Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients

Objectives The aims of the study were to assess the correlation between the plasma concentration of ophthalmic timolol and cardiovascular parameters, and the influence of timolol on advanced haemodynamic variables, such as stroke (SI), cardiac (CI) and systemic vascular resistance (SVRI) indices and arterial pulse wave velocity (PWV).Methods Twenty-five glaucoma or ocular hypertensive patients were treated with 0.5% aqueous and 0.1% hydrogel formulations of timolol using a randomised, double-masked, crossover, multicentre design. All the patients were subjected to passive head-up tilt, electrocardiography, exercise test and measurement of plasma concentration of timolol. In the analysis, the data on the two treatments were combined, and the Spearman correlation coefficients between the plasma level of timolol and physiological effects were calculated.Results During the head-up tilt test before rising the bed up, the resting heart rate (HR; R=–0.52, P=0.001) and PWV (R=–0.34, P=0.04) were inversely correlated with timolol level. In the upright position, ophthalmic timolol effectively suppressed the rise in HR (R=–0.36, P=0.03). The SI did not change with timolol concentration, while CI diminished as timolol concentration rose (R=–0.39, P=0.02). The SVRI correlated with timolol concentration (R=0.38, P=0.02). In the exercise test, correlation between HR and plasma level of timolol steadily grew stronger as the load increased, reaching R=–0.60 (P<0.0001) at the maximum load. Systolic and diastolic arterial pressures were not associated with the timolol concentration.Conclusion The plasma concentration of ophthalmic timolol correlates with several haemodynamic effects. As HR decreases, SVRI increases and blood pressure is kept unchanged.     

Anti-HIV-1 and cytotoxicity studies of piperidyl-thienyl chalcones and their 2-pyrazoline derivatives

A series of 12 new pyrazoline derivatives was prepared from piperidyl chalcones, which in turn were synthesized by condensing 4-piperidin-1-ylbenzaldehyde with diverse acetylthiophenes. The target compounds were characterized by spectroscopic techniques (NMR, IR, MS) and elemental analysis. All the compounds were screened for cytotoxic and anti-HIV-1 activities. Compounds 1c, 1g, 1j, 2a, 2c, 2e, 2g, and 2k demonstrated potential anti-HIV activity but were cytotoxic except for 2e and 2k, which displayed no cytotoxicity in primary human cells. Bioassay results show that the type and positions of the substituents seem to be critical for their cytotoxic and anti-HIV-1 activities.     

Varenicline and Nicotine Patch Therapies in Young Adults Motivated to Quit Smoking: A Randomized,Placebo‐controlled,Prospective Study

This study compares the nicotine patch to placebo in young adult light smokers, and the nicotine patch to varenicline in heavy smokers. Volunteer daily smokers were recruited into a randomized, placebo‐controlled study via community media, colleges and the army (aged 18–26 years). Those subjects with light tobacco dependence were randomized to (i) placebo patch (n = 86) and (ii) nicotine patch 10 mg/16 hr for 8 weeks (n = 94), and those with stronger dependence to (iii) nicotine patch 15 mg/16 hr for 8 weeks (n = 51) and (iv) varenicline for 12 weeks (n = 60). The primary outcome variable was self‐reported smoking abstinence at week 12. Secondary outcome variables were self‐reported smoking abstinence at weeks 4 and 26, and self‐reported abstinence verified by saliva cotinine level at week 12. The prevalence of self‐reported smoking abstinence did not differ statistically significantly in light smokers during the follow‐up (week 4: 19.8% for placebo patch and 26.6% for nicotine patch 10 mg/16 hr; week 12: 17.4% versus 23.4%; week 26: 15.1% versus 20.2%), but the groups of heavy smokers differed significantly for 12 weeks (week 4: 19.6% for nicotine patch 15 mg/16 hr and 73.3% for varenicline, p < 0.001; week 12: 15.7% versus 36.7%, p = 0.018). This statistically significant difference did not endure for the entire follow‐up (week 26: 9.8% versus 18.3%, p = 0.280). However, saliva cotinine verified abstinence at week 12 did not support self‐reported abstinence. Varenicline may be more effective than the nicotine patch as a smoking cessation pharmacotherapy among young adult heavy smokers in the short‐term.     

