Laparoscopic approach in perforated appendicitis: increased incidence of surgical site infection?

BACKGROUND: The role of laparoscopy in the setting of perforated appendicitis remains controversial. A retrospective study was conducted to evaluate the early postoperative outcomes of laparoscopic appendectomy (LA) compared to open appendectomy (OA) in patients with perforated appendicitis. METHODS: A total of 1,032 patients required an appendectomy between January 2005 and December 2009. Among these patients, 169 presented with perforated appendicitis. Operation times, length of hospital stay, overall complication rates within 30 days, and surgical site infection (SSI) rates were analyzed. RESULTS: Out of the 169 evaluated patients, 106 required LA and 63 OA. Although operation times were similar in both groups (92 ± 31 min for LA vs. 98 ± 45 for OA, p = 0.338), length of hospital stay was shorter in the LA group (6.9 ± 3.8 days vs. 11.5 ± 9.2, p < 0.001). Overall complication rates were significantly lower in the LA group (32.1 vs. 52.4 %, p < 0.001), as were incisional SSI (1.9 vs. 22.2 %, p < 0.001). Organ/space SSI rates were similar in both groups (23.6 % after LA vs. 20.6 % after OA, p = 0.657). CONCLUSIONS: For perforated appendicitis, LA results in a significantly shorter hospital stay, fewer overall postoperative complications, and fewer wound infections compared to OA. Organ/space SSI rates were similar for both procedures. LA provides a safe option for treating patients with perforated appendicitis.

PRESS survey: PREvention of surgical site infection-a global pan-specialty survey of practice protocol.

Background: Surgical site infections (SSI) complicate up to 40% of surgical procedures, leading to increased patient morbidity and mortality. Previous research identified disparities in SSI prevention guidelines and clinical practices across different institutions. The study aims to identify variations in SSI prevention practices within and between specialties and financial systems and provide a representation of existing SSI preventative measures to help improve the standardization of SSI prevention practices. Methods: This collaborative cross-sectional survey will be aimed at pan-surgical specialties internationally. The study has been designed and will be reported in line with the CROSS and CHERRIES standards. An international study steering committee will design and internally validate the survey in multiple consensus-based rounds. This will be based on SSI prevention measures outlined in the CDC (2017), WHO (2018), NICE (2019), Wounds UK (2020) and the International Surgical Wound Complications Advisory Panel (ISWCAP) guidelines. The questionnaire will include demographics, SSI surveillance, preoperative, peri-operative and postoperative SSI prevention. Data will be collected on participants' surgical specialty, operative grade, of practice and financial healthcare system of practice. The online survey will be designed and disseminated using QualtricsXM Platform™ through national and international surgical colleges and societies, in addition to social media and snowballing. Data collection will be open for 3 months with reminders, and raking will be used to ascertain the sample. Responses will be analyzed, and the chi-square test used to evaluate the impact of SSI prevention variables on responses. Discussion: Current SSI prevention practice in UK Vascular surgery varies considerably, with little consensus on many measures. Given the inconsistency in guidelines on how to prevent SSIs, there is a need for standardization. This survey will investigate the disparity in SSI preventative measures between different surgical fields and countries.

Asymptomatic bacteriuria in candidates for active treatment of renal stones: results from an international multicentric study on more than 2600 patients.

The occurrence of asymptomatic bacteriuria concomitant to urolithiasis is an issue for patients undergoing renal stone treatment. Disposing of a preoperative urine culture is essential to reduce the risk of septic events. The endpoint of the study is to report which characteristics of candidates for renal stone treatment are frequently associated with positive urine culture. 2605 patients were retrospectively enrolled from 14 centers; inclusion criteria were age > 18 and presence of a single renal stone 1-2 cm in size. The variables collected included age, gender, previous renal surgery, comorbidities, skin-to-stone distance, stone size, location, density, presence of hydronephrosis. After a descriptive analysis, the association between continuous and categorical variables and the presence of positive urine culture was assessed using a logistic regression model. Overall, 240/2605 patients (9%) had preoperative bacteriuria. Positive urine culture was more frequent in females, patients with previous renal interventions, chronic kidney disease, congenital anomalies, larger stones, increased density. Multivariate analysis demonstrated that previous renal interventions (OR 2.6; 95% CI 1.9-3.4; p < 0.001), renal-related comorbidities (OR 1.31; 95% CI 1.19-1.4; p < 0.001), higher stone size (OR 1.06; 95% CI 1.02-1.1; p = 0.01) and density (OR 1.00; 95% CI 1.0-1.00; p = 0.02) were associated with bacteriuria; male gender and lower caliceal location were inversely related to it. Beyond expected risk factors, such as female gender, other parameters are seemingly favoring the presence of positive urine culture. The awareness of variables associated with bacteriuria allows to assess which individuals are at increased risk of presenting bacteriuria and reduce the rate of septic complications.

