Non-specific abdominal pain remains as the most common reason for acute abdomen: 26-year retrospective audit in one emergency unit.

OBJECTIVE: Distribution of diagnoses causing acute abdominal pain (AAP) may change because of population aging, increased obesity, advanced diagnostic imaging and changes in nutritional habits. Our aim was to evaluate the diagnoses causing AAP during a 26-year period. MATERIALS AND METHODS: This was a retrospective cross-sectional cohort study in one emergency department (ED) covering population about 250,000. All patients admitted to the ED in 1986, 2003 and 2012 were evaluated from hospital electronic database. Demographic data, utilization of diagnostic tests, surgical treatment and discharge diagnosis were analyzed. Statistical data of population aging, obesity and alcohol consumption during 1980-2012 were obtained from national registers. RESULTS: The AAP patients represented 10-20% of our total ED census. The most common causes of AAP were nonspecific abdominal pain (NSAP, 31-37%), acute appendicitis (11-23%), biliary disease (9-11%), bowel obstruction (5-7%), acute pancreatitis (4-8%) and acute diverticulitis (1-7%). The percentage of NSAP remained highest throughout the study period. Decrease in the number of acute appendicitis (from 23 to 11%; p < .0001), increase in acute diverticulitis (from 1 to 5%; p ≤ .0001) and acute pancreatitis (from 4 to 7%; p = .0273) was observed over time. The utilization of diagnostic imaging increased significantly (CT from 2 to 37% and US from 4 to 38%, p < .0001). Hospital mortality was very low (1-2%). CONCLUSIONS: NSAP is still the main differential diagnostic problem in the ED. Except acute appendicitis, distribution of specific diagnoses causing AAP remained rather stable through 26-year audit.

Long-Term Response to Cholinesterase Inhibitor Treatment Is Related to Functional MRI Response in Alzheimer's Disease.

BACKGROUND: Treatment of Alzheimer's disease (AD) with cholinesterase inhibitors (ChEI) enhances cholinergic activity and alleviates clinical symptoms. However, there is variation in the clinical response as well as system level changes revealed by functional MRI (fMRI) studies. METHODS: We investigated 18 newly diagnosed mild AD patients with fMRI using a face recognition task after a single oral dose of rivastigmine, a single dose of placebo and 1-month treatment with rivastigmine. The clinical follow-up took place at 6 and 12 months. RESULTS: MMSE score difference between baseline and the follow-ups showed a positive correlation with fMRI activation difference between treatment and placebo in the right prefrontal cortex. A negative correlation was found for the left prefrontal cortex and the left fusiform gyrus. In addition, greater signal intensity in the right versus the left fusiform gyrus predicted a response to ChEI with increasing MMSE scores during the follow-up with 77.8% sensitivity and 77.8% specificity. CONCLUSIONS: The increased fMRI activation by cholinergic stimulation in brain areas associated with the processing of the visual task reveals still functioning brain networks and a subsequent positive effect of ChEI on cognition. Thus, fMRI may be useful for identifying AD patients most likely to respond to treatment with ChEI.

Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss.

AIMS/HYPOTHESIS: The insulin receptor (INSR) has two protein isoforms based on alternative splicing of exon 11. INSR-A promotes cell growth whereas INSR-B predominantly regulates glucose homeostasis. In this study we investigated whether weight loss regulates INSR alternative splicing and the expression of splicing factors in adipose tissue. METHODS: To determine the relative ratio of the INSR splice variants, we implemented the PCR-capillary electrophoresis method with adipose tissue samples from two weight-loss-intervention studies, the Kuopio Obesity Surgery study (KOBS, n = 108) and a very low calorie diet (VLCD) intervention (n = 32), and from the population-based Metabolic Syndrome in Men study (METSIM, n = 49). RESULTS: Expression of INSR-B mRNA variant increased in response to weight loss induced by both bariatric surgery (p = 1 × 10(-5)) and the VLCD (p = 1 × 10(-4)). The adipose tissue expression of INSR-B correlated negatively with fasting insulin levels in the pooled data of the three studies (p = 3 × 10(-22)). Finally, expression of several splicing factors correlated negatively with the expression of the INSR-B variant. The strongest correlation was with HNRNPA1 (p = 1 × 10(-5)), a known regulator of INSR exon 11 splicing. CONCLUSIONS/INTERPRETATION: INSR splicing is regulated by weight loss and associates with insulin levels. The effect of weight loss on INSR splicing could be mediated by changes in the expression of splicing factors.

Effect of omeprazole dose, nonsteroidal anti-inflammatory agents, and smoking on repair mechanisms in acute peptic ulcer bleeding.

BACKGROUND: Peptic ulcer bleeding (PUB) is a major cause of upper gastrointestinal bleeding. The effect of omeprazole on mucosal repair is unknown. AIMS: We studied the effect of omeprazole, nonsteroidal anti-inflammatory agents, and smoking on PUB. METHODS: There were 43 PUB patients who received regular or high dose of omeprazole for 72 h. Biopsies from antrum and corpus were taken before and after treatment. Biopsy samples from 20 celiac disease patients worked as controls. The expression of Ki-67, Bcl-2, COX-2, Hsp27, and Hsp70 was analyzed from patients and controls. RESULTS: Bcl-2 expression in PUB patients was lower than in controls. However, Bcl-2 increased significantly from 5.0 (SD 4.5) to 9.1 % (SD 6.7), p = 0.0004, in the antrum after omeprazole. In univariate analysis, a high omeprazole dose caused a more profound increase in Ki-67 expression in the corpus: 35.3 % (SD 54.8) than a regular dose: -10.1 % (SD 40.6), p = 0.022. In multivariate analysis, Ki-67 decreased significantly in the corpus between the pre- and posttreatment period (p = 0.011), while a high omeprazole dose (p = 0.0265), the use of NSAIDs (p = 0.0208), and smoking (p = 0.0296) significantly increased Ki-67 expression. Bcl-2 in the corpus increased significantly (p = 0.0003) after treatment. CONCLUSIONS: Our findings suggest that Bcl-2 may be an important factor in the pathogenesis of a peptic ulcer and PUB. In addition, high-dose omeprazole increased the expression of Ki-67, which may enhance the healing process of a peptic ulcer.

Impact of routine contrast-enhanced CT on costs and use of hospital resources in patients with acute abdomen. Results of a randomised clinical trial.

OBJECTIVES: To evaluate the costs of treatment and use of hospital resources when comparing routine abdominal CT and selective imaging practice based on clinical assessment in patients with acute abdomen. METHODS: Altogether 300 patients with acute abdominal pain were randomised to computed tomography (CT, n = 150) or selective imaging practice (SIP, n = 150) groups. Final analysis included 254 patients, 143 in the CT and 111 in the SIP group. All CT group patients underwent contrast-enhanced abdominal CT within 24 h of admission. In the SIP group, imaging was individually tailored based on clinical assessment. The numbers of various examinations and procedures as well as costs of treatment arising from acute abdomen were calculated for each patient. Length of hospital stay was registered. RESULTS: Total treatment cost per patient was 1,202 euros () higher in the CT group compared to the SIP group (P = 0.002). The length of hospital stay was 1.2 days longer in the CT group (3.7 vs. 2.5 days, P = 0.010). Routine CT had no impact on ED discharge times. Imaging costs accounted for approximately 10 % of total costs. CONCLUSION: Routine abdominal CT results in higher treatment costs compared to selective use of imaging in patients with acute abdomen. KEY POINTS: • CT is widely used almost routinely in the diagnostics of acute abdomen. • Patients with acute abdomen were randomised to routine CT or selective imaging. • The treatment costs were significantly higher in the routine CT group. • Length of hospital stay was longer in the CT group. • Selective use of imaging may help control continuous increases of treatment costs.

Structure and function of medial temporal and posteromedial cortices in early Alzheimer's disease.

Medial temporal lobe (MTL) atrophy and posteromedial cortical hypometabolism are consistent imaging findings in Alzheimer's disease (AD). As the MTL memory structures are affected early in the course of AD by neurofibrillary tangle pathology, the posteromedial metabolic abnormalities have been postulated to represent remote effects of MTL alterations. In this study, we investigated with functional MRI (fMRI) the structure-function relationship between the MTL and posteromedial regions, including the retrosplenial, posterior cingulate and precuneal cortices, in 21 older controls (OCs), 18 subjects with amnestic mild cognitive impairment (MCI) and 16 AD patients during a word list learning task. In the voxel-based morphometric and volumetric analyses, the MCI subjects showed smaller entorhinal volume than OCs (P = 0.0001), whereas there was no difference in the hippocampal or posteromedial volume. AD patients, as compared with MCI patients, showed pronounced loss of volume in the entorhinal (P = 0.0001), hippocampal (P = 0.01) and posteromedial (P = 0.001) regions. The normal pattern of posteromedial fMRI task-induced deactivation during active encoding of words was observed bilaterally in the OCs, but only in restricted unilateral left posteromedial areas in the MCI and AD patients. Across all subjects, more extensive impairment of the retrosplenial and posterior cingulate function was significantly related to smaller entorhinal (P = 0.001) and hippocampal (P = 0.0002) volume. These findings demonstrate that entorhinal atrophy and posteromedial cortical dysfunction are early characteristics of prodromal AD, and precede and/or overwhelm atrophy of the hippocampus and posteromedial cortices. Disturbances in posteromedial cortical function are associated with morphological changes in the MTL across the continuum from normal aging to clinical AD.

Laparoscopic versus open cholecystectomy in diabetic patients and postoperative outcome.

BACKGROUND: Diabetes mellitus is associated with an increased risk of complications after abdominal surgery. We evaluated retrospectively the impact of preoperative risk factors and outcome of diabetic patients after laparoscopic cholecystectomy (LC) compared with open cholecystectomy (OC) for symptomatic gallstones. METHODS: Altogether 2,548 consecutive patients (1,581 LC, 967 OC) with symptomatic gallstones underwent cholecystectomy at our secondary referral center, being the only operative unit in the catchment area. Between the years 1995 and 2008, we operated 227 (9%) patients with diabetes, of whom 45 (20%) had type 1 diabetes. Preoperative data and operative outcome of the diabetic patients undergoing LC (n = 102) and OC (n = 125) were compared. The effect of comorbidities of diabetes on the risk for postoperative complications was analyzed by multiple logistic regression analysis. RESULTS: The percentage of morbidly obese diabetic patients did not change during the study period. Almost half of the cholecystectomies (n = 111) in diabetics were performed as acute surgery due to cholecystitis. Conversion to open surgery was required in 16% of the diabetic patients undergoing LC compared with 7% in the nondiabetic controls (p < 0.0001). Mortality rate was zero and nine patients (7.2%), respectively, in the LC and OC groups (p < 0.01). Other complications were also more frequently observed in the OC than LC groups. This outcome difference was unchanged during time. On multivariate analysis, comorbidities of diabetes were associated with an elevated risk for complications, but obesity or acute surgery was not independently associated with postoperative complications. CONCLUSIONS: When feasible, LC was a safe procedure in diabetes. Open surgery with comorbidities increased the operative risks. Our study was not randomized, and therefore selection bias to type of procedure may affect the results.

Changing incidence of acute appendicitis and nonspecific abdominal pain between 1987 and 2007 in Finland.

BACKGROUND: The incidence of acute appendicitis has declined in many countries. The aim of this study was to determine the trends in incidence of acute appendicitis (AA), appendectomies for AA, and nonspecific abdominal pain (NSAP) in Finland between 1987 and 2007. METHODS: We carried out a national register study. Demographic features were investigated. Diagnoses and procedures were classified according to the World Health Organization International Classification of Diseases. Data were analyzed for each of all five University Hospital districts (UHD) of Finland. RESULTS: During the observation period of 21 years, 186,558 appendectomies were performed in Finland, of which 137,528 (74%) cases were reported as AA. The incidence of acute appendicitis declined 32%. The diagnostic accuracy improved from 73 to 82% and was higher in men. The accuracy rate among the male patients was stable throughout the two decades; among the female patients it rose from 63 to 75%. The incidence of appendicitis was highest in patients aged 15-24 years. The average incidence of NSAP was 34/10,000/year, and it was higher in older age groups. There was a large geographical disparity in the incidence of NSAP. CONCLUSION: The incidence of acute appendicitis as well as the incidence of appendectomies is declining in Finland. The incidence of the NSAP has also been declining but we did not find any correlations between the incidences of the acute appendicitis and NSAP. There were clear geographical differences in the incidence of NSAP but not in the incidence of AA.

Laparoscopic and open cholecystectomy in surgical training.

BACKGROUND: Open cholecystectomy (OC) may still be necessary in surgical training to perform safe conversions of laparoscopic cholecystectomy (LC). Our aim was to study the outcome of LCs and OCs performed by surgical trainees. METHODS: All consecutive cholecystectomies (1,581 LCs and 984 OCs) were retrospectively analyzed from 1995 until 2008. Operative complications were compared between the cholecystectomies performed by 20 trainees alone (n = 822), assisted operations (n = 754, trainees/specialist surgeons) and 9 specialists alone (n = 989). RESULTS: Surgical trainees performed 787 (50%) LCs and 789 (80%) OCs either alone or assisted. The conversion rate of LC for trainees and specialist surgeons were 34 (7.0%) and 44 (5.5%), respectively. Complication rates and mortality were similar between the trainees and specialist surgeons. No bile duct injuries were associated with LCs or OCs performed by trainees alone. LCs were associated with 9 (0.57%) cases of bile leakage from cystic stump and 2 (0.13%) other bile duct injuries. CONCLUSION: Surgical trainees performed over half of our cholecystectomies with good results. The patient selection for LC versus OC was good, because no total transection of the common bile duct was observed in over 1,500 LC operations.

Comparison of outcomes twelve years after antireflux surgery or omeprazole maintenance therapy for reflux esophagitis.

BACKGROUND & AIMS: It is important to evaluate the long-term effects of therapies for gastroesophageal reflux disease (GERD). In a 12-year study, we compared the effects of therapy with omeprazole with those of antireflux surgery. METHODS: This open, parallel group study included 310 patients with esophagitis enrolled from outpatient clinics in Nordic countries. Of the 155 patients randomly assigned to each arm of the study, 154 received omeprazole (1 withdrew before therapy began), and 144 received surgery (11 withdrew before surgery). In patients who remained in remission after treatment, post-fundoplication complaints, other symptoms, and safety variables were assessed. RESULTS: Of the patients enrolled in the study, 71 who were given omeprazole (46%) and 53 treated with surgery (37%) were followed for a 12-year follow-up period. At this time point, 53% of patients who underwent surgery remained in continuous remission, compared with 45% of patients given omeprazole with a dose adjustment (P = .022) and 40% without dose adjustment (P = .002). In addition, 38% of surgical patients required a change in therapeutic strategy (eg, to medical therapy or another operation), compared with 15% of those on omeprazole. Heartburn and regurgitation were significantly more common in patients given omeprazole, whereas dysphagia, rectal flatulence, and the inability to belch or vomit were significantly more common in surgical patients. The therapies were otherwise well-tolerated. CONCLUSIONS: As long-term therapeutic strategies for chronic GERD, surgery and omeprazole are effective and well-tolerated. Antireflux surgery is superior to omeprazole in controlling overall disease manifestations, but post-fundoplication complaints continue after surgery.

A randomised clinical trial of routine versus selective CT imaging in acute abdomen: Impact of patient age on treatment costs and hospital resource use.

OBJECTIVES: To evaluate the impact of patient age on hospital resource use and treatment costs of acute abdominal pain (AAP). MATERIALS AND METHODS: A total of 300 adult patients with AAP were randomised to either computed tomography (CT, n=150) or selective imaging practice (SIP, n=150) groups. Final analysis included 254 patients, 143 (42 patients ≥65years) in the CT and 111 (32 patients ≥65years) in the SIP group. All CT group patients underwent abdominal CT whereas in the SIP group, imaging was based on the clinical assessment. For each patient, the hospital length of stay (LOS), the numbers and costs of diagnostic and treatment procedures arising from AAP were calculated and registered. The incremental cost-effectiveness ratio (ICER) and bootstrapped cost-effectiveness acceptability curve (CEAC) were estimated for routine CT. RESULTS: Treatment costs, imaging costs and LOS increased in conjunction with aging in both study groups, and were generally higher in the CT group compared to the SIP group. In the SIP group, CT was undertaken in 34% (27/79) of the <65year olds but in 59% (19/32) of the older patients (≥65years) (p=0.02). The proportion of patients with non-specific abdominal pain was significantly lower in patients ≥65years than in their younger counterparts (p=0.04). In the routine CT group, the ICER of obtaining a specific diagnosis was 1682 € for patients <65years and 1055 € for patients ≥65years. According to CEAC estimation, routine CT for every patient with AAP has a 95% probability of being cost-effective if society is willing to pay 14087 € for an additional specific diagnosis for patients <65 years but only 4204 € in those ≥65years. CONCLUSION: Treatment costs of AAP increase in parallel with aging, and the costs are generally higher with routine CT compared to selective imaging. The probability of obtaining a specific diagnosis of AAP increases with aging. If obtaining a specific diagnosis is deemed crucial, then routine CT is more cost-effective in patients over 65 years compared to younger patients. Considering the diagnostic challenges of AAP in the elderly, liberal CT use can be advocated in this patient group.

The effect of regular and high doses of omeprazole on the intragastric acidity in patients with bleeding peptic ulcer treated endoscopically: a clinical trial with continuous intragastric pH monitoring.

OBJECTIVE: In peptic ulcer bleeding (PUB), pH level >4 is considered necessary to prevent dissolving of a formed fibrin clot. The effect of regular or high doses of omeprazole on the intragastric pH in patients with acute PUB was studied. METHODS: In our earlier study, after endoscopic therapy, PUB patients were randomized to receive a regular dose of intravenous omeprazole (20 mg; i.e. 60 mg/3 days) or a high dose of omeprazole (80 mg bolus + 8 mg/h; i.e. 652 mg/3 days). Of these 142 analysed and reported patients, 13 PUB patients also had intragastric pH monitoring for these 3 days; seven of these patients had a regular dose and six received a high dose of omeprazole. RESULTS: The mean 24-h intragastric pH (regular versus high dose) on day 1 was 4.9 +/- 1.6 versus 6.3 +/- 0.5 (P = 0.035), on day 2 was 4.9 +/- 1.8 versus 6.7 +/- 0.3 (P = 0.001), and on day 3 was 5.7 +/- 1.1 versus 6.7 +/- 0.5 (P = NS). The medians of the intragastric pH were 6 versus 6.5 (P = 0.082) on day 1, 5.8 versus 6.8 (P = 0.001) on day 2, and 6.2 versus 6.8 (P = 0.17) on day 3. The proportion of time when pH <4 on day 1 was 29.2 +/- 34.1 versus 5.4 +/- 5.7% (P = NS). CONCLUSIONS: A regular dose of omeprazole raises the mean and median 24-h intragastric pH >4 in patients with PUB. This reduction in the acidity together with endoscopic therapy is probably sufficient to maintain haemostasis. A high dose of omeprazole keeps the pH almost constantly >6.

Characteristic changes in microbial community composition and expression of innate immune genes in acute appendicitis.

Appendicitis represents a common and severe gastrointestinal illness in younger individuals worldwide. The disease is characterized by an excessive inflammatory response and it is believed that bacterial overgrowth due to blockage of the appendix lumen might be involved. Despite the high incidence, only limited data on the pathophysiological changes exist; in particular, the innate immune responses involved are largely unknown. Real-time PCR analysis of tissue samples from inflamed and normal appendices demonstrated differentially regulated expression patterns of epithelial-derived antimicrobial peptides (AMP). The α-defensins human neutrophil peptides 1-3, HD5 and HD6, as well as the two ß-defensins, human ß-defensins (hBD)-2 and hBD-3, were up-regulated, whereas hBD-1 was down-regulated in acute appendicitis. Expression of upstream regulators of AMP expression, NOD-2 and TLRs 1, 2, 4, 5, 7, 8 and 10 was significantly increased as detected by real-time PCR. Finally, we confirmed the involvement of the pro-inflammatory cytokines IL-1ß and IL-8, and detected characteristic changes in microbial community composition in appendicitis tissue specimens by 16S rDNA based detection techniques. In this study, we demonstrate a differential regulation of the innate immune system along with an altered bacterial diversity in acute appendicitis.

Innate BDNF expression is associated with ethanol intake in alcohol-preferring AA and alcohol-avoiding ANA rats.

We have shown recently that acute administration of ethanol modulates the expression of brain-derived neurotrophic factor (BDNF) in several rat brain areas known to be involved in the development of addiction to ethanol and other drugs of abuse, suggesting that BDNF may be a factor contributing to the neuroadaptive changes set in motion by ethanol exposure. The purpose of the present study was to further clarify the role of BDNF in reinforcement from ethanol and in the development of addiction to ethanol by specifying the effect of acute administration of ethanol (1.5 or 3.0 g/kg i.p.) on the expression profile of BDNF mRNA in the ventral tegmental area and in the terminal areas of the mesolimbic dopamine pathway in the brain of alcohol-preferring AA and alcohol-avoiding ANA rats, selected for high and low voluntary ethanol intake, respectively. The level of BDNF mRNA expression was higher in the amygdala and ventral tegmental area of AA than in those of ANA rats, and there was a trend for a higher level in the nucleus accumbens. In the amygdala and hippocampus, a biphasic change in the BDNF mRNA levels was detected: the levels were decreased at 3 and 6h but increased above the basal levels at 24h. Furthermore, there was a difference between the AA and ANA lines in the effect of ethanol, the ANA rats showing an increase in BDNF mRNA levels while such a change was not seen in AA rats. These findings suggest that the innate levels of BDNF expression may play a role in the mediation of the reinforcing effects of ethanol and in the control of ethanol intake.

The need for surgery in acute abdominal pain: a randomized study of abdominal computed tomography.

AIM: To assess the need for surgical treatment in patients with acute abdominal pain in a prospective randomized study. PATIENTS AND METHODS: Initially 203 patients with acute abdominal pain were randomized to the routine abdominal computed tomography CT (rCT, n=118), or selective abdominal CT group (sCT, n=85) over a period of 16 months. Ninety-three of the randomized patients (45.8%) underwent the study design and were reached for follow-up at three months. RESULTS: Diagnostic accuracy improved significantly in the rCT group (p<0.001). The surgeon's assessment of the need for surgery changed more often in the rCT group than in the sCT group (78.7% vs. 46.9%, p=0.002). The confidence to treat operatively increased significantly in the rCT vs. the sCT group (65.6% vs. 40.6%, p=0.028). The rCT was the only independent parameter for the change of the assessment of surgery. CONCLUSION: Routine CT allows for more confidence in decision making for the surgical treatment of patients with acute abdominal pain.

Seasonal variations of acute appendicitis and nonspecific abdominal pain in Finland.

AIM: To investigate whether seasonal changes had an effect on the incidence of acute appendicitis (AA) or nonspecific abdominal pain (NSAP). METHODS: We carried out a national register study of all patients with a hospital discharge diagnosis of AA and acute NSAP in Finland. Data were analyzed for the whole country and correlated to seasonal and weather parameters (temperature, humidity). Moreover, additional sub-analyses were performed for five geographically different area of Finland. RESULTS: The observation period spanned 21 years, with 186558 appendectomies, of which 137528 (74%) cases were reported as AA. The incidence of AA declined for 32% over the study period. The average incidence of the NSAP was 34/10000 per year. The mean annual temperature, but not relative humidity, showed clear geographical variations. The incidence of AA decreased significantly during the cold months of the year. No correlation was detected between temperature and incidence of NSAP. Humidity had a statistically significant impact on NSAP. CONCLUSION: The incidence of acute appendicitis is declining in Finland. We detected a clear seasonality in the incidence of AA and NSAP.

Outpatient antibiotic use and the incidence of acute appendicitis in Finland: a nationwide study from 1990-2008.

BACKGROUND: The incidence of acute appendicitis (AA) has decreased in Finland. We hypothesized that changing trends in outpatient antibiotic use might explain at least part of this declining incidence of AA. METHODS: The number of all patients with AA in Finland was extracted from the national data base from 1990 to 2008. For comparison, the incidence of acute diverticulitis of the colon (AD) was also recorded. All outpatient prescriptions of antibiotics belonging to the major groups of these drugs were also recorded. We used unit root and co-integration analyses for statistical analysis of the data in the study. RESULTS: The incidence of AA in Finland declined from 14.5 to 9.8 per 10,000 inhabitants (32%) and the incidence of AD increased by 47% between 1993 and 2007. The total outpatient use of antibiotics did not increase during this same period, but the use of antibiotics effective widely against colonic pathogens (macrolides, fluoroquinolones, and cephalosporins) increased significantly. No correlation was found between the incidence of AA, that of AD, and the use of different groups of antibiotics. CONCLUSIONS: Our nationwide registry study indicated that changes in outpatient antibiotic use do not explain the decreasing trend in AA in Finland. Other factors, such as improved diagnosis of AA, may have some role in the decreasing incidence of AA.

Response to Brosch et al.

We would like to respond to Brosch et al. regarding our manuscript "Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis" (Pihlajamäki et al., 2011b). Brosch performed RT-PCR in liver samples from 13 lean and 34 obese individuals, finding no differences in SFRS10 or LPIN1 expression. We wish to address points raised by Brosch, including experimental strategy and analysis of human SFRS10 expression.

Effect of cholinergic stimulation in early Alzheimer's disease - functional imaging during a recognition memory task.

Treatment of Alzheimer's disease (AD) with acetylcholinesterase inhibitors (AChEI) enhances cholinergic activity and alleviates clinical symptoms. In the present functional magnetic resonance imaging (fMRI) study, we investigated the effect of the AChEI rivastigmine on cognitive function and brain activation patterns during a face recognition memory task. Twenty patients with newly-diagnosed mild AD were administered a single oral dose of placebo, a single dose of rivastigmine (acute), and twice-daily treatment with rivastigmine for 4 weeks (chronic). After each treatment, the patients underwent a facial recognition task during fMRI. The prefrontal areas known to be involved in face recognition memory processing demonstrated greater fMRI activity in both the acute and chronic rivastigmine conditions compared to the placebo condition. In the same brain areas, differences in both fMRI activation at the map level and regional fMRI signal intensity measures between the placebo and chronic treatment conditions correlated negatively with the Mini- Mental State Examination score. In the chronic rivastigmine condition, patients with better preserved cognitive abilities demonstrated less enhanced prefrontal activity, whereas patients with poorer cognition showed greater prefrontal activity. These findings suggest that the prefrontal attention/working memory systems are already impaired in the early stages of AD and that the effect of cholinergic medication in the brain areas involved in recognition memory, i.e., increased or decreased fMRI activation patterns, depends on the severity of the disease. These findings also suggest the importance of early AChEI treatment in the course of AD, at the point when there is still some cognitive reserve available and the therapy has the highest potential efficacy.

Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis.

Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, downregulated in both obese human liver and muscle and in high-fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic ß isoform of LPIN1. Importantly, LPIN1ß-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity.