The effect of metabolic syndrome on postoperative outcomes following laparoscopic colectomy.

BACKGROUND: Among the criteria used to diagnose metabolic syndrome (MS), obesity and diabetes mellitus (DM) are associated with poor postoperative outcomes following colectomy. MS is also associated with colorectal cancer (CRC) and diverticulosis, both of which may be treated with colectomy. However, the effect of MS on postoperative outcomes following laparoscopic colectomy has yet to be clarified. METHODS: In an academic tertiary hospital, data from all consecutive patients undergoing laparoscopic colectomy from 2005 to 2014 were prospectively recorded and analysed. Patients presenting with MS [defined by the presence of three or more of the following criteria: elevated blood pressure, body mass index > 28 kg/m2, dyslipidemia (decreased serum HDL cholesterol, increased serum triglycerides) and increased fasting glucose/DM] were compared with patients without MS regarding peri-operative outcome [mainly anastomotic leaks, severe postoperative complications (Clavien-Dindo III and IV)] and mortality. RESULTS: Overall, 1236 patients were included: 508 (41.1%) right colectomies and 728 (58.9%) left colectomies. Seven hundred seventy-two (62.4%) of these procedures were performed for CRC. MS was diagnosed in 85 (6.9%) patients, who were significantly older than the others (70 vs. 64.2 years, p < 0.001), and presented with more cardiac comorbidities (p < 0.001). MS was associated with increased blood loss (122.5 vs. 79.9 mL p = 0.001) and blood transfusion requirement (5.9 vs. 1.7%, p = 0.021). The anastomotic leak rate was 6.6% (with 2.2% of anastomotic leaks requiring surgical treatment), and the overall reoperation rate was 6.9%. The incidence of severe postoperative complications was 11.5%, and the overall mortality rate 0.6%. No differences were found between the groups in overall postoperative morbidity and mortality. Median length of stay was similar in both groups (7 days). CONCLUSIONS: MS does not jeopardize postoperative outcomes following laparoscopic colectomy.

Plants and Small Molecules: An Up-and-Coming Synergy.

The emergence of Arabidopsis thaliana as a model system has led to a rapid and wide improvement in molecular genetics techniques for studying gene function and regulation. However, there are still several drawbacks that cannot be easily solved with molecular genetic approaches, such as the study of unfriendly species, which are of increasing agronomic interest but are not easily transformed, thus are not prone to many molecular techniques. Chemical genetics represents a methodology able to fill this gap. Chemical genetics lies between chemistry and biology and relies on small molecules to phenocopy genetic mutations addressing specific targets. Advances in recent decades have greatly improved both target specificity and activity, expanding the application of this approach to any biological process. As for classical genetics, chemical genetics also proceeds with a forward or reverse approach depending on the nature of the study. In this review, we addressed this topic in the study of plant photomorphogenesis, stress responses and epigenetic processes. We have dealt with some cases of repurposing compounds whose activity has been previously proven in human cells and, conversely, studies where plants have been a tool for the characterization of small molecules. In addition, we delved into the chemical synthesis and improvement of some of the compounds described.

Toxicological aspects of cannabinoid, pesticide and metal levels detected in light Cannabis inflorescences grown in Italy.

Recently, the cultivation of light Cannabis, with a total THC content less than 0.6%, has been encouraged due to its industrial and therapeutic potential. This has increased the consumption of hemp for both smoking purposes and food preparation. Even so, Cannabis inflorescences are not subject to EU regulations and standards provided for food and tobacco products. A study was carried out on thirty-one inflorescences samples, collected in different Italian regions, in order to determine cannabinoids, pesticides and metals and to evaluate the exposure of consumers to contaminants and ensure a safe consumption. Contents of THC were always below 0.5%, while CBD ranged between 0.3 and 8.64%. The determination of 154 pesticides showed that 87% of the samples contained fungicides and insecticides in the range 0.01-185 µg/g. The most found are spinosad and cyprodinil. The concentration of metals ranged from 1 to more than 100 µg/g and As, Cd, Co, Cr, Hg, Cu, Mo, Ni and V exceeded the regulatory US limits for inhaled Cannabis products, while Pb exceeded them for both oral and inhaled products. These contaminants are intrinsically toxic and may affect public health. Actions are needed to establish regulatory measures and reduce the adverse effects caused by contaminants in Cannabis.

Routine laparoscopic cholecystectomy after endoscopic sphincterotomy for choledocholithiasis in octogenarians: is it worth the risk?

