Cytotoxic bastadin 24 from the Australian sponge Ianthella quadrangulata

A new cytotoxic bastadin, bastadin 24 ( 1), and the previously reported bastadins 4, 5, 6, 7, 12, 13, and 21 ( 2- 8) were isolated from a polar extract of the Australian marine sponge Ianthella quadrangulata. The planar structure of bastadin 24 ( 1) was elucidated as the 25-hydroxy derivative of bastadin 6 ( 4) by employing spectroscopic techniques (NMR, MS, UV, and IR). All isolated bastadins were evaluated for their cytotoxicity toward a panel of 36 human tumor cell lines and were found to be moderately cytotoxic. Bastadin 24 ( 1) exhibited selective cytotoxic activity toward five of the 36 investigated tumor cell lines. Bastadins 7 ( 5) and 12 ( 6) significantly inhibited the serum + hEGF-induced (human epithelial growth factor) tubular formation of human umbilical vein endothelial cells (HUVEC) at a concentration of 1 mug/mL.     

Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling

OBJECTIVE: We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP. METHOD: The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP. RESULTS: Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A>T observed in the prenatal benign form of HP and common in USA was not found in this series. CONCLUSION: The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP.     

Early onset vulvar Lichen Sclerosus in premenopausal women and oral contraceptives

OBJECTIVE: For vulvar Lichen sclerosus (LS) immunological factors, genetic predisposition, and decreased 5 alpha-reductase activity have been discussed as aetiological factors. During the last decade an increase of LS in young women has been suspected. Aim of this study was to evaluate data of premenopausal women with early onset LS to find potential risk factors focussing on the use of oral contraceptives. STUDY DESIGN: We retrospectively analyzed the data of 40 premenopausal patients with early onset LS regarding use of oral contraceptives (OCPs), and first occurrence of LS. To compare these data in a case-control study we analyzed a matched control group of 110 healthy women. RESULTS: All our LS patients were using OCPs compared to 73 women (66.4%) in the control group. OCPs with anti-androgenic activity (chlormadinone acetate, cyproterone acetate, dienogest, and drospirenone) were used by 28 (70%) of the LS patients and by 35 (47.9%) of the 73 women using OCPs in the control group. Thus, the odds ratio for early onset LS for women using anti-androgenic OCPs was 2.53 (95% CI: 1.12-5.75). CONCLUSION: Our data suggest that disturbance of the androgen dependent growth of the vulvar skin by OCPs and especially by OCPs with anti-androgenic properties might trigger the early onset of LS in a subgroup of susceptible young women.     

Brief Report: Cornelia de Lange syndrome mutations in NIPBL can impair cohesin-mediated DNA loop extrusion

Cornelia de Lange syndrome (CdLS) is a developmental multisystem disorder frequently associated with mutations in NIPBL. CdLS is thought to arise from developmental gene regulation defects, but how NIPBL mutations cause these is unknown. Here we show that several NIPBL mutations impair the DNA loop extrusion activity of cohesin. Because this activity is required for the formation of chromatin loops and topologically associating domains, which have important roles in gene regulation, our results suggest that defects in cohesin-mediated loop extrusion contribute to the etiology of CdLS by altering interactions between developmental genes and their enhancers.     

Money and trust among strangers

What makes money essential for the functioning of modern society? Through an experiment, we present evidence for the existence of a relevant behavioral dimension in addition to the standard theoretical arguments. Subjects faced repeated opportunities to help an anonymous counterpart who changed over time. Cooperation required trusting that help given to a stranger today would be returned by a stranger in the future. Cooperation levels declined when going from small to large groups of strangers, even if monitoring and payoffs from cooperation were invariant to group size. We then introduced intrinsically worthless tokens. Tokens endogenously became money: subjects took to reward help with a token and to demand a token in exchange for help. Subjects trusted that strangers would return help for a token. Cooperation levels remained stable as the groups grew larger. In all conditions, full cooperation was possible through a social norm of decentralized enforcement, without using tokens. This turned out to be especially demanding in large groups. Lack of trust among strangers thus made money behaviorally essential. To explain these results, we developed an evolutionary model. When behavior in society is heterogeneous, cooperation collapses without tokens. In contrast, the use of tokens makes cooperation evolutionarily stable.     

