Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease

A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.     

Editorial comment: feasibility of central gastrectomy for gastric cancer

BACKGROUND: Central gastrectomy (CG) for gastric cancer was developed to preserve pyloric function and maintain a large gastric volume. Whether this procedure is feasible for limited cases of gastric cancer is unclear. METHODS: On the basis of Union Internationale Contre le Cancer TNM classification, pathologic characteristics, perioperative parameters, and long-term results, we analyzed 100 patients who underwent CG. RESULTS: Pathologic findings included T1 (tumor depth, mucosal or submucosal) in 82 patients and T2 (muscularis propria or subserosal) in 18 patients. Mean number of dissected lymph nodes was 17.3, and pathologic N1 (node metastasis, 6 or less) was found in 14 patients. There were no operative deaths, but 5 patients had postoperative complications: anastomotic leakage in 1, severe gastric stasis in 2, ischemic gastric ulcer in 1, and intra-abdominal bleeding in 1. No patient had a cancer recurrence in a mean follow-up of 49 months. New early gastric cancer was detected in 3 patients during follow-up endoscopic examination. The 5-year cumulative survival was 0.97. One year after CG, 63 patients had early satiety after food intake. Mean ratio of 1-year postoperative/preoperative body weight was 95%. CONCLUSIONS: Central gastrectomy with sufficient node dissection resulted in good long-term survival and minimal postoperative weight loss. CG is a safe and useful procedure for selected patients with gastric cancer, although close follow-up for recurrence and a more precise analysis on physiologic states is needed.     

Hypertonic resuscitation of hemorrhagic shock upregulates the anti-inflammatory response by alveolar macrophages

BACKGROUND: Resuscitated hemorrhagic shock predisposes patients to the development of acute respiratory distress syndrome (ARDS). Hypertonic saline (HTS) has been shown to inhibit immune cell activation in response to lipopolysaccharide (LPS) in vitro and to reduce lung damage when used for resuscitation of hemorrhagic shock in vivo. We hypothesize that HTS resuscitation of hemorrhagic shock may exert this anti-inflammatory effect by modulating alveolar macrophage function leading to an altered balance between the proinflammatory and the counter-inflammatory response. METHODS: A 2-hit rat model of shock resuscitation was used. Alveolar macrophages were harvested by bronchoalveolar lavage (BAL), and tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were quantified in the cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Alternatively, 1 hour after resuscitation, animals received endotracheal LPS followed by endotracheal anti-IL-10 neutralizing antibody. Lung injury was determined by measuring BAL neutrophil counts 4 hours after LPS in vivo administration. RESULTS: Systemic administration of HTS significantly modulates the responsiveness of alveolar macrophages. Specifically, HTS resuscitation inhibited LPS-induced TNF-alpha production while enhancing IL-10 release in response to LPS administered ex vivo and in vivo. Anti-IL-10 antibody in vivo partially reversed the lung protective effect of HTS resuscitation. CONCLUSIONS: HTS resuscitation exerts an immunomodulatory effect on alveolar macrophages by shifting the balance of pro- and counter-inflammatory cytokine production in favor of an anti-inflammatory response. The in vivo data suggest a causal role for HTS-induced augmented IL-10 as protective. These findings suggest a novel mechanism for the in vivo salutary effect of HTS resuscitation on lung injury after resuscitated hemorrhagic shock.     

Treatment of ulcerative colitis using fecal bacteriotherapy

BACKGROUND: Although the etiology of idiopathic ulcerative colitis (UC) remains poorly understood, the intestinal flora is suspected to play an important role. Specific, consistent abnormalities in flora composition peculiar to UC have not yet been described, however Clostridium difficile colitis has been cured by the infusion of human fecal flora into the colon. This approach may also be applicable to the treatment of UC on the basis of restoration of flora imbalances. GOAL: To observe the clinical, colonoscopic and histologic effects of human probiotic infusions (HPI) in 6 selected patients with UC. CASE REPORTS: Six patients (3 men and 3 women aged 25-53 years) with UC for less than 5 years were treated with HPI. All patients had suffered severe, recurrent symptoms and UC had been confirmed on colonoscopy and histology. Fecal flora donors were healthy adults who were extensively screened for parasites and bacterial pathogens. Patients were prepared with antibiotics and oral polyethylene glycol lavage. Fecal suspensions were administered as retention enemas within 10 minutes of preparation and the process repeated daily for 5 days. By 1 week post-HPI some symptoms of UC had improved. Complete reversal of symptoms was achieved in all patients by 4 months post-HPI, by which time all other UC medications had been ceased. At 1 to 13 years post-HPI and without any UC medication, there was no clinical, colonoscopic, or histologic evidence of UC in any patient. CONCLUSIONS: Colonic infusion of donor human intestinal flora can reverse UC in selected patients. These anecdotal results support the concept of abnormal bowel flora or even a specific, albeit unidentified, bacterial pathogen causing UC.     