BACKGROUND: No unanimous consensus has been reached as to the need for routine laparoscopic cholecystectomy (LC) after endoscopic sphincterotomy (ES) for choledocholithiasis in very elderly patients, who are considered as high-risk subjects for surgery. METHODS: From 1991 through 1997, 170 patients were referred to undergo preoperative ES and routine LC for common bile duct (CBD) stones. The results for 27 patients (age 80 years or older) were compared with those achieved for younger patients. Successively, in a retrospective case-control study, the results for the selected patients were compared with those for 27 very elderly patients who underwent endoscopic retrograde cholangiopancreatography (ERCP), but did not receive LC. The mean follow-up period was 126 months. RESULTS: Octogenarians showed longer surgery time (79 vs 51 min) and postoperative hospital stay (2.8 vs 1.2 days), as well as more early low-grade complications (15% vs 3%), whereas there were no differences in conversion rate or serious complications. Recurrent symptoms or complications developed in 48% of octogenarians not undergoing routine LC, and 30% finally needed surgery. One patient in the control group died after emergency cholecystectomy for acute cholecystitis. The results of surgery were significantly poorer for the control group. CONCLUSIONS: Although a "wait-and-see" policy allowed two-thirds of LCs to be avoided in octogenarians, biliary-related events developed for every second patient, often requiring delayed surgery, with poorer results. Sequential treatment (ES followed by elective LC) is a safe procedure for octogenarians, and should be considered as a standard, definitive treatment for cholecystocholedocholithiasis even after the age of 80 years.

Intraoperative cholangiography and bile duct injury.

We are not in agreement with the opinion that the credit for excellent results after laparoscopic cholecystectomy is to be attributed to the routine performing of intraoperative cholangiography. We performed 2538 laparoscopic cholecystectomies without routine intraoperative cholangiography and we obtained very low rate and severity of common bile duct injuries: there was a total of four common bile duct injuries (0.16%), in no case was the injury a major transaction, and injuries were detected intraoperatively and easily repaired with a T-tube. Cholangiography could prevent bile duct transaction, but that it is not necessary for intraoperative cholangiography to be routinely performed for this purpose. It is sufficient for intraoperative cholangiography to be performed whenever the surgeon is in doubt as to the biliary anatomy or common bile duct clearance, and that when dissection of the cholecystic peduncle proves difficult he does not hesitate to convert to open access.

Anorectal reconstruction by electrostimulated graciloplasty as part of abdominoperineal resection.

AIMS: To report the outcomes of anorectal reconstruction by electrostimulated graciloplasty as part of abdominoperineal resection, on data prospectively collected over 10 years. PATIENTS AND METHODS: Twenty-three abdominoperineal resections were associated to coloperineal pull through, double graciloplasty and loop abdominal stoma. Fifteen patients also received an implantable pulse generator, either for unsatisfactory result after external-source intermittent electrostimulation and biofeedback (five cases) or during graciloplasty (10 cases). Follow-up was to a maximum of 10 years. Functional outcome was followed up in sixteen patients who underwent stoma takedown. RESULTS: Mean actuarial survival at 5 years was 72.3%. Satisfactory results (score < or =8) occurred in 75% of patients (three without and 13 with stimulator) in the early stages, decreasing to 57% at 1 year and gradually increasing up to 100% at 5 years and over. CONCLUSIONS: Total anorectal reconstruction yields a good functional outcome over time. Thus, despite, and because of, a high complication rate and a great drain on resources, it should be considered a suitable procedure only for selected, strongly motivated patients.

Design, synthesis and biological evaluation of heteroaryl diketohexenoic and diketobutanoic acids as HIV-1 integrase inhibitors endowed with antiretroviral activity.

Highly active anti-retroviral therapy (HAART) using reverse transcriptase (RT) and protease (PR) inhibitors and, more recently, inhibitors of the fusion is currently the best clinical approach in combating acquired immunodeficiency syndrome (AIDS), caused by infection from human immunodeficiency virus type 1 (HIV-1). However, this therapy does not completely eradicate the virus, so that resistant strains easily emerge. The above problem calls urgently for research on inhibitors of further viral targets such as integrase (IN), the third enzyme produced by HIV. Recently, our research group was engaged in studies on conformationally restrained cinnamoyl compounds related to curcumin as anti-IN agents. Compounds containing both a 3,4,5-trihydroxyphenyl group and a carboxylic acid function were potent IN inhibitors active against viral replication. More recently, a promising new class of inhibitors synthesized by Merck Company has emerged, which contain aryldiketoacid (ADK) functionality. The ADKs selectively inhibited the stand transfer (ST) step of integration and were proven to be effective IN inhibitors in vivo. Our interest in the field of IN inhibitors led us to design pyrrole and indole derivatives containing both a cinnamoyl moiety and a diketoacid group. A number of the cited derivatives were proven potent IN inhibitors, which selectively inhibited the ST step at submicromolar concentrations and were effective against virus replication in HIV-1 infected cells.