Gene therapy of experimental brain tumors using neural progenitor cells.

Glioblastomas, the most frequent and malignant of primary brain tumors, have a very poor prognosis. Gene therapy of glioblastomas is limited by the short survival of viral vectors and by their difficulty in reaching glioblastoma cells infiltrating the brain parenchyma. Neural stem/progenitor cells can be engineered to produce therapeutic molecules and have the potential to overcome these limitations because they may travel along the white matter, like neoplastic cells, and engraft stably into the brain. Retrovirus-mediated transfer of the gene for interleukin-4 is an effective treatment for rat brain glioblastomas. Here, we transferred the gene for interleukin-4 into C57BL6J mouse primary neural progenitor cells and injected those cells into established syngeneic brain glioblastomas. This led to the survival of most tumor-bearing mice. We obtained similar results by implanting immortalized neural progenitor cells derived from Sprague-Dawley rats into C6 glioblastomas. We also documented by magnetic resonance imaging the progressive disappearance of large tumors, and detected 5-bromodeoxyuridine-labeled progenitor cells several weeks after the injection. These findings support a new approach for gene therapy of brain tumors, based on the grafting of neural stem cells producing therapeutic molecules.

Effects of low- and high-intensity exercise training on body composition and substrate metabolism in obese adolescents.

The objective was to investigate the effects of a 3- week weight-management program including moderate energy restriction and exercise training at 2 intensities [low intensity (LI): 40% and high intensity (HI): 70% maximal oxygen uptake (V'O(2)max)] on body composition, energy expenditure, and fat oxidation rate in severely obese adolescents. Twenty obese adolescents, aged 15-17 yr (body mass index: 37.5 kg/m(2); 38.2% fat mass) participated in this study. Before starting (week 0, W0) and at the end of the weight-management period (week 3,W3), body composition was assessed by a multifrequency tetrapolar impedancemeter; basal metabolic rate (BMR), energy expenditure, and substrate oxidation rate during exercise and post-exercise recovery by indirect calorimetry. At W3, body mass and fat mass decreased significantly (p<0.005) in all groups, and the decreases were significantly greater in the LI than in the HI group (-8.1±1.6 vs -5.9±1.6 kg and -4.2±1.9 vs -2.3±1.7 kg, p<0.05, respectively). Predicted V'O(2)max, expressed in relative values, changed significantly only in the HI group by +0.010±0.006 l/(kg fat-free mass × min) (p=0.010). By contrast, no significant changes were observed at W3 in BMR, energy expenditure, and substrate oxidation rate during exercise and post-exercise recovery. In conclusion, LI (40% of V'O(2)max) physical activity favors fat oxidation and it seems advisable to encourage obese adolescents to perform LI physical activity which is more feasible and acceptable than intense exercise.

Metabolic responses to submaximal treadmill walking and cycle ergometer pedalling in obese adolescents.

Physical activity is essential in obesity management because of the impact of exercise-related energy expenditure (EE) and fat oxidation (Fox) rate on a daily balance, but the specific physiological effects of different exercise modalities are scarcely known in obese individuals. The objective of the study was to compare the metabolic responses to treadmill (TM) and cycle ergometer (CE) exercise in obese adolescents. Gas exchange, heart rate (HR), blood lactate (LA) concentration, EE and Fox were determined at different intensity levels (up to about 85% of maximal oxygen uptake) during TM and CE in 14 pubertal (Tanner stage: >3) obese (BMI SDS: 2.15-3.86) male adolescents (age: 13-18 years). At comparable HR, oxygen uptake, EE and Fox were higher, and LA lower, during TM than CE (P<0.05-0.001), suggesting that cycling imposes a metabolic involvement at the level of the single active muscles greater than walking. Therefore, due to different physiological responses to TM and CE, walking was more convenient than cycling in obese adolescents, permitting to attain the same EE at lower HR, with lower blood LA concentration and with greater Fox. These conclusions seem clinically relevant when using exercise as a part of multidisciplinary treatment for juvenile obesity and amelioration of related metabolic disturbances.