The effects of weight loss on renal function in patients with severe obesity

Severe obesity is associated with increased renal plasma flow (RPF) and glomerular filtration rate (GFR). The aim of the present study was to examine whether weight loss may reverse glomerular dysfunction in obese subjects without overt renal disease. Renal glomerular function was studied in eight subjects with severe obesity (body mass index [BMI] 48.0 +/- 2.4) before and after weight loss. Nine healthy subjects served as controls. GFR and RPF were determined by measuring inulin and PAH clearance. In the obese group, GFR (145 +/- 14 ml/min) and RPF (803 +/- 39 ml/min) exceeded the control value by 61% (90 +/- 5 ml/min, P = 0.001) and 32% (610 +/- 41 ml/min, P < 0.005), respectively. Consequently, filtration fraction was increased. Mean arterial pressure, although normal, was higher than in the control group (101 +/- 4 versus 86 +/- 2 mmHg, P < 0.01). After weight loss, BMI decreased by 32 +/- 4%, to 32.1 +/- 1.5 (P = 0.001). GFR and RPF decreased to 110 +/- 7 ml/min (P = 0.01) and 698 +/- 42 ml/min (P < 0.02), respectively. Albumin excretion rate decreased from 16 microg/min (range, 4 to 152 microg/min) to 5 microg/min (range, 3 to 37 microg/min) (P < 0.01). Fractional clearance of albumin decreased from 3.2 x 10(-6) (range, 1.1 to 23 x 10(-6)) to 1.2 x 10(-6) (range, 0.5 to 6.8 x 10(-6)) (P < 0.02). This study shows that obesity-related glomerular hyperfiltration ameliorates after weight loss. The improvement in hyperfiltration may prevent the development of overt obesity-related glomerulopathy.     

The effect of reduction of the peripheral fat content by liposuction-assisted lipectomy (SAL) on serum leptin levels in the postoperative period: a prospective study

The purpose of this study was to investigate the relationship between a decrease in the peripheral fat content by suction-assisted lipectomy (SAL) and serum leptin levels. Twenty-two healthy females who underwent SAL for aesthetic reasons participated in the study. The data included height, weight, dietary habits, and leptin levels before surgery and at 1 and 6 weeks postoperatively. The aspirate ranged between 1000 and 6000 ml, with an average of 2700 ml. Thirteen patients with an aspirate of over 2700 ml all experienced an immediate postoperative decrease in appetite which returned gradually by 12 to 17 days postoperatively. They lost an average of 7% of the total body weight at 6 weeks. The leptin levels 1 week postoperatively were significantly lower than the preoperative levels (p < 0.01); at 6 weeks the decrease in leptin level was not statistically significant. In conclusion, a reduction of the peripheral fat content of more than 2700 ml by SAL has an immediate effect on leptin levels that lasts at least 1 week and correlates with voluntary changes in energy intake.     

mRNA expression of serotonin receptors of type 2C and 5A in human resting lymphocytes

We investigated the presence of mRNA for serotonin receptors of type 2C (5-HT(2C)) in resting lymphocytes by means of RT-PCR and Southern blotting analyses, given their possible role in the pathophysiology of anxiety and eating disorders. At the same time, we explored also the presence of the specific mRNA for 5-HT(5A) receptors, a novel subtype for which still no functional data exist. Healthy subjects and patients with obsessive-compulsive or bipolar disorders were included in the study. The results showed the presence of the specific mRNAs for both 5-HT(2C) and 5-HT(5A) receptors in resting lymphocytes of the three groups of subjects. An additional band was also observed after the amplification of the 5-HT(5A) cDNA in each sample. These findings, while revealing the presence of 5-HT(2C) and 5-HT(5A) receptor mRNAs in an easily available tissue, can be considered preliminary for future quantitative analyses in patients with different psychiatric conditions.