Quality of life assessment in geriatric surgery.

An excessive number of studies on health-related quality of life (HRQOL) has rendered results often contradictory and difficult to interpret. HRQOL evaluation in the aged is even more difficult, due to intrinsic conceptual and methodological problems. Since no structured instruments are available for use in geriatric surgery, it would be necessary either to work out a new specific instrument or to adapt/adopt an already existing method. Properties and methodological steps for development and validation are set forth. The Functional Assessment for Cancer Therapy (FACT) scale was developed for patients with cancer and has been recently validated also in the elderly. The Multidimensional Assessment for Cancer in the Elderly (MACE) was originally developed for elderly cancer patients. Since both methods are irrespective of subjects undergoing surgery, its use requires further validation. The MACE gives a broad information spectrum, but in geriatric surgery it seems too complex. The FACT-G is a simple core item questionnaire which can be integrated by disease-specific items and seems more compliant. A disease-specific and treatment-specific application of FACT questionnaires by multicenter studies might be useful in evaluating surgical procedures in patients in whom significant advantages in survival cannot be expected, but QOL can still significantly improve.

Geometrically and conformationally restrained cinnamoyl compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation, and molecular modeling.

Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disposition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curcumin) which favorably interact with an "accessory" region of IN. This region is supposed to be located adjacent to the binding site accommodating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of coplanarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain energy of the coplanar conformation.

Molecular modeling of azole antifungal agents active against Candida albicans. 1. A comparative molecular field analysis study.

A series of 56 azole antifungal agents belonging to chemically diverse families related to bifonazole, one of the antimycotic drugs of clinical use, were investigated using the comparative molecular field analysis (CoMFA) paradigm. The studied compounds, which have been already synthesized and reported to be active in vitro against Candida albicans, were divided into a training set and a test set. The training set consisted of 40 molecules from all the different structural classes. Due to the lack of experimental structural data on these derivatives, molecular mechanics techniques were used to obtain putative active conformations for all the compounds. the correctness of this molecular modeling work was confirmed a posteriori by comparison with structural data of the analog 2w obtained by X-ray crystallographic analysis (Massa, S.; et al. Eur. J. Med. Chem. 1992, 27, 495-502). Two different alignment rules of the training set molecules were used in this study and are based on the assumption that according to published results on azole antifungal agents, all the studied compounds exert their inhibitory activity through the coordination of their azole moiety to the protoporphyrin iron atom of the fungal lanosterol 14alpha-demethylase enzyme. The predictive ability of each resultant CoMFA model was evaluated using a test set consisting of 16 representative compounds that belong to all the different structural classes. The best 3D-quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.57, 0.95, and 0.69, respectively. The average absolute error of predictions of this model is 0.30 log units, and the structural moieties of the studied antifungal agents which are thought to contribute to the biological activity were identified. The predictive capability of this model could be exploited in further synthetic studies on antifungal azoles. Furthermore, the results obtained by using two different alignments of the inhibitors suggest that the binding mode of these molecules involves both a coordination to the iron protoporphyrin atom and an additional, likewise relevant, hydrophobic interaction with the active site.

Antifungal agents. 9. 3-Aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]pyrroles: a new class of potent anti-Candida agents.

A new class of potent antifungal agents, namely, 3-aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]-pyrroles, is described. These compounds are related to bifonazole and pyrrolnitrin, two compounds belonging to the class of antimycotic drugs. The synthesis of the title pyrroles has been performed starting from 1,3-diaryl-2-propen-1-ones, which were reacted with tosylmethyl isocyanide to give 3-aroyl-4-arylpyrroles. Reduction of the resulting compounds by lithium aluminum hydride furnished the related alcohols, which were treated with 1,1'-carbonyldimidazole to afford the required imidazole derivatives. Forty-four new pyrroles which incorporate an (arylmethyl)imidazole moiety in the 3-arylpyrrole structure were prepared by the above procedure and tested in vitro against Candida albicans and Candida spp. Among test compounds, 10 were found to be highly active against C. albicans. The most active derivative (27) was twice as potent (MIC90) as bifonazole, and its activity was 4 times greater than those of miconazole and ketoconazole. The other nine compounds showed antifungal activity of the same order of that of bifonazole and were ca. 2 times as active as miconazole and ketoconazole. Derivatives 21 and 27 tested in vivo against C. albicans A170 were shown to be highly effective in rabbit skin candidosis. Pharmacological studies on compounds 27 and other related pyrroles (19, 35, 36, 38, 39, and 49) are in progress to select one of them as a potential candidate for clinical experiments.

