Pteridine reductase (PTR1): initial structure-activity relationships studies of potential leishmanicidal arylindole derivatives compounds.

Leishmaniasis is a public health concern, especially in Brazil and India. The drugs available for therapy are old, cause toxicity and have reports of resistance. Therefore, this paper aimed to carry out initial structure-activity relationships (applying molecular docking and dynamic simulations) of arylindole scaffolds against the pteridine reductase (PTR1), which is essential target for the survival of the parasite. Thus, we used a series of 43 arylindole derivatives as a privileged skeleton, which have been evaluated previously for different biological actions. Compound 7 stood out among its analogues presenting the best results of average number of interactions with binding site (2.00) and catalytic triad (1.00). Additionally, the same compound presented the best binding free energy (-32.33 kcal/mol) in dynamic simulations. Furthermore, with computational studies, it was possible to comprehend and discuss the influences of the substituent sizes, positions of substitutions in the aromatic ring and electronic influences. Therefore, this study can be a starting point for the structural improvements needed to obtain a good leishmanicidal drug.

Randomized clinical trial of 24 versus 72 h antimicrobial prophylaxis in patients undergoing open total gastrectomy for gastric cancer.

BACKGROUND: Open total gastrectomy carries a high risk of surgical-site infection (SSI). This study evaluated the non-inferiority of antimicrobial prophylaxis for 24 compared with 72 h after open total gastrectomy. METHODS: An open-label, randomized, non-inferiority study was conducted at 57 institutions in Japan. Eligible patients were those who underwent open total gastrectomy for gastric cancer. Patients were assigned randomly to continued use of ß-lactamase inhibitor for either 24 or 72 h after surgery. The primary endpoint was the incidence of SSI, with non-inferiority based on a margin of 9 percentage points and a 90 per cent c.i. The secondary endpoint was the incidence of remote infection. RESULTS: A total of 464 patients (24 h prophylaxis, 228; 72 h prophylaxis, 236) were analysed. SSI occurred in 20 patients (8·8 per cent) in the 24-h prophylaxis group and 26 (11·0 per cent) in the 72-h group (absolute difference -2·2 (90 per cent c.i. -6·8 to 2·4) per cent; P < 0·001 for non-inferiority). However, the incidence of remote infection was significantly higher in the 24-h prophylaxis group. CONCLUSION: Antimicrobial prophylaxis for 24 h after total gastrectomy is not inferior to 72 h prophylaxis for prevention of SSI. Shortened antimicrobial prophylaxis might increase the incidence of remote infection. Registration number: UMIN000001062 ( http://www.umin.ac.jp).

Ibudilast, a phosphodiesterase inhibitor, in combination with low-dose aspirin potently inhibits guinea pig carotid artery thrombosis without extending bleeding time and causing gastric mucosal injury.

A combination of low-dose aspirin (ASA) and a phosphodiesterase inhibitor has been clinically tried for the secondary prevention of atherothrombotic diseases. The in vivo antithrombotic property of ibudilast (CAS 50847-11-5), a phosphodiesterase 4 (PDE4) inhibitor, was evaluated in a photochemically-induced guinea pig carotid artery thrombosis model in combination with low-dose ASA. The time required to decrease the carotid artery blood flow to the reading "zero" was defined as the time to occlusion (TTO) of the artery through thrombogenesis. Each independent use of ASA (300 mg/kg, p.o.) and ibudilast (3 and 10 mg/kg, p.o.) significantly prolonged the TTO, and ASA (300 mg/kg) significantly increased bleeding time (BT) and gastric mucosal injury. A selective PDE4 inhibitor rolipram (1 and 5 mg/kg, p.o.) tended to prolong the TTO without extending BT. ASA (100 mg/kg) plus ibudilast (3 mg/kg) and ASA (100 mg/kg) plus rolipram (5 mg/kg) markedly prolonged the TTO compared with each agent alone. Interestingly, ASA (100 mg/kg) plus ibudilast (3 mg/kg) caused a longer TTO than ASA (300 mg/kg) alone, without significant extension of BT and gastric mucosal injury as observed in ASA (300 mg/kg). These results indicate that the combination of low-dose ASA and ibudilast has a more potent antithrombotic effect than ASA alone without increasing bleeding tendency and gastric mucosal injury. The potent in vivo antithrombotic effect of this combination may be brought about by an action that is associated with PDE4 inhibition of ibudilast.

