In a program aimed at the design and synthesis of novel azole inhibitors of Candida albicans CYP51 (CA-CYP51), a series of azole 1,4-benzothiazines (BT) and 1,4-benzoxazines (BO) were recently ...synthesized. A morphological study of the enzyme active site highlighted a hydrophobic access channel, and a docking study pointed out that the C-2 position of the BT or BO nucleus was oriented toward the access channel. Here, we report the design, synthesis, and microbiological evaluation of C-2-alkyl BT and BO compounds. In both series, introduction of the alkyl chain maintained and in some cases improved the anti-Candida in vitro activity; however, there was not always a strict correlation between in vitro and in vivo activity for several compounds.
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An efficient, green, and atom economic methodology for the stereoselective synthesis of C2 symmetry (3R,4R)-TTFOL diester derivatives has been developed. The procedure occurs through ...a (2R,3R)-TADDOL dioxolane cleavage and rearrangement under mild conditions by its reaction with a carboxylic acid in the presence of TFAA/H3PO4 without the need for an inert atmosphere to give generally high yields.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Aim Although extensively addressed in US registries, the utilitazion rate of Partial Nephrectomy has been poorly addressed in European settings. Our aim is to evaluate the impact of hospital ...volume on the use of PN for cT1 renal tumors. Methods 2526 patients with cT1N0M0 renal tumors treated with either PN or radical nephrectomy at 10 European centres in the last decade were included in the analysis. Joinpoint regression analysis was used to identify significant changes over time in linear slope of the trend for each center. The correlation between yearly caseload and the slopes was assessed with the non-parametric Spearman test. Coincident pairwise tests and regression analyses were used to generate and compare the trends of high-volume (HV), mid-volume (MV) and low-volume (LV) groups. Results Yearly caseload was significantly associated with increased use of PN (R=0.69, p=0.028). The utilization rate of PN was stable at LV centres (p=0.67, p=0.7, p=0.76, for cT1, cT1a, and cT1b tumors, respectively), while increased significantly at MV (p=0.002, 0.0005 and 0.007, respectively) and HV centers (all p<0.0001). Regression analysis confirmed the trends for HV and MV as significantly different from those observed in LV centres (all p≤0.002) and highlighted significant differences also between MV and HV centres (all p≤0.03). Conclusions We confirmed the association between caseload and the use of PN for cT1 tumors. Our findings suggest that a minimum caseload might turn the tide also in LV centres while a selective referral to HV centers for cT1b tumors should be considered.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background Endoscopic resection of colorectal nonpolypoid lesions requires adequate submucosal lifting of the lesion. Objective To evaluate a self-assembled hydro-jet system for tissue elevation to ...improve endoscopic resection of colorectal nonpolypoid lesions. Design Prospective study. Setting Single-center teaching hospital. Main Outcome Measurements Efficacy and safety of the hydro-jet system and rate of complete resection. Results The system was clinically applied in 31 patients to remove a total of 34 lesions throughout the colon. An adequate submucosal fluid cushion was achieved in all but 1 case without any lifting-associated complications. Complete endoscopic resection was possible in all 33 lifted lesions by using a snare. The size of the resected lesions ranged from 7 to 60 mm. Major intraprocedure bleeding occurred in only 1 case. No perforation or late bleeding was recorded. Histological examination showed a selective accumulation of fluid in the submucosa with edema and dissociation of submucosal structures, with no damage to the muscularis mucosa and very limited “burn effect” hampering assessment of radial margins. Limitations Lack of controls. Conclusions This inexpensive system allows safe and rapid submucosal lifting of colorectal nonpolypoid lesions to assist endoscopic resection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Nonylphenol polyethoxylates (A9PEs) are complex mixtures of isomers and oligomers widely used as surfactants. The weakly estrogenic effects of the A9PE breakdown products are impelling reformulation ...of many commercial products and have made “A9PE free” products an industry trend. Initial A9PE biotransformation is known to produce metabolites with shortened ethoxy chains, mainly A9PE2, and carboxylated ethoxy chains, mainly A9PE2C. Very little is known on the ultimate fate of the branched alkyl side chain. We have used liquid chroma tography−electrospray−mass spectrometry to elucidate structures of species generated from biotransformation of the branched alkyl chain. According to an OECD protocol, a laboratory A9PE biodegradation experiment was conducted. After about two weeks from the beginning of the experiment, relevant amounts of species having both side chains oxidized (CAPECs) and 3−8 carbons in the residual alkyl chain appeared in the test solution. These species were presumably generated from less extensively alkyl branched A9PEC isomers by various oxidative mechanisms. The unreacted most extensively alkyl branched A9PEC isomers disappeared from the test liquor after more than 3 months by an unknown mechanism. Less abundant, metabolites having only the alkyl chain carboxylated (CAPEs) were also formed. With time, these species were slowly transformed to CAPECs. Apart from a very slow conversion of CAPE2Cs to CAPE1Cs, this metabolite class was extremely recalcitrant to further biotransformation, as they persisted in the test liquor even more than 5 months after their generation. Analysis of a sewage treatment plant effluent showed CAPECs, as a total, were present at concentration of 58 μg/L, accounting for 63% of the total A9PE metabolites leaving the plant.