Does laparoscopic cholecystectomy worsen the prognosis of unsuspected gallbladder cancer?

BACKGROUND: Several reports claim that there is a risk that laparoscopic cholecystectomy (LC) might worsen the prognosis of unsuspected gallbladder cancer. HYPOTHESIS: Several factors rather than LC could influence prognosis. METHODS: A retrospective clinicopathologic study was performed on 20 patients, 9 patients (3 men and 6 women, aged from 36 to 75 years [mean age, 62.3 years]) undergoing LC and 11 patients (2 men and 9 women, aged from 53 to 91 years [mean age, 65.3 years]) undergoing open cholecystectomy (OC), with postoperatively diagnosed gallbladder cancer. The correlation was evaluated between cumulative survival rates and the following 7 prognostic factors: age, sex, histopathological grade, pathologic stage, occurrence of bile spillage, type of cholecystectomy (LC or OC), and additional surgical treatments. RESULTS: Seven patients (87%) after LC and 9 patients (82%) after OC had cancer recurrence: the difference is of no statistical significance (P =.9). There were no recurrences of cancer in the abdominal wall after either LC or OC. Survival rate was statistically correlated to tumor stage (P =.007) and to the occurrence of bile spillage (P =.002). Survival rate did not change according to whether the operation was carried out using LC or OC (P =.60). CONCLUSION: These results would seem to lend support to the opinion that LC does not worsen the prognosis for unsuspected gallbladder cancer.

Structure-activity relationship studies on potential non-nucleoside DABO-like inhibitors of HIV-1 reverse transcriptase.

Using 2,6-dichloro-4-aminopyrimidine, a number of uracil and cytosine derivatives with both arylthio and alkoxy moieties were prepared. These novel pyrimidines share chemical similarities with DABOs and HEPTs, two classes of non-nucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors (NNRTIs), which have been widely studied of late. All new derivatives were tested in MT-4 cells to explore their potential in vivo anti-HIV activity. Like other NNRTIs, they selectively inhibit HIV-1 but not HIV-2. The majority of test derivatives were found to have low potency and were sometimes more cytotoxic than zidovudine and emivirine (formerly MKC-442), used here as reference drugs. Uracil and cytosine derivatives bearing a sec-butoxy chain and a methyl-substituted benzenesulphonyl moiety were the most potent. Enzyme assays proved that these derivatives target RT. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the meta substitution on the phenyl ring; furthermore, oxidation of sulphide to sulphone significantly increased the potency of certain derivatives.

1,2,5-Benzothiadiazepine and pyrrolo[2,1-d]-[1,2,5]benzothiadiazepine derivatives with specific anti-human immunodeficiency virus type 1 activity.

We synthesized and tested as novel inhibitors of human immunodeficiency virus type 1 (HIV-1) bi- and tricyclic thiadiazine ring homologues of 7-chloro-2-ethyl-2H-1,2,4-benzothiadiazin-3-(4H)-one 1,1-dioxide, which is a compound endowed with anti-HIV-1 activity at low micromolar concentrations. Benzothiadiazepine derivatives were obtained by alkylation of 8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide, which was obtained by intramolecular cyclization of 2-(2-amino-5-chloro-benzenesulphonamido) propanoic acid. Pyrrolobenzothiadiazepines were synthesized from N-substituted 5-chloro-2-(1H-pyrrol-1-yl)benzene-sulphonamides by treating with triphosgene. N6-substituted pyrrolo[2,1-d][1,2,5]benzothiazepin-7(6H)-one 5,5-dioxides were active, though not very potent. Both a chlorine atom and an unsaturated alkyl chain were found to be determinants of anti-HIV-1 activity. The highest potency was shown by a derivative with a TIBO-related 3,3-dimethylallyl chain. 2,3-Dihydro-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxides were scarcely active in HIV-1-infected MT-4 cell assays; however, the introduction of the dimethylallyl chain into 7-chloro-1,2,5-benzothiadiazepine moiety led to a bicyclic derivative which was more potent and less cytotoxic than the tricyclic pyrrole-containing counterpart.