What influences the acidity in the gastric conduit in patients who underwent cervical esophagogastrostomy for cancer?

The aim of this study was to determine the factors influencing acidity in the gastric conduit after esophagectomy for cancer. Acidity and bile reflux in the stomach and in the gastric conduit were examined by 24-h pH monitoring and bilimetry in 40 patients who underwent transthoracic subtotal esophagectomy followed by esophageal reconstruction using a gastric conduit, which was pulled up to the neck through a posterior mediastinal route in 17 patients, through a retrosternal route in 10 patients, and through a subcutaneous route in 13 patients. They were examined at 1 week before surgery, at 1 month after surgery, and at 1 year after surgery. Helicobacter pylori infection was examined pathologically and using the (13) C-urea breath test. The factors influencing acidity of the gastric conduit were analyzed using the stepwise regression model. Gastric acidity assessed by percentage (%) time of pH < 4 was reduced after surgery and was significantly less in patients with H. pylori infection compared with those without H. pylori infection throughout the period from 1 week before surgery to 1 year after surgery. Duodenogastric reflux (DGR) assessed by % time absorbance > 0.14 into the lower portion of the gastric conduit was significantly increased after surgery throughout the period from 1 month after surgery to 1 year after surgery. Multivariate analysis showed that the acidity in the gastric conduit was influenced by H. pylori infection and DGR at 1 month after surgery, and by H. pylori infection and the route for esophageal reconstruction at 1 year after surgery. Acidity in the gastric conduit was significantly decreased after surgery. Acidity in the gastric conduit for esophageal substitutes is influenced by H. pylori infection and surgery. DGR influences the gastric acidity in the short-term after surgery, but not in the long-term after surgery.

Helicobacter pylori infection influences the acidity in the gastric tube as an esophageal substitute after esophagectomy.

It is commonly considered that acidity in a gastric tube used as an esophageal substitute after esophagectomy decreases due to truncal vagotomy. However, there have been few, if any, studies on the factors influencing the acidity in the gastric tube. It is well known that Helicobacter pylori (H. pylori) plays an important role in acid secretion of the stomach. The aim of this study was to investigate whether or not H. pylori infection also influenced the acidity in the gastric tube as an esophageal substitute. We investigated the changes in the levels of gastric acidity and the status of H. pylori infection from the preoperative period to 1 year after surgery. In 65 Japanese patients who underwent resection of esophageal cancer followed by reconstruction using a gastric tube, 24-h gastric pH monitoring and examination of H. pylori infection using the 13C-urea breath test and biopsy specimen obtained from the gastric mucosa under upper gastrointestinal endoscopy were performed pre- and postoperatively. Twenty-seven among the 65 patients underwent the same examinations at 1 year after surgery. The levels of postoperative gastric acidity and at 1 year after surgery were significantly lower than that of preoperative gastric acidity (P = 0.031, P = 0.001, respectively). There was no difference in the levels of gastric acidity between 1.5 months and 1 year after surgery (P = 0.282). The levels of gastric acidity in the stomach and in the gastric tube were significantly influenced by H. pylori infection, while age, gender, and past history of peptic ulcer showed no influence. The level of gastric acidity in patients who had H. pylori infection pre- and postoperatively were significantly lower than that in patients who had no H. pylori infection pre- and postoperatively (P < 0.0001). H. pylori infection was indicated to be an important factor influencing the levels of gastric acidity in the reconstructed esophagus as well as in the stomach before surgery.