Bronchial carcinoid tumors: clinical and radiological correlation

PURPOSE: To evaluate the incidence of bronchial carcinoid tumor (BCT) in population affected by various lung tumors, retrospectively reviewed between 1986-2001, and to emphasize the radiographic patterns if they are characteristic. MATERIALS AND METHODS: In the above mentioned period, chest x-ray and CT were performed in 1110 patients, both male and female, affected by lung neoplasms. RESULTS: 20 patients were affected by BCT (16 males, and 13 females), aged between 26 and 75 years (mean age 57.5), with histopathologic diagnosis of typical (9 cases, 31%) and atypical (20 cases, 69%) bronchial carcinoid tumors. Localized right lung lesion were as follows: 7 cases in superior, 9 in middle and 4 in inferior lobes; in the left lung, 5 cases in superior, and 4 in inferior lobes. Size of the lesions was as average 2.4 cm in diameter (with a range of 0.5-12 cm). On x-ray and CT images, BCT appeared as a well marginated nodule, of which 9 were peripheral and 20 central. DISCUSSION AND CONCLUSION: BCT are classified as neuroendocrine carcinomas,and are divided in typical and atypical forms, with variable grade of malignancy. Central neoplasms are symptomatic due to bronchial obstruction (i.e., pneumonia, atelectasis, bronchiectasis, emphysema and/or lung abscess); if airway obstruction is partial, then cough, wheezing and recurrent pulmonary infections occur. Peripheral tumors are generally asymptomatic and they are discovered occasionally, when chest x-ray is made for other reasons. Radiographic features are similar in typical and atypical BCT. In central tumors a rounded well circumscribed hilar mass is noted, with lobulated or bumpy margins. Central cavitation is not referred to. Peripheral BCT appear as a solitary nodule, inferioer then 3 cm in size, marginated, surrounded by normal pulmonary tissue. Signs and symptoms of BCT are evasive and vague. No current clinical or laboratory procedures are useful in confirming the diagnosis; particularly, no imaging modalities are able to differentiate between BCT and other pulmonary tumors. For this reason, a clinical radiologic endoscopic and histopathologic approach is necessary. CT is more sensiticve then conventional radiography, especially in detecting small lesions, calcification and enlarged lymph nodes. MRI may be useful in those patients, who cannot tolerate IV contrast media. Scintigraphy may be employed in discovering relapses and long standing metastases.     

Endorectal coil MRI in local staging of rectal cancer

PURPOSE: The choice of the therapeutic strategies in patients affected with rectal cancer is strictly dependent by the tumor stage. So, in order to obtain an improvement in preoperative staging accuracy, new imaging modalities are now under investigation. The aim of this work is the evaluation of endorectal-coil MRI in the local staging of rectal cancer. MATERIAL AND METHODS: Fourty-three patients affected with histologically proven rectal cancer, have been evaluated by an high-field strength magnet (1.5 T). In 14/43 patients neoadjuvant pre-operative chemotherapy had been previously performed. In all cases axial SE T1w and FSE T2w sequences and coronal or sagittal FSE T2w sequences, with and without fat suppression, were performed. Basing upon the TNM staging system and the previously reported MRI signs the local extent of the tumor was evaluated, focusing about the rectal wall infiltration and the perirectal lymph nodes involvement. All the patients underwent surgery and a comparative evaluation of MRI and pathological staging was done. RESULTS: At MRI the tumor was detected in 38/43 patients. In evaluating wall infiltration the MRI results agreed with pathological results in 89% of patients and showed 92% accuracy in T1-T2 stage and 94% in T3. In evaluating perirectal lymph nodes metastases MRI showed 69% accuracy, 82% sensitivity and 55%specificity. DISCUSSION AND CONCLUSIONS: The poor accuracy of CT and body-coil MRI in evaluating wall involvement in patients with rectal cancer is mainly related to their