Analytical and semipreparative enantiomeric separation of azole antifungal agents by high-performance liquid chromatography on polysaccharide-based chiral stationary phases. Application to in vitro biological studies.

High-performance liquid chromatography (HPLC) was used for the enantiomeric separation of chiral imidazole derivatives endowed with antimycotic activity. Enantioselective columns, containing carbamates of cellulose and amylose, were used. The influence of the nature and content of an alcoholic modifier in the mobile phase was studied. The isolated enantiomers, separated on semipreparative columns, were submitted to in vitro biological investigations.

Enantioselective liquid chromatography of C3-chiral 2,3-dihydro-1,2,5-benzothiadiazepin-4(5H)-one and thione 1,1-dioxides on polyacrylamide- and polysaccharide-based chiral stationary phases.

Optically active synthetic and semisynthetic polymers were utilized as chiral stationary phases (CSPs) for the direct chromatographic enantioseparation of a series of 8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one and thione 1,1-dioxide. Evaluation of stereochemical integrity of chiral analytes was assessed by enantioselective temperature and flow-dependent HPLC. A stopped-flow high-performance liquid chromatography (sfHPLC) procedure was developed for the determination of the rate constants and free energy barriers of enantiomerization of enantiomers of 8-chloro-2-(3-methylbut-2-enyl)-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-thione 1,1-dioxide (compound 2) in the presence of Chiraspher and Chiralcel OD CSPs. In order to study the chiroptical properties of the individual enantiomers of analytes investigated, semipreparative chromatographic resolutions were performed. The assignment of the absolute configuration was empirically established by comparing the CD spectra of the separated enantiomers with those obtained from structural analogues.

Asymptomatic bile duct stones: selection criteria for intravenous cholangiography and/or endoscopic retrograde cholangiography prior to laparoscopic cholecystectomy.

OBJECTIVE: Routine use of endoscopic retrograde cholangiography (ERC) and/or intravenous cholangiography (IVC) or magnetic resonance cholangiopancreatography (MRCP) before laparoscopic cholecystectomy (LC) is not cost-effective. The objective of this study was to determine precise and easily applicable criteria to select patients who should undergo IVC, MRCP and/or ERC before LC. DESIGN AND METHODS: Prospectively collected data from 74 consecutive patients who were diagnosed with asymptomatic common bile duct stones (CBDS) before undergoing LC, were compared with data from 74 matched controls without CBDS. Using the chi2 test, those variables were identified which were significantly related to the presence of CBDS. These were inserted into a logistic multiple regression model and, by means of conditional regression analysis, each variable was assigned a score from -2 to +4 proportional to the odds ratio. By adding up the scores obtained, a classification was made as to high, medium and low CBDS risk. RESULTS: As a result, 51 patients were found to be low-risk cases, 53 medium-risk and 44 high-risk. Assuming no further assessment of the bile duct needed to be carried out in low-risk patients, an IVC or MRCP in those at medium risk and an ERC in those at high risk, a calculation was made of the positive predictive value and the sensitivity of the system proposed. The positive predictive value and the sensitivity of the procedure were calculated as being greater than 90%. CONCLUSIONS: This predictive system for the risk of CBDS allows the selective use of ERC, IVC and MRCP to ensure a high yield and improve cost-effectiveness. A controlled prospective study will verify these results.

Mini-laparoscopic cholecystectomy vs laparoscopic cholecystectomy.

BACKGROUND: We set out to assess the safety and efficacy of mini-laparoscopic cholecystectomy (MLC) in uncomplicated situations. METHODS: MLC was performed on 30 consecutive selected patients (< 60 years old, ASA I-II, uncomplicated cholecystectomy) with one 12-mm and three 3-mm ports. The total operating time, conversion rate, degree of postoperative pain, duration of postoperative hospital stay, complications, and cosmetic results were all reviewed and compared with 30 cases of consecutive conventional laparoscopic cholecystectomy (LC). RESULTS: None of the patients in either group required conversion to open cholecystectomy. No complications were observed. The operating time and duration of hospital stay were similar in both groups. The level of postoperative pain was lower in the MLC group (p < 0.001). More patients in the MLC group expressed satisfaction with the cosmetic result (p < 0.05). CONCLUSIONS: MLC was shown to be feasible in uncomplicated situations. Furthermore, it was associated with less pain and produced better cosmetic results than conventional LC. Randomized studies are still needed to confirm these findings.