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IJS, KILJ, NUK, PNG, UL, UM
CCL21 is a homeostatic lymphoid chemokine instrumental in the recruitment and organization of T cells and dendritic cells into lymphoid T areas. In human secondary lymphoid organs (SLOs), CCL21 is ...produced by cells distributed throughout the T zone, whereas high endothelial venules (HEVs) lack CCL21 mRNA. A critical question remains whether the development of ectopic lymphoid tissue (ELT) in chronic inflammation recapitulates the features of SLOs. Thus, we systematically investigated in situ the cellular sources of CCL21 in SLOs and ELTs in several human diseases characterized by lymphoid neogenesis. By in situ hybridization and the use of combinatorial cell markers, we show that CCL21-producing vessels in inflamed tissues systematically display typical markers of lymphatic vessels, whereas, as in SLOs, ectopic HEVs do not synthesize detectable levels of CCL21. We also provide first-time evidence that a common pattern of CCL21 expression by CD45-negative myofibroblast-like cells localized in extra-HEV position and organized in a fibroblastic reticular network similarly characterizes human SLOs and organized ELTs. Altogether, our results demonstrate that in humans the pattern of CCL21 production in SLOs is maintained during inflammation and that the phenotypic and functional properties of stromal cells, found in SLO T-cell areas, are reproduced at ectopic sites.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The clinical and histopathological records of 149 consecutive patients with papillary thyroid microcarcinoma (PTMC), homogeneously studied and operated on by the same surgeon in the period 1990 to ...2001, were reviewed. After a mean 6.5-year follow-up, three cases of loco-regional recurrence (2%) were observed. These three patients had all undergone partial thyroidectomy only and tumour relapse occurred in the residual thyroid tissue. No recurrence was observed in patients treated by total thyroidectomy and I. At variance with other reported series, no lymph node recurrence was observed in our series, in particular in the group of 23 patients with evidence of nodal metastases at initial diagnosis (three of whom were revealed by I scan after surgery). Therefore, a preventive effect of I treatment in our patient population can be hypothesized. However, prolonged follow-up will be necessary to clarify this. Due to the inability of current imaging modalities to select pre-operatively PTMC patients at risk for recurrence (presence of thyroid capsular invasion, multifocality and microscopic lymph node metastases), it appears reasonable to offer the patient total thyroidectomy when a pre-operative diagnosis of PTMC is reached. Moreover, the policy of our thyroid cancer centre is that, in these patients, post-surgical I scan should be obtained in order to detect unknown metastatic deposits, and I treatment should also be considered in patients with poor clinical and histopathological prognostic factors. In contrast, in patients operated on for benign thyroid disease and with delayed diagnosis of PTMC at definitive histopathological examination, re-operation might be avoided in the presence of unifocal disease without thyroid capsular invasion and with ultrasound-‘normal’ residual thyroid tissue. Close clinical and ultrasound follow-up is recommended, especially in patients who have undergone conservative surgery only.
Paget disease (PD) is a chronic metabolically active bone disorder. The spine is the second most commonly involved site; the pathologic changes can cause back pain, myeloradiculopathy, and vertebral ...fracture. Symptomatic patients are treated medically, and surgery is required when certain complications occur. A case is presented of monostotic vertebral PD treated by percutaneous vertebroplasty (PV) with successful outcome characterized by pain relief and improved disability at 6-month follow-up. PV is proposed as a primary treatment for back pain secondary to PD when unresponsive to conservative therapy and when not associated with other complications.
BACKGROUND AND AIM:Papillary thyroid carcinoma (PTC) is universally regarded as a curable malignancy with a favorable prognosis. However, a minority of patients may present, or subsequently develop, ...locoregional and distant metastases that may adversely affect survival. The value of the various staging methods is complicated by different approaches to diagnostic, therapeutic and follow-up strategies. We aimed at assessing the prognostic factors and survival rate in a large cohort of patients treated and followed up in the same center.
MATERIALS AND METHODS:A total of 1858 patients with PTC operated on by the same surgeon, and followed in the same center over a period of 35 years, were included. Total thyroidectomy was performed in the majority of patients after I-131 diagnostic scans and thyroglobulin assays. When the latter 2 were positive, therapy with I-131 was given. Follow-up was performed periodically and further therapy doses were administered when necessary. All patients were maintained on life-long thyroxine.
RESULTS:Ninety-three patients (5%) developed evidence of locoregional or distant metastases after an average follow-up period of 7.9 years (range 1.53–30.5 years). Univariate analysis showed all variables (except for gender) to be significantly correlated with disease recurrence and survival. Multivariate analysis showed 4 variables to be significant and independent prognostic factorspatient age at first treatment, extent of disease, extent of surgery, and the presence of I-131 positive metastases.
DISCUSSION AND CONCLUSION:Our data agree with other scoring systems in that patient age at first treatment and the extent of disease are significant and independent prognostic factors. However, and at variance with other methods, we found that the extent of primary surgery and the presence of I-131 positive or negative metastases have similar prognostic significance. In high risk patients, total thyroidectomy and lymphadenectomy followed by I-131 treatment and TSH-suppressive hormonal therapy are recommended.
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