Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect.

Metformin, a commonly used antidiabetic drug, exerts its glucose-lowering effect due to metabolic activities at several sites of action (biophases), including liver, intestine, muscle cells, and adipocytes. The relative contribution of the individual biophases to the overall glucose-lowering effect is not known. Thus, the aims of this investigation were to study the influence of mode of drug administration on the kinetics of glucose-lowering action of metformin in diabetic rats and identify the contribution of different sites of action to the overall response. Streptozotocin diabetic rats received metformin in crossover fashion via intraduodenal, intravenous, and intraportal routes as bolus dose or infusion regimens designed to yield similar pharmacokinetic profiles. Metformin plasma concentrations and blood glucose levels were measured following each mode of administration. Despite the similarity in the concentration-time profiles obtained for different routes of metformin administration, intraduodenal administration produced larger response than intraportal metformin infusion, and lowest response was observed following intravenous administration. This finding indicates that a significant "first-pass" pharmacodynamic effect, which occurs in the presystemic sites of action (liver and the gastrointestinal wall), contributes to the overall glucose-lowering response of metformin. We applied a combined pharmacokinetic-pharmacodynamic modeling approach to study the nature of the first-pass pharmacodynamic effect. The observed data were successfully described by a novel integrated indirect response pharmacokinetic-pharmacodynamic model that revealed a correlation between the temporal metformin concentrations that transit the portal vein and through the gut wall rather than with drug concentrations that accumulated in the liver and the intestinal wall.     

Retinotopic mapping in cat visual cortex using high-field functional magnetic resonance imaging

In the field of neuroscience, there has always been a need for imaging techniques that provide high-resolution, large field-of-view measurements of neural activity. Functional MRI has this capability, but the link between the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal and neural activity is indirect. High magnetic field strengths (>3 T) improve the strength and specificity of the BOLD signal, but there are additional concerns about imaging artifacts at high field. We have tested the capabilities of ultra high field fMRI in the anesthetized juvenile cat, demonstrating rapid, non-invasive retinotopic mapping of early visual areas. Maps of topographic organization and measured cortical magnification factors are in good agreement with electrophysiological studies. Measurement precision was estimated at 1 mm. This mapping, performed with an MRI scanner at ultra high field (9.4 T), demonstrates the capabilities of high-resolution functional mapping of the visual system at ultra high field.     

Prospective evaluation of plasma cortisol in recent trauma survivors with posttraumatic stress disorder

Hypothalamic pituitary adrenal axis abnormalities have been described in posttraumatic stress disorder (PTSD), and among the recently traumatized. Plasma cortisol and continuous measures of PTSD symptoms were obtained from 21 survivors, at 1 week and 6 months after traumatic events. Eight survivors met Clinician Administered PTSD Scale criteria for PTSD at 6 months. Cortisol levels at 1 week did not predict subsequent PTSD. Survivors with and without PTSD had similar mean levels of cortisol at both time points. Cortisol levels at 6 months negatively correlated with self-reported PTSD symptoms within PTSD subjects.     

Apoptosis is associated with triacylglycerol accumulation in Jurkat T-cells

Magnetic resonance spectroscopy is increasingly used as a non-invasive method to investigate apoptosis. Apoptosis was induced in Jurkat T-cells by Fas mAb. (1)H magnetic resonance spectra of live cells showed an increase in methylene signal as well as methylene/methyl ratio of fatty acid side chains at 5 and 24 h following induction of apoptosis. To explain this observation, (1)H magnetic resonance spectra of cell extracts were investigated. These demonstrated a 70.0+/-7.0%, 114.0+/-8.0% and 90.0+/-5.0% increase in the concentration of triacylglycerols following 3, 5 and 7 h of Fas mAb treatment (P<0.05). Confocal microscopy images of cells stained with the lipophilic dye Nile Red demonstrated the presence of lipid droplets in the cell cytoplasm. Quantification of the stained lipids by flow cytometry showed a good correlation with the magnetic resonance results (P > or =0.05 at 3, 5 and 7 h). (31)P magnetic resonance spectra showed a drop in phosphatidylcholine content of apoptosing cells, indicating that alteration in phosphatidylcholine metabolism could be the source of triacylglycerol accumulation during apoptosis. In summary, apoptosis is associated with an early accumulation of mobile triacylglycerols mostly in the form of cytoplasmic lipid droplets. This is reflected in an increase in the methylene/methyl ratio which could be detected by magnetic resonance spectroscopy.     

Local application of steroids following lumbar discectomy

In this prospective randomized clinical study, the effectiveness of epidural steroids to reduce pain following lumbar disc surgery was assessed. Sixty-one patients undergoing lumbar discectomy were included. They were assigned randomly to receive, immediately after removal of the disc, either 80 mg methylprednisolone acetate (Depomedrol) or the same amount (2 mL) of saline. Both were soaked in 2.5 x 2.5 cm of collagen absorbable hemostat (Instat) that was left on the decompressed nerve root. All discs were removed in the same way via unilateral flavectomy. The patients were asked to grade the pain intensity daily in the first 2 weeks and 1 year after surgery. Pain intensity was evaluated by the visual analog scale from 0 to 10, zero being no pain and 10 being the most severe pain. Statistically significant back pain relief was observed on postoperative days 1, 2, 6, and 14 in the study group (the group that received steroids). No difference between the two groups was found 1 year after surgery or when leg pain was compared. No side effects that could be related to the steroids were observed.     