[Rotator cuff diseases in occupational medicine between occupational diseases and accidents: medical-legal considerations]. / La patologia della cuffia dei rotatori in Medicina del Lavoro tra tecnopatia ed infortunio: considerazioni medico-legali.

The authors have gone through the complaints concerning all the cases of shoulder accidents at work filed by the Genoa office of the Italian Workers' National compensation Agency (INAIL) during the two years' period 2006-2007, reviewing in particular those somehow affecting rotator components. The aim of this paper is to assess the real role played by the occupational trauma in the rotator cuff tear. The data gathered so far have shown, on the one hand, a high prevalence of pre-existing inflammatory and degenerative diseases and, on the other, a rather modest influence of the trauma which, for this reason, has usually borne, as an immediate medico-legal consequence, the rejection of a cause-effect relationship between the accident and the rotator cuff lesion, without taking into any account whether the worker was likely to be affected by an occupational disease (ex table Ministerial Decree n. 81 April 9th 2008- item 78). In such cases a systematic and in-depth investigation of the occupational case history is suggested, in order to highlight the possible pre-existence of a former biomechanical overload of the upper limbs, so as to allow the physician to detect a pathology often misdiagnosed.

Physical activity ratios for various commonly performed sedentary and physical activities in obese adolescents.

The physical activity ratio (PAR) values are commonly used to convert subjects' physical activity recalls into estimates of daily energy expenditure (DEE). A PAR is defined as the ratio between energy expenditure corresponding to a sedentary or a physical activity (kJ/min) and basal metabolic rate [(BMR) kJ/min]. The objective of the present study was to determine the PAR for different sedentary and physical activities in obese adolescents. Thirty-three obese adolescents [mean body mass index: 35.1 kg/m2; 40.3 % fat mass] aged 11 to 17 yr participated in this study. BMR was assessed by indirect calorimetry after an overnight fast by means of an open-circuit, indirect computerised calorimetry with a rigid, transparent, ventilated canopy. Energy expenditures corresponding to various sedentary and physical activities in free-living conditions were determined using a portable metabolic unit, and body composition by bioelectrical impedance analysis (BIA). The PAR of each activity was obtained by dividing the assessed energy expenditure by BMR. In this study, the PAR of various sedentary and physical activities did not vary significantly with sex, age, and body mass. Thus, the data for boys and girls were combined and the PAR for 27 sedentary and physical activities were determined. The PAR values can be applied to determine the mean DEE (kJ) using the specific equation considering BMR (kJ/min), PAR, and duration (min) of each activity performed by the subject during the 24 h. This information will be useful to health-care professionals because estimation of DEE in obese adolescents is necessary in order to prescribe an adequate dietary therapy to induce a desired level of energy deficit.

The energy cost of cycling and aerobic performance of obese adolescent girls.

In order to assess the energy cost of cycling and aerobic capacity in juvenile obesity, responses to cycle ergometer exercise were studied in 10 pubertal obese (OB) [body mass index (BMI) SD score (SDS): 3.40+/-0.58 SD] adolescent girls (age: 16.0+/-1.2 yr) and in 10 normal-weight (NW, BMI SDS: -0.30+/-0.54) girls of the same age (15.1+/-1.9). To this aim, gas exchange, heart rate (HR), and energy expenditure (EE) were studied during graded cycle ergometer test at 40, 60, 80, 100, and 120 W. The energy cost of cycling was higher in OB, being oxygen uptake (VO2) higher (about 20%) in OB than in NW girls at all workloads (p<0.01-0.001). Estimated maximal VO2 and VO2 at anaerobic threshold were significantly (p<0.05) higher in OB girls [although lower per unit body mass (p<0.01) and similar for unit fat-free mass], and explained the higher oxygen pulse and lower HR for any EE observed during submaximal exercise in OB. While net mechanical efficiency (ME) was significantly lower in OB (p<0.01), delta ME was similar in both groups, indicating no substantial derangement of muscle intrinsic efficiency. It is concluded that, despite a higher cost of cycling, OB girls can rely on a larger aerobic capacity which makes them able to sustain this kind of exercise within a wide range of work loads, with relevant implications when planning protocols of physical activity in the context of interventions for the reduction of juvenile obesity.