Effects of reproduction norms on contraception practice among Muslim women in Amman, Jordan.

Based on the authors' interview survey for 275 Muslim women of an ethnically divergent community in Amman, Jordan, this study examined the psychosocial effects of reproduction norms on contraception practice, using the normative interpretations of legal provisions in Islam (hukm). The categorical principal component analysis (CATPCA) reduced the eight items regarding family planning and contraception use to two factors, i.e. the pressures of childbearing and acceptability of contraception use, accounting for 55% of the total variance. Even though the majority of the female subjects were conservative rather than innovative in terms of reproduction norms and significant interrelations were observed between their reproduction norms and contraception practice, approximately 70% of the female subjects who were closely in consonance with the normative interpretations of their religious leader had used contraception. It is thus indicated that religious leaders may play significant roles in increase of contraception practice among Muslim women.

Esophageal perforation caused by a press through pack.

A 73-year-old woman complaining of sudden hoarseness visited our hospital 17 days after the onset. The upper gastrointestinal contrast study showed a shallow ulcer crater with moderate bulging in the upper thoracic esophagus. Endoscope and computed tomography revealed an esophageal foreign body, a Press Through Pack (PTP), in the esophageal ulcer. The PTP could be removed endoscopically. Two months after extraction of the PTP, the patient was taking normal food orally and was discharged. The esophageal perforation, looking like a diverticle, was still present more than 1 year after the onset.

[Experimental gene therapy using p21/WAF1 gene in esophageal squamous cell carcinoma--adenovirus infection and gene gun technology].

p21/WAF1 (p21) inhibits the activity of the cyclin/cdk complex and controls the G1 to S cell phase transition. In the present study, we used a recombinant adenoviral approach and gene gun technology to introduce p21 into esophageal cancer cells in order to assess the effect of p21 on cell growth. Infection with the p21 adenovirus (AdV) using gene gun technology resulted in inhibition of TE9 and KE3 cell growth. The levels of involucrin, which is a marker of squamous epithelium differentiation, markedly increased at 48 h and 72 h after p21 AdV infection in TE9 cells. These results indicate that p21 plays an important role in esophageal cancer cell proliferation. Overexpression of the p21 gene can inhibit cell growth and induce differentiation in esophageal cancer cells. p21 gene therapy may prove beneficial in the treatment of esophageal cancer.

Optimum treatment strategy for superficial esophageal cancer: endoscopic mucosal resection versus radical esophagectomy.

This study was designed to determine the optimum treatment for a superficial esophageal cancer involving the mucosal or submucosal layer of the esophagus. The subjects were 150 patients with a superficial esophageal cancer who underwent endoscopic mucosal resection (EMR) or esophagectomy in Kurume University Hospital from 1981 to 1997. The mortality and morbidity rates, survival rate, and recurrence rate were retrospectively compared for (1) 35 patients who underwent EMR and 37 patients who underwent esophagectomy for a mucosal esophageal cancer and (2) 45 patients who underwent extended radical esophagectomy and 33 patients who underwent less radical esophagectomy for a submucosal esophageal cancer. Among the 72 patients with a mucosal cancer, lymph node metastasis/recurrence was observed in only one (1%); whereas of 78 patients with a submucosal cancer it was observed in 30 (38%). Among patients with a mucosal cancer the mortality and morbidity rates after EMR were lower than for those after esophagectomy. The survival rate after EMR was the same as that after esophagectomy. No recurrence was observed after either treatment modality. Among the patients with a submucosal cancer, the survival rate was higher and the recurrence rate lower after extended radical esophagectomy; than after less radical esophagectomy; the mortality and morbidity rates after extended radical esophagectomy were the same as those after less radical esophagectomy. Multivariate analysis demonstrated that the treatment modality (EMR versus esophagectomy) did not influence the survival of patients with a mucosal esophageal cancer, whereas it strongly influenced the survival of patients with a submucosal esophageal cancer. We concluded that EMR was the mainstay of treatment for a mucosal esophageal cancer, and extended radical esophagectomy was the mainstay of treatment for a submucosal esophageal cancer.