Frequency and gravity of human envenomations caused by marine catfish (suborder siluroidei): a clinical and epidemiological study

INTRODUCTION AND OBJECTIVES: Catfish occur in marine and freshwater environments worldwide. They have three serrated venomous bony stings in the dorsal and pectoral fins that are used for defence against predators and are refilled by glandular tissues under the epithelium. However, some catfishes do not have poisonous glands next to the sting and cause traumatic wounds without poisoning. The objective of this study was to provide data for, and comment on, the epidemiological and clinical problems caused by marine catfish. PATIENTS AND METHODS: The authors have observed, followed and documented 127 injuries caused by marine catfish stings during different phases of the envenoming over a time period of 8 years at three points along the Western Atlantic Ocean coast. RESULTS: The patients presented intense pain during the acute phase of envenoming and complications, such as bacterial and fungi infections and retention of bony fragments, in the later phase. Immersion of the affected extremity in hot water was used in about 20% of cases with excellent results. DISCUSSION: Injuries caused by marine catfish are common (about 20% of injuries caused by marine animals in a series of more than 700 injuries recorded by the author) and cause intense pain and later complications. Immersion of the affected extremity in hot water results in improvement in the acute phase, but does not prevent the appearance of secondary infection or foreign body reactions.     

Inner ear decompression sickness and mal de debarquement.

OBJECTIVE: To present a case series of vestibular symptoms appearing after combined sailing and diving activity, and to discuss the differential diagnosis and the workup algorithm. STUDY DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: Three patients aged 25 to 31 years suffering from unsteadiness and movement sensations after sailing and scuba diving. INTERVENTIONS: Neurotologic evaluation and recompression therapy in a hyperbaric chamber. MAIN OUTCOME MEASURES: The increasing popularity of marine sports and leisure activities has resulted in the exposure of a growing number of people to unique abnormalities not encountered under terrestrial conditions. The otolaryngologist who is involved in the care of these patients is required to diagnose and treat diving-related sinus and ear injuries such as barotrauma and decompression sickness, and also to be familiar with sailing-related disorientation syndromes such as seasickness and mal de debarquement. Treatment modalities for the various abnormalities differ significantly, and early commencement of treatment is often crucial for a successful outcome. CONCLUSION: Whenever doubt exists, recompression treatment must be instituted as soon as possible because of the potential for severe sequelae if the patient is left untreated, and because the risks involved in this therapy are minimal.     

Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy

PURPOSE: To determine whether long-term treatment with valproate (VPA) and/or lamotrigine (LTG) in children with epilepsy is associated with altered growth and/or bone metabolism. METHODS: Twenty-seven boys and 26 girls, aged 3 to 17 years (9.2 +/- 3.9, mean +/- SD), with epilepsy treated with VPA and/or LTG for > or =2 years were evaluated for growth, nutrient intakes, physical activity, bone mineral density (BMD), and blood biochemical indices of mineral and bone metabolism. RESULTS: Twenty-three (43.4%) of the children had a body height below the 10th percentile. Z-scores for BMD below -1.5 occurred in 24.4% of the children. When patients were divided into two groups according to daily activity score, a significantly lower Z-score for total body BMD (p = 0.007), percentile for body height (p = 0.05), and plasma parathyroid hormone (PTH; p = 0.04), osteocalcin (p = 0.04) and 25-hydroxyvitamin D (25OHD) (p = 0.01) were found in the inactive compared with the active group. Z-score for total body BMD was correlated with daily activity score (r = 0.43, p = 0.008). Plasma intact osteocalcin and intact PTH values correlated significantly (r = 0.36, p = 0.02). Plasma 1,25-dihydroxyvitamin D was within normal range for all subjects. When patients were divided into LTG-alone, VPA-alone, and LTG-plus-VPA treatment groups, significantly lower (p < 0.05) plasma osteocalcin and percentile for body height were found in the VPA-plus-LTG treatment group. CONCLUSIONS: Long-term VPA and LTG therapy, particularly when combined, is associated with short stature, low BMD, and reduced bone formation. These alterations may be mediated primarily through reduced physical activity rather than through a direct link to the VPA and/or LTG therapy.     

Clinical applications and future trends in cardiac CTA

The new 64-slice multi-detector computed tomographic scanners with improved temporal and special resolution are well suited to cardiac scanning allowing large area coverage and very short scan time. Current applications include plaque and stenosis assessment, evaluation of bypass graft patency and stenosis, coronary artery anomalies and recently, assessment of implanted coronary stents. Possible fields of utilization include emergency room triage of chest pain, and screening prior to invasive angiography in order to reduce the load of invasive studies. The future holds the prospect of automatic analysis of coronary plaque and luminal stenosis possibly opening up a new vista for non-invasive risk assessment.