Skeletal myogenic potential of human and mouse neural stem cells.

Distinct cell lineages established early in development are usually maintained throughout adulthood. Thus, adult stem cells have been thought to generate differentiated cells specific to the tissue in which they reside. This view has been challenged; for example, neural stem cells can generate cells that normally originate from a different germ layer. Here we show that acutely isolated and clonally derived neural stem cells from mice and humans could produce skeletal myotubes in vitro and in vivo, the latter following transplantation into adult animals. Myogenic conversion in vitro required direct exposure to myoblasts, and was blocked if neural cells were clustered. Thus, a community effect between neural cells may override such myogenic induction. We conclude that neural stem cells, which generate neurons, glia and blood cells, can also produce skeletal muscle cells, and can undergo various patterns of differentiation depending on exposure to appropriate epigenetic signals in mature tissues.

CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity.

Astrocytes actively participate in synaptic integration by releasing transmitter (glutamate) via a calcium-regulated, exocytosis-like process. Here we show that this process follows activation of the receptor CXCR4 by the chemokine stromal cell-derived factor 1 (SDF-1). An extraordinary feature of the ensuing signaling cascade is the rapid extracellular release of tumor necrosis factor-alpha (TNFalpha). Autocrine/paracrine TNFalpha-dependent signaling leading to prostaglandin (PG) formation not only controls glutamate release and astrocyte communication, but also causes their derangement when activated microglia cooperate to dramatically enhance release of the cytokine in response to CXCR4 stimulation. We demonstrate that altered glial communication has direct neuropathological consequences and that agents interfering with CXCR4-dependent astrocyte-microglia signaling prevent neuronal apoptosis induced by the HIV-1 coat glycoprotein, gp120IIIB. Our results identify a new pathway for glia-glia and glia-neuron communication that is relevant to both normal brain function and neurodegenerative diseases.

Current approaches to avoid the culling of day-old male chicks in the layer industry, with special reference to spectroscopic methods.

The negative correlation between fattening and laying performance prevents breeding improvement in both laying performance and meat yield. Therefore, specialized chicken lines have been bred in order to achieve either an efficient production of high-quality eggs or high growth rates. As a result, day-old male chicks are culled in the layer hatchery, which poses animal welfare and ethical problems. Breeding companies, scientific groups, and hatcheries are attempting to resolve this issue, with a common aim to find feasible alternatives for the routine killing of male layer chicks. Some approaches aim to influence the sex ratio, while others target at the economically feasible use of the male layer offspring, such as the fattening of "laying hen brothers" or crossbreedings of layers and broilers to create "dual-purpose chickens." Another approach is the sex determination prior to hatch. One of the prerequisites of in ovo sex determination is a practicable method that can be used in industry. The analysis needs to be rapid, cost-efficient, and highly precise; in addition, negative impacts on hatching rate, animal health, and/or performance parameters should be limited. Furthermore, sex determination should be performed before the sensory nervous system's response of the chick embryo to certain or potentially harmful stimuli is developed, which according to current knowledge is before the d 7 of incubation.

A videodensitometric study of transmural heterogeneity of cyclic echo amplitude variation in human myocardium.

The aims of this study were: (1) to assess whether variations in cyclic echo amplitude might be detected across the human myocardium by videodensitometric analysis of images obtained with epicardial echocardiography; and (2) to explore the possible relation between cyclic gray level variation and left ventricular (LV) hypertrophy and function. Experimental studies show that transmural differences in contractile performance across the normal myocardium are paralleled by differences in the cyclic (diastolic-to-systolic) variation of myocardial echo amplitude. Thirty-three patients (aged 60 +/- 11 years) undergoing cardiac surgery were studied by intraoperative epicardial echocardiography. LV mass index as normal (<110 g/m2 in women, <131 g/m2 in men) in 10 patients and increased in 22. Two-dimensional echocardiographic images were obtained with a 5 MHz transducer and digitized off-line. Videodensitometric analysis was performed at end-diastole and end-systole with regions of interest across the septal and posterior wall. The cyclic variation was more pronounced in the left than in the right septal subendocardium (31% +/- 14% vs 16% +/- 14% <0.01) and higher in the subendocardial than in the subepicardial layer of the posterior wall (30% +/- 21% vs 23 +/- 18%, p <0.01). Cyclic variation of the left septal subendocardium was higher in 11 patients with nonhypertrophic ventricles than in 22 with hypertrophic left ventricles (42% +/- 15% vs 27% +/- 12%; p <0.01). The percent cyclic variation of the left septal subendocardium appeared to be much more tightly related to percent systolic thickening in patients with eccentric LV hypertrophy (r=0.80 p <0.01) than in patients with concentric LV hypertrophy (r=0.27, p=0.9) or normal LV mass (r=0.43, p=0.2). A cyclic gray level variation can be consistently detected in different human myocardial regions and layers. It is more obvious in the subendocardial than in the subepicardial layer, and in nonhypertrophic than hypertrophic ventricles. The cyclic subendocardial variation is tightly related to regional systolic thickening in patients with eccentric LV hypertrophy.