Expression of peroxisome proliferator-activated receptor subtypes in human atherosclerosis.

To clarify the involvement of peroxisome proliferator-activated receptors (PPARs) in atherosclerotic plaque formation, we investigated the expression patterns of mRNA and protein of PPARalpha and PPARgamma in human aorta. Atheromatous plaque, fatty streak, and diffuse intimal thickening (DIT) were separated macroscopically, and each sample was divided into halves. Half of them were used for analysis of mRNA expression with reverse transcription-polymerase chain reaction and the others were used for histologic analysis. Both PPARalpha and PPARgamma mRNA were detected in all atheromatous plaques, all fatty streaks, and in some DIT. However, expressions of PPARalpha and PPARgamma were obviously less frequently found in DIT than in atheromatous plaques, and the intensity of these expressions was stronger in the atheromatous plaques than in the DIT. Compared with PPARalpha, PPARgamma mRNA was expressed more frequently in atheromatous plaques. In atheromatous plaques, PPARgamma mRNA was expressed independently, whereas PPARalpha mRNA was coexpressed with PPARgamma. PPARgamma protein was obviously found in the nuclei of endothelial cells, macrophages, mononuclear cells, and smooth muscle cells in the aortic intima. These results suggest that expressions of PPARalpha and PPARgamma in human aortic wall are involved in atherogenesis from the early stages.

[New trends in neoadjuvant chemoradiotherapy for locally-advanced esophageal cancer: esophagectomy--is it necessary?].

In responders to neoadjuvant chemoradiotherapy for locally-advanced esophageal cancer, there was no significant difference in the long-term outcome between patients who underwent esophagectomy and those who did not. Esophagectomy might be unnecessary for patients who achieve a complete response with chemoradiotherapy for an esophageal cancer, in cases when salvage surgery is considered in order to treat any future recurrence.

Radical esophagectomy and secondary anastomosis for high-risk patients with intrathoracic esophageal carcinoma.

OBJECTIVE: We have often conducted esophageal reconstruction via a thoracic subcutaneous route in high-risk patients to avoid major complications following anastomotic leakage. This type of reconstruction is nonphysiological, however, and presents a poor cosmetic appearance. In better risk patients, therefore, we usually conduct gastric-tube replacement via a posterior mediastinal route. We have recently begun gastric-tube replacement via the posterior mediastinal route with secondary anastomosis for high-risk patients to avoid anastomotic leakage. RESULTS: From 1996 to 1999, secondary anastomosis was conducted in 25 patients with different degrees of risk--10 with diabetes mellitus, 7 with liver dysfunction, 3 with simultaneous laryngeal and/or pharyngeal cancer, 2 each with induction chemoradiotherapy, cardiac failure, renal dysfunction, respiratory failure, and cardiorespiratory dysfunction, and 1 with cerebral infarction. 6 patients had with multiple combined diseases. Secondary anastomosis was conducted 3-12 weeks (mean: 5.5 weeks) after esophagectomy. Stomach-tube necrosis was not seen in any of the 25 patients undergoing this 2-step procedure. Anastomosis leakage was seen in 5 of the 25 patients (20%), but was slight, in all but 1. CONCLUSION: Our 2-step procedure has the following advantages: low risk of anastomotic leakage, radical surgery for esophageal cancer, the potential for early adjuvant therapy after esophagectomy, easy and early training in swallowing, and no cosmetic problem. Its disadvantages are prolonged hospitalization, multiple surgery, and esophageal stoma formation. Secondary anastomosis thus appears helpful in treating high-risk patients with advanced esophageal cancer.

Histopathological analysis of non-malignant and malignant epithelium in achalasia of the esophagus.