Synthesis of novel pyrazolobenzothiazine 5,5-dioxide derivatives as potent anti-HIV-1 agents

A new series of pyrazolobenzothiazine-based carbohydrazides was prepared in a facile way, starting with commercially available sodium saccharine. The final products were sufficiently characterized by spectroscopic techniques. In addition, compound 5k was confirmed with X-ray crystallography as well. All the compounds were screened for anti-HIV-1 and cytotoxicity activities. Overall, out of 15 compounds, seven exhibited good activity with EC₅₀ values <20 μM. Compounds 5c, 5d, 5g, 5j and 5k appeared as the potent anti-HIV-1 agents with EC₅₀ values <5.0 μM. The structure–activity relationship would facilitate the discovery of new molecules with better profile of HIV inhibition activity.     

How do tutors intervene when conflicts on knowledge arise in tutorial groups?

Recent research on problem-based learning (PBL) has shown that students need support when dealing with conflicting ideas in PBL-tutorial discussions. In the present study, we examined tutor facilitation during tutorial discussions, and particularly how the facilitation helped students to collaboratively resolve conflicts on knowledge. The study involved four PBL-tutorial sessions that included altogether 33 first-year medical and dental students. The sessions were videotaped and analysed using qualitative interaction analysis. Our aim was to find out how the tutor interventions encouraged students to elaborate on conflicting ideas, and how the interventions differed between conflict and non-conflict situations. We also examined how the tutors intervened during conflicts about factual or conceptual knowledge. The tutorial discussions included 92 tutor intervention episodes and 43 conflict episodes. The tutors intervened during 24 of the conflict episodes and resolved 13 of these episodes. Generally, the tutors often intervened by confirming what the students had said or by giving explanations, but they rarely asked questions that would stimulate the elaboration of knowledge. During conflicts on knowledge the tutors gave more explanations, but did little to encourage the students to deal with conflicting ideas. The tutors more often resolved conflicts on factual knowledge than conceptual knowledge. The findings suggest that tutor training should focus on promoting tutors’ understanding on when to give direct explanations, and when and how to encourage students to collaboratively elaborate on conflicting ideas.     

Inflammatory response to acute exposure to welding fumes during the working day

Objectives

To investigate cardiorespiratory and inflammatory responses in male workers following exposure to welding fumes and airborne particles in actual workplace conditions.

Materials and Methods

We measured blood leukocytes and their differential counts, platelet count, hemoglobin, sensitive C-reactive protein, fibrinogen, E-selectin, IL-(interleukin)1β, IL-6, IL-8, tumor necrosis factor alpha (TNF-α) and endothelin-1 in blood samples of twenty workers before and after their working day. We also studied peak expiratory flow (PEF), forced expiratory volume in one second (FEV₁), and exhaled nitric oxide (NO). We assessed heart rate variability (HRV) by obtaining 24-hour ambulatory electrocardiograms.

Results

The total blood leukocytes and neutrophils increased after the work shift, whereas IL-1β and E-selectin decreased significantly. There were no statistically significant changes in exhaled NO, FEV₁, PEF or HRV.

Conclusion

Occupational exposure to welding fumes and particles caused a slight, acute inflammatory effect estimated based on the increased values of leukocytes and neutrophils in blood and a decrease in the interleukin 1β and E-selectin values, but no changes in the pulmonary function (exhaled NO, FEV₁, PEF) or HRV during the working day were observed.     