Isolation and intracerebral grafting of nontransformed multipotential embryonic human CNS stem cells.

In this work, we show that the embryonic human brain contains multipotent central nervous system (CNS) stem cells, which may provide a continuous, standardized source of human neurons that could virtually eliminate the use of primary human fetal brain tissue for intracerebral transplantation. Multipotential stem cells can be isolated from the developing human CNS in a reproducible fashion and can be exponentially expanded for longer than 2 years. This allows for the establishment of continuous, nontransformed neural cell lines, which can be frozen and banked. By clonal analysis, reverse transcription polymerase chain reaction, and electrophysiological assay, we found that over such long-term culturing these cells retain both multipotentiality and an unchanged capacity for the generation of neuronal cells, and that they can be induced to differentiate into catechlaminergic neurons. Finally, when transplanted into the brain of adult rodents immunosuppressed by cyclosporin A, human CNS stem cells migrate away from the site of injection and differentiate into neurons and astrocytes. No tumor formation was ever observed. Aside from depending on scarce human neural fetal tissue, the use of human embryonic CNS stem cells for clinical neural transplantation should provide a reliable solution to some of the major problems that pertain to this field, and should allow determination of the safety characteristics of the donor cells in terms of tumorigenicity, viability, sterility, and antigenic compatibility far in advance of the scheduled day of surgery.

Long-term survival of cortical neurones from adult guinea-pig maintained in low-density cultures.

In vitro survival of neurones isolated from adult mammalian brain is normally scarce and the postnatal age limit for obtaining viable cultures of cortical, hippocampal and diencephalic neurones is commonly two weeks. Here we describe a novel procedure for the establishment and long-term maintenance of cortical neurones of the adult mammalian brain in low-density cultures. Neurones isolated from the piriform cortex of 30- to 90-day-old guinea-pigs were initially grown in a chemically defined medium enriched with basic fibroblast growth factor (bFGF); later, a small quantity of foetal bovine serum (FBS) was added to facilitate cell differentiation. Under these conditions cells could be maintained in culture for at least 3 weeks, when indirect immunocytochemistry and whole-cell patch-clamp recordings were performed. Cells exhibiting neuronal morphology expressed the neuronal marker microtubule associated protein-2 (MAP2) and generated action potentials. Moreover, about 70% of the MAP2-immunoreactive cells were simultaneously labelled with anti-gamma-aminobutyric acid (GABA) antibody. Cells expressing neuronal antigens were never labelled by antibody raised against the glial marker glial fibrillary acidic protein (GFAP). These results indicate that long-term survival of adult neurones can be achieved under definite culture conditions.

Inhibition of beta-lactamase-induced resistance in soft-tissue infections.

Sulbactam ([CP45,899] penicillanic acid sulfone) inhibits many of the beta-lactamases commonly found to be the cause of penicillin resistance. This agent was combined with either penicillin G potassium or ampicillin sodium in the treatment of 97 patients admitted with serious soft-tissue infections. Fifty-one of the infections were caused by at least one bacteria resistant to the antibiotic alone. Staphylococcus aureus was the most common pathogen (48 isolations) followed by the coliforms (30 isolations). Ninety percent of the isolates that were tested produced beta-lactamase. Susceptibility studies showed a high degree of resistance to the penicillin alone that was significantly lowered by the addition of sulbactam. The overall clinical results showed 81% of the infections to be either well controlled or cured. Three patients failed to show improvement. Thirteen patients showed transitory increases relatively safe and efficacious in the treatment of soft-tissue infection caused by penicillin-resistant and penicillin-susceptible organisms.

Surgical indications and timing of repair of traumatic ruptures of the thoracic aorta.

BACKGROUND: The outcome of patients with acute traumatic rupture of the thoracic aorta after motor vehicle accidents is strongly conditioned by injuries to other districts. The timing of repair is controversial when the patients arrive alive to the hospital. METHODS: A series of 42 patients with acute traumatic rupture of the thoracic aorta observed between January 1980 and June 1996 was divided into two groups: group I underwent immediate repair (21 patients) and in group II operation was performed after intensive medical treatment and management of the associated lesions and monitoring of the aortic tear. RESULTS: The mortality in group I patients was 19% and the morbidity was more significant than in group II where no deaths were reported and complications were minor. CONCLUSIONS: Patients with acute traumatic rupture of the thoracic aorta may have a better fighting chance if aortic operation is postponed to the most favorable moment after undergoing life-sustaining measures and management of the major associated lesions. Needless to say, evolution should be closely monitored by computed tomographic scans and magnetic resonance imaging.

Neurophysiological evaluation of vigilance in epileptic patients on monotherapy with lamotrigine.

OBJECTIVE: Limited research has focused to date on daytime sleepiness in epileptic patients treated with either conventional or newer antiepileptic drugs. We evaluated the level of vigilance in 15 consecutive, newly diagnosed and never medicated adult epileptic patients, receiving initial monotherapy with lamotrigine (LTG). METHODS: Patients underwent the Multiple Sleep Latency Test (MSLT), visual reaction times (VRT) and Stanford Sleepiness Scale (SSS) on two separate occasions, i.e. before and 2 months after LTG treatment. A group of 15 age-matched healthy volunteers was taken as control. RESULTS: At baseline, mean sleep latencies on the MSLT were comparable in epileptic patients and in controls. In patients, 2 months after monotherapy with LTG 200 mg/day, MSLT scores did not significantly change as compared with pre-treatment values. Accordingly, subjective evaluation of vigilance by the SSS and psychomotor performance by VRT were superimposable in controls and in untreated patients, and did not change in patients after LTG treatment. CONCLUSIONS: These results suggest that in adult, newly diagnosed epileptic patients initial monotherapy with LTG does not impair vigilance.

Basic fibroblast growth factor supports the proliferation of epidermal growth factor-generated neuronal precursor cells of the adult mouse CNS.

Stem cells isolated from the CNS of both embryonic and adult mice undergo extensive proliferation in the presence of epidermal growth factor (EGF). Removal of EGF determines the differentiation of these cells into neurons and glia. We have recently demonstrated that basic fibroblast growth factor (bFGF) regulates the proliferation of EGF-generated progenitors of the embryonic mouse striatum. We report here that bFGF induces proliferation of some EGF-generated precursors of the adult mouse striatum which, in turn, differentiate in vitro into cells possessing neuron-like morphology and neuronal antigenic properties. These results demonstrate that EGF and bFGF can act sequentially to regulate the de novo generation of neurons from the adult mouse CNS in vitro and suggest the existence of a lineage relationship between EGF- and bFGF-responsive progenitor cells of the adult murine brain.

Effects of M2 antagonists on in vivo hippocampal acetylcholine levels.

There is evidence that muscarinic receptors of the M2 subtype are presynaptic autoreceptors that modify the release of acetylcholine (ACh) through a negative feedback mechanism. Blocking these receptors by selective antagonists may therefore lead to increased ACh release. This in vivo microdialysis study examined the effects of three M2 antagonists, AF-DX 116, AF-DX 384, and AQ-RA 741, on hippocampal cholinergic neurotransmission. Drug (2, 4, 8, or 16 microM) or vehicle (Ringer's solution) was perfused via a microdialysis probe into the CA1 hippocampal region of conscious male Fischer 344 rats. Levels of ACh and choline were assessed by HPLC-EC. When the dose was expressed in K1 multiples, all drugs (except AQ-RA 741 at the two highest concentrations) were found to be on the same linear dose-response curve. Choline levels were not affected by drug administration. All three compounds elevated ACh levels in a similar K1-normalized dose-response fashion, strongly supporting the concept that the proposed presynaptic mechanism of action is indeed based on the same M2 receptor. Such elevations of ACh may not only improve performance on memory tasks, but may also have therapeutic advantages in conditions of cholinergic hypofunction, such as Alzheimer's disease.