We studied the premalignant nature of achalasia using anti-Ki-67 and anti-p53 monoclonal antibodies immunohistochemically. In this study, four patients with esophageal carcinoma and achalasia were investigated. Three tumors were pT4 (UICC pTNM) and one tumor was pT1. The majority of non-malignant esophageal epithelium showed esophagitis and/or dysplasia histologically. Esophageal epithelial cells in the lesions of esophagitis and/or dysplasia had a higher number of Ki-67-positive cells than normal epithelial cells. p53 protein was expressed in two tumors and it was not expressed in non-malignant epithelium. From these results, we found that esophageal epithelium in achalasia lesions is changed to varying degrees of esophagitis and/or dysplasia by stagnation of intake foods, and these abnormal epithelial cells showed a high proliferative state compared with the normal cells without the p53 gene mutation. We suggest that the distinct proliferative status is a cause of carcinogenesis.

[Nitric oxide (NO) donor].

Nitric oxide (NO), which is synthesized from L-arginine by nitric oxide synthase (NOS) in mammals, acts as a signal molecule for vasorelaxation, cytotoxicity and neurotransmission. The difficulty in handling of a gaseous and labile NO causes problems with the effective and precise studies using NO. The increasing interest in the biological roles of NO requires the use of NO donors which releases NO under the various desirable conditions. We systematized the most commonly used NO donors in this article to support the biological investigation. NO donors were classified according to the functional groups based on NO-donating characteristics. The preparation, chemical properties and NO-donating ability of these NO donors are summarized. It is particularly described in some detail on the stability both as a solid and in solution and the handling of the compounds.

Locoregional cellular immunotherapy for patients with advanced esophageal cancer.

The objectives of the present study were to determine the safety of locoregional administration of autologous lymphocytes stimulated with autologous tumor cells and interleukin (IL) 2 in vitro and to find laboratory markers to predict either clinical toxicity or clinical response. Eleven patients with advanced (n = 4) or recurrent (n = 7) esophageal cancers received the locoregional administration of these activated lymphocytes every 2 weeks for two to nine times (mean, 5.6 times), and mean numbers of the administered cells were 0.8 x 10(9) cells per treatment. The activated lymphocytes that were pretested for their surface markers and CTL activity were endoscopically injected into primary tumor sites (n = 4) or directly injected into metastatic lymph nodes (n = 2), pleural (n = 4) or ascitic (n = 1) regions. Grade 3 hypotension, grade 2 diarrhea, and grade 1 fever were observed in 1, 1, and 6 patients, respectively, and there was no adverse effect in the remaining three patients. The clinical outcome was as follows: one, complete response (CR); three, partial response (PR); two, stable response (SR); and five, progressive disease (PD). CTL activity in the administered cells was observed in 5 of the 11 patients (1 CR, 3 PR, and 1 PD) and was not observed in the remaining 6 patients (2 SR and 4 PD). Percentages of CD16+ cells in the peripheral blood of the responder group (CR+PR) significantly increased when compared with those before treatment or with those of the nonresponder group before as well as after treatment. Because the clinical toxicity was moderate and tolerable, this new method of locoregional immunotherapy will be applicable for use in treatment of patients with advanced and recurrent esophageal cancers. Both CTL activity in the administered cells and the percentages of CD16+ cells in the peripheral blood may be useful laboratory markers for predicting of clinical response.

Focal attenuation differences in pericystic liver tissue as seen on CT hepatic arteriography and CT arterial portography: observation using a unified helical CT and angiography system.