Phytoestrogens alter the reproductive organ development in the mink (Mustela vison)

The aim of the present study was to examine the reproductive effects of two perorally applied phytoestrogens, genistein (8 mg/kg/day) and beta-sitosterol (50 mg/kg/day), on the mink (Mustela vison) at human dietary exposure levels. Parental generations were exposed over 9 months to these phytoestrogens and their offspring were exposed via gestation and lactation. Parents and their offspring were sampled 21 days after the birth of the kits. Sex hormone levels, sperm quality, organ weights, and development of the kits were examined. The exposed females were heavier than the control females at the 1st postnatal day (PND). The control kits were heavier than the exposed kits from the 1st to the 21st PND. Phytoestrogens did not affect the organ weights of the adult minks, but the relative testicular weight of the exposed kits was higher than in the control kits. The relative prostate weight was higher and the relative uterine weight lower in the beta-sitosterol-exposed kits than in the control kits. Moreover, the plasma dihydrotestosterone levels were lower in the genistein-exposed male kits compared to the control male kits. This study could not explain the mechanisms behind these alterations. The results indicate that perinatal phytoestrogen exposures cause alterations in the weight of the reproductive organs of the mink kits.     

Phytosterols act as endocrine and metabolic disruptors in the European polecat (Mustela putorius).

Phytosterols or plant sterols (PS) are consumed as natural remedies and margarines by the general population in developed countries to lower elevated serum cholesterol levels. They are also present in high concentrations in pulp mill effluents. The aim of the study was to screen the endocrine and metabolic parameters of the European polecat (Mustela putorius) for the effects of PS. The results showed an increase in the plasma estradiol and TH levels with no effects on the hypophyseal regulatory hormones. The plasma ghrelin levels decreased. PS also affected intermediary metabolism. The liver glycogen content increased as did the kidney glucose-6-phosphatase activity. The liver lipase esterase activity, on the other hand, decreased due to PS. In serum lipids the total cholesterol did not change, but the low-density lipoprotein levels increased and the high-density lipoprotein-cholesterol ratio decreased. PS had widespread previously unreported effects on the physiology of the polecat. The multiple effects indicate the need of a thorough risk assessment of the effects and interactions of PS.     

Assessment of acute behavioral toxicity of low doses of diisopropylfluorophosphate (DFP) in rats.

The effect on behavior of single subtoxic doses (100 and 600 micrograms/kg i.p., i.e. 1/77 and 1/13 of LD50, respectively) of an organophosphorous compound, diisopropylfluorophosphate (DFP), was studied in male Wistar rats. In the open-field test, the lower dose of DFP tended to increase ambulation, while the higher dose showed a trend towards a decrease in ambulation, rearing and frequency of defecation. In the elevated plus-maze, rotarod, elevated bridges and hot plate tests, DFP-treated rats did not differ significantly from the olive oil-treated controls. DFP significantly impaired the performance of rats in the one-trial passive avoidance task and dose-dependently decreased spontaneous locomotor activity for 4 hours after administration. At the doses used DFP only slightly inhibited acetylcholinesterase activity in the blood and different brain areas. The results show that the higher dose of DFP had an inactivating effect on the behavior of rats, while the lower dose did not markedly change their behavioral pattern. Our findings indicate that anticholinesterase compounds, such as DFP, can alter behavior even after single small subtoxic doses.     

Melkersson-Rosenthal syndrome.

OBJECTIVES: To study characteristics of Melkersson-Rosenthal syndrome (MRS) patients with facial palsy (FP) and differences in patients treated at the Departments of Otorhinolaryngology and Dermatology. METHODS: Clinical picture of MRS was studied from patient charts at two departments. Patients with FP received a questionnaire and were examined. Tissue biopsies were searched for non-necrotizing granulomatous infiltrations typical of MRS and blood DNA for UNC-93B1 gene mutations predisposing to herpesvirus infection. RESULTS: At the Department of Otorhinolaryngology, all 18 MRS patients had FP, 9 the triad form. Two patients revealed non-necrotizing granulomatous infiltrations during acute edema episodes; another two had association with uveitis. Edema was rarely persistent and did not dominate the clinical picture. No UNC-93B1 mutations were found. At the Department of Dermatology, 2 patients had triad MRS and 15 had monosymptomatic granulomatous cheilitis with persistent edema and typical MRS histology. CONCLUSION: The clinical picture of MRS with FP differed from the current knowledge of edema-dominated MRS. More studies focusing on MRS with FP would broaden our understanding of the syndrome.