Selective immunolesion of cholinergic neurons leads to long-term changes in 5-HT2A receptor levels in hippocampus and frontal cortex

Although loss of cholinergic neurons in the basal forebrain is considered a key initial feature in Alzheimer's disease (AD), changes in other transmitter systems, including serotonin and 5-HT_2A receptors, are also associated with early AD. The aim of this study was to investigate whether elimination of the cholinergic neurons in the basal forebrain directly affects 5-HT_2A receptor levels. For this purpose intraventricular injection of the selective immunotoxin 192 IgG-Saporin was given to rats in doses of either 2.5 or 5 μg. The rats were sacrificed after 1, 2, 4 and 20 weeks. 5-HT_2A protein levels were determined by western techniques in frontal cortex and hippocampus. A significant 70% downregulation in frontal cortex and a 100% upregulation in hippocampus of 5-HT_2A receptor levels were observed 20 weeks after the cholinergic lesion when using the highest dose of 192 IgG-Saporin. Our results show that cholinergic deafferentation leads to decreased frontal cortex and increased hippocampal 5-HT_2A receptor levels. This is probably a consequence of the interaction between the serotonergic and the cholinergic system that may vary depending on the brain region.     

Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized,three-period,reference-replicated,crossover study

Background: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations.

Research design and methods: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC_0-72h, AUC_0-∝, C_max, T_max, T_1/2 and K_el.

Results: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC_0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for C_max, the 90% CI for this parameter for itraconazole was 93.49–133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15–138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events.

Conclusions: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.     

Robotic surgery using Senhance® robotic platform: single center experience with first 100 cases

Journal of Robotic Surgery - Until recently, robotic surgery has been associated only with the da Vinci robotic system. A novel Senhance® robotic system (TransEnterix Surgical Inc.,...     

Alpha 7 nicotinic receptor subunit is present on serotonin neurons projecting to hippocampus and septum

The serotonergic transmitter system regulates hippocampal activity through its raphe projection to hippocampus and medial septum/diagonal band of Broca complex (MS/DBB), and most likely also indirectly through its interaction with the cholinergic neurotransmitter system. Nicotine, e.g., enhances hippocampal serotonin release probably through presynaptic nicotinic receptors. We investigated the possible presence of the alpha 7-nicotinic subunit on serotonergic neurons projecting to hippocampus and MS/DBB. By retrograde neuronal tracing, hippocampal serotonergic neurons were identified and with double fluorescence immunostaining and Alexa-488 bound alpha-bungarotoxin the presence of active alpha 7 receptor on their soma was determined. Most of the retrogradely labeled serotonin neurons contained the alpha 7 subunit. A low degree of colocalization between alpha-bungarotoxin and serotonin-positive neurons suggest that the alpha 7 subunit may be transported anterogradely to the serotonergic axonal terminals.     

Comprehensive strategy to prevent nosocomial spread of methicillin-resistant Staphylococcus aureus in a highly endemic setting

BACKGROUND: The effectiveness and feasibility of a comprehensive strategy to reduce nosocomial transmission of methicillin-resistant Staphylococcus aureus (MRSA) in a highly endemic setting have not yet been proved. Limited benefits and the high cost of such programs are the main concerns. METHODS: We prospectively evaluated the effect of an aggressive infection control program on transmission of MRSA in the University Clinic of Respiratory and Allergic Diseases. All patients with MRSA carriage during 5 years (January 1, 1998, through December 31, 2002) were included and categorized into imported or hospital-acquired cases. RESULTS: Methicillin-resistant S aureus was recovered from 223 hospitalized patients; 142 cases were imported and 81 were acquired at our institution. After introduction of the comprehensive infection control program in 1999, the annual incidence of MRSA carriage per 1000 admissions increased from 4.5 in 1998 to 8.0 in 1999 (P = .02), and remained stable thereafter. In this period, the proportion of MRSA cases acquired in our institution decreased from 50.0% in 1999 to 6.1% in 2002 (P<.001), whereas the proportion of MRSA cases transferred from other hospitals (P<.001) and nursing homes (P = .03) increased. All 19 MRSA carriers with 3 sets of follow-up cultures were successfully decolonized. CONCLUSIONS: With a comprehensive infection control program, it was possible to reduce nosocomial transmission of MRSA in a highly endemic setting. With good hand hygiene using alcohol handrub, early detection, isolation, and a decolonization strategy, containment of MRSA was achievable, despite a high rate of transferred patients with MRSA.     

The effect of pharmacotherapeutic counseling on readmissions and emergency department visits

Objective To evaluate the impact of pharmacotherapeutic counseling on the rates and causes of 30-day post-discharge hospital readmissions and emergency department visits. Setting The study was conducted at the Medical Clinic of University Hospital Dubrava, Zagreb, Croatia. Methods The study included elderly patients prescribed with two or more medications for the treatment of chronic diseases. The patients randomized into the intervention group received pre-discharge counseling by the clinical pharmacologist about each prescribed medication. The control group received no counseling. Main outcome measures The rates and causes of 30-day postdischarge hospital readmissions and emergency department visits. Medication compliance was also evaluated, using the pill count method. Results A total of 160 patients were randomly selected for the study. No significant difference was found in the readmission and emergency department visit rates between the intervention and control groups (p = 0.224). There were 34.9 % more compliant patients in the intervention group. Significantly more non-compliant patients in the control group were readmitted or visited emergency department because of the disease progression (p = 0.031). In the intervention group, significantly more patients were readmitted or visited emergency department because of an adverse drug reaction (p = 0.022). Conclusion Pharmacotherapeutic counseling can reduce readmission and emergency department visit rates for disease progression. Improved patient knowledge about adverse drug reactions could be the reason for increased rates of readmissions and emergency department visits due to adverse drug reactions in the intervention group.     