BACKGROUND: To investigate nontumorous focal enhancement (FE) with computed tomographic hepatic arteriography (CTHA) and perfusion defect (PD) with computed tomographic arterial portography (CTAP) in pericystic liver tissue. METHODS: Incidence, shape, and size of nontumorous FE on CTHA and PD on CTAP were examined in 100 consecutive noncirrhotic and 100 consecutive cirrhotic patients. RESULTS: FE was observed on CTHA in 77 noncirrhotic and 61 cirrhotic patients, whereas PD was observed on CTAP in 50 noncirrhotic and 51 cirrhotic patients. When both findings were visualized in both CT studies, the shape of the FE on CTHA was similar to the overlapping PD on CTAP in 81% of patients but was larger in 92% of patients. CONCLUSIONS: FE on CTHA and PD on CTAP are frequently noted in pericystic liver tissue. The size of FE on CTHA is often larger than PD on CTAP, although the shapes are generally the same. Size discrepancy suggests the presence of both portal supply and splanchnic venous drainage.

Total esophagectomy versus proximal esophagectomy for esophageal cancer at the cervicothoracic junction.

To investigate the adequate extent of esophagectomy and lymphadenectomy for an esophageal cancer localized at the cervicothoracic junction, the mortality and morbidity rates, survival rates, and patterns of recurrence were retrospectively analyzed in two groups-14 patients who underwent total esophagectomy with or without laryngectomy and 15 patients who underwent proximal esophagectomy with or without laryngectomy-at Kurume University Hospital from 1981 to 1996. Proximal esophagectomy with or without laryngectomy resulted in a lower hospital mortality rate and better overall survival for patients who underwent curative esophagectomy compared with total esophagectomy with or without laryngectomy. Multivariate analysis indicated that the extent of esophagectomy (total esophagectomy versus proximal esophagectomy) was not a prognostic factor. The incidence of recurrence was not different between the two groups. Lymph node metastasis or recurrence from such esophageal cancers was localized to the neck and upper mediastinum. For an esophageal cancer localized at the cervicothoracic junction, therefore, proximal esophagectomy with or without laryngectomy and with cervical and upper mediastinal lymphadenectomy could be better indicated for preselected patients.

The cause of nontumorous defects of portal perfusion in the hepatic hilum revealed by CT during arterial portography.

OBJECTIVE: We investigated the cause of nontumorous defects of portal perfusion in the hepatic hilum revealed by CT during arterial portography (CTAP). MATERIALS AND METHODS: One hundred sixty patients who simultaneously underwent CTAP and CT during hepatic arteriography of the common hepatic artery formed the basis of our study. The frequency, site, and shape of nontumorous defects of portal perfusion in the hepatic hilum on CTAP and the findings on CT during hepatic arteriography were determined. In 13 patients in whom nontumorous portal perfusion defects were observed on CTAP, CT was performed during selective angiography via the gastric artery, pancreaticoduodenal artery, or both. RESULTS: Nontumorous defects of portal perfusion were detected in 49 regions in 33 of the 160 patients (dorsum of segment IV, n = 30; dorsum of the lateral segment, n = 11; segment I, n = 8). Of the 33 patients, 16 had two defects each. Of the 49 nontumorous defects of portal perfusion, 38 showed enhancement on CT during hepatic arteriography. In the 13 patients who underwent CT during selective arteriography, enhancement due to nonportal venous inflow was seen in 16 of the 19 areas of decreased nontumorous portal perfusion (dorsum of segment IV, nine of 11; dorsum of the lateral segment, four of five; segment I, three of three). CONCLUSION: The main cause of nontumorous defects of portal perfusion in the hepatic hilum revealed by CTAP is decreased portal inflow due to nonportal supply via the parabiliary venous system. Thus, such lesions were also enhanced at a high frequency on CT during hepatic arteriography.

Growth and residential conditions of a slum community in Colombo, Sri Lanka.

Based on the authors' fieldwork, this article examined the spatial and demographic growth of a slum community in Colombo, Sri Lanka, in association with the inhabitants' socioeconomic conditions. In this slum community, which is near the industrial and commercial centers and has developed especially since the early 1970s, most dwellers are migrants from other parts of Colombo. The increase of dwellers resulted in a high-density residential condition, represented by an extremely small floor area per person, despite an income level that is not extremely low.