cohort (European Prospective Investigation into Cancer and Nutrition).

OBJECTIVES: To identify dietary and lifestyle variables that may affect cognitive function in the elderly. DESIGN: Population-based prospective cohort study. SETTING: General community residing in Athens and the surrounding Attica region of Greece. SUBJECTS: A total of 732 men and women, 60 years or older, participating in the EPIC-Greece cohort (European Prospective Investigation into Cancer and Nutrition) and residing in the Attica region had sociodemographic, anthropometric, medical, dietary and lifestyle variables ascertained at enrolment (1993-1999). Six to 13 years later, cognitive function was evaluated through the Mini-Mental State Examination (MMSE) score and affective state through the Geriatric Depression Scale (GDS). RESULTS: MMSE score was positively associated with years of formal education, height and physical activity and inversely with age, diabetes mellitus and GDS score (P < 0.05 for all). Among dietary variables, intake of PUFA was inversely associated with cognitive function and this association was largely accounted for by a similar association with seed oils. Adherence to the Mediterranean diet, as well as intake of olive oil, MUFA and SFA exhibited weakly positive but not significant associations. CONCLUSION: Physical activity and early life factors as reflected in height are significant predictors of cognitive function in the elderly. Seed oil consumption may adversely affect cognition, whereas other nutritional factors do not appear to have a quantitatively large effect.

Glycosylated hemoglobin monitoring of diabetic patients: a pilot study and case report.

Fasting and post-prandial blood glucose values have been found to be not totally representative of daily mean blood glucose concentration. Glycosylated hemoglobin (HbA1c) can be used as a supplemental monitoring device in the management and control of the diabetic patient. A pilot study on HbA1c was performed on a severe insulin dependent diabetic who had fasting glucose levels of 200-400 mg/dl over a six month period. The experimental data indicates that for every 10 mg/dl increase in glucose level, there is a corresponding increase in HbA1c of about .35%. Rate of formation of HbA1c depends on blood glucose concentration and is a slow continuous non-enzymatic process occurring during the normal 120 life span of the red blood cell. As such, it can be a useful monitoring tool.

[Properties of the polycarboxylate and glass-ionomer cements]. / Idiotetes ton konion tou polyakrylikou oxeos.

This paper is a review article on the properties of the polycarboxylate and glass-ionomer cements. Much research has been done during the past years on the strength, solubility and adhesion of these cements with the dental tissues and the conclusions on these topics are discussed in this paper.

Nephrobronchial fistula. Case report.

A 26-year-old woman presented with a six-year history of right staghorn calculus and pyonephrosis. Intravenous pyelography showed a non-functioning right kidney and chest radiography, an elevated right hemidiaphragm and fluid in the right costaphrenic space. At operation a nephrobronchial fistula was found, and nephrectomy and subdiaphragmatic drainage of the lung abscess was carried out. Culture of the pus grew Proteus mirabilis. The patient made an uneventful recovery and was discharged on the sixteenth day after operation.

A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients.

Nausea and emesis are common side effects of opioid drugs administered for pain relief in cancer patients. The aim of this study was to compare the anti-emetic efficacy and safety of ondansetron, placebo and metoclopramide in the treatment of opioid-induced nausea and emesis (OIE) in cancer patients. This was a multinational, multicentre, double-blind, parallel group study in which cancer patients who were receiving a full opioid agonist for cancer pain were randomised to receive one of oral ondansetron 24 mg once daily, metoclopramide 10 mg three times daily, or placebo. Study medication was started only if the patient experienced nausea and/or emesis following opioid administration. Efficacy and safety assessments were made over a study period of 24 h from the time of the first dose of anti-emetics/placebo. The study was terminated prematurely because of the difficulties in recruiting patients satisfying the stringent entry criteria. Ninety-two patients were included in the intent-to-treat population: 30 patients received placebo, 29 patients ondansetron and 33 patients metoclopramide. There was no statistically significant difference between the groups in the proportion achieving complete control of emesis (33% of patients on placebo, 48% on ondansetron and 52% on metoclopramide) or complete control of nausea (23% of patients on placebo, 17% on ondansetron and 36% on metoclopramide). Rescue anti-emetics were required in 8 of 33 patients on metoclopramide, 4 of 29 on ondansetron, and 3 of 30 on placebo. The incidence of adverse events was very low and similar in all treatment groups. Neither ondansetron 24 mg once daily nor metoclopromide 10 mg t.d.s. given orally was significantly more effective than placebo in the control of OIE in cancer patients.