When virtual and real worlds coexist: Visualization and visual system affect spatial performance in augmented reality

New visualization approaches are being actively developed aiming to mitigate the effect of vergence-accommodation conflict in stereoscopic augmented reality; however, high interindividual variability in spatial performance makes it difficult to predict user gain. To address this issue, we investigated the effects of consistent and inconsistent binocular and focus cues on perceptual matching in the stereoscopic environment of augmented reality using a head-mounted display that was driven in multifocal and single focal plane modes. Participants matched the distance of a real object with images projected at three viewing distances, concordant with the display focal planes when driven in the multifocal mode. As a result, consistency of depth cues facilitated faster perceptual judgments on spatial relations. Moreover, the individuals with mild binocular and accommodative disorders benefited from the visualization of information on the focal planes corresponding to image planes more than individuals with normal vision, which was reflected in performance accuracy. Because symptoms and complaints may be absent when the functionality of the sensorimotor system is reduced, the results indicate the need for a detailed assessment of visual functions in research on spatial performance. This study highlights that the development of a visualization system that reduces visual stress and improves user performance should be a priority for the successful implementation of augmented reality displays.     

Impact of aminoglycoside cycling in six tertiary intensive care units: prospective longitudinal interventional study

Aim

To determine the effect of aminoglycoside cycling in six tertiary intensive care units (ICU) on the rates of sepsis, aminoglycoside resistance patterns, antibiotic consumption, and costs.

Methods

This was a prospective longitudinal interventional study that measured the effect of change from first-line gentamicin usage (February 2002-February 2003) to amikacin usage (February 2003-February 2004) on the aminoglycoside resistance patterns, number of patients with gram-negative bacteremia, consumption of antibiotics, and the cost of antimicrobial drugs in 6 tertiary care ICUs in Zagreb, Croatia.

Results

The change from first-line gentamicin to amikacin usage led to a decrease in the overall gentamicin resistance of gram-negative bacteria (GNB) from 42% to 26% (P<0.001; z-test of proportions) and netilmicin resistance from 33% to 20% (P<0.001), but amikacin resistance did not change significantly (P = 0.462), except for Acinetobacter baumanni (P = 0.014). Sepsis rate in ICUs was reduced from 3.6% to 2.2% (P<0.001; χ² test), with a decline in the number of nosocomial bloodstream infections from 55/100 patient-days to 26/100 patient-days (P = 0.001, χ² test). Furthermore, amikacin use led to a 16% decrease in the overall antibiotic consumption and € 0.1/patient/d cost reduction.

Conclusion

Exclusive usage of amikacin significantly reduced the resistance of GNB isolates to gentamicin and netilmicin, the number of GNB nosocomial bacteremias, and the cost of total antibiotic usage in ICUs.Despite the introduction of newer, less toxic antimicrobial agents, aminoglycosides continue to have a role in the treatment of serious gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals, with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa (1). Most gram-negative bacteria (GNB) isolated from patients in intensive care units (ICU) have become more resistant to gentamicin (2) and ICU patients are more likely to have antimicrobial-resistant organisms than other patients or outpatients (3).Aminoglycoside resistance is mediated through three key mechanisms: a ribosomal mutation, reduced transport into the cell, and activity of plasmid-mediated aminoglycoside-modifying enzymes (4,5). These enzymes include three acetyltransferases, four adenyltransferases, and five phosphotransferases (5). Aminoglycoside-modifying enzymes are substrate-specific. Gentamicin and tobramycin are susceptible to at least five enzymes and the result is considerable cross-resistance between these two agents. Netilmicin is susceptible to four modifying enzymes, while amikacin is susceptible to aminoglycoside 6’-N-acetyltransferase, and is therefore useful against gentamicin-resistant GNB (6). No significant increase in the resistance to amikacin has been noticed during the past ten years, even with extensive and exclusive use (7-9). However, frequent use of amikacin usually results in a decreased resistance to other aminoglycosides (10).Several discrete strategies have been suggested to prevent or reduce microbial resistance to antimicrobials, including optimal use of agents, control, removal or restriction of antimicrobials, use of antimicrobials in combination, and rotation or cyclic use of antimicrobials (11). The latter strategy is attractive because it periodically removes certain classes or specific agents that could induce or select resistance from the institutional environment (12). The cyclic exposure prevents the development of resistance by a growth disadvantage of microorganisms when the selective antibiotic pressure is withdrawn and by eliminating the resistant microorganisms by different antibiotics (13). Studies showed that resistance to gentamicin was significantly reduced when amikacin was used (14), but it reappeared in the first gentamicin recycle. The second introduction of amikacin led to a decreased resistance to gentamicin, but the second introduction of gentamicin did not lead to reappearance of resistance (11). Trials that monitor the resistance are required to design optimal protocols and provide clinically meaningful results (15). However, the effect of empirical amikacin therapy on ICU patients with GNB in blood cultures has not been so far shown. Decreasing the number of GNB infections has both clinical and economical significance.The aim of this study was to evaluate prospectively the effect of intensive amikacin usage on the aminoglycoside resistance patterns, number of gram-negative isolates and gram-negative bacteremias, consumption of antibiotics, and the cost of antimicrobial treatment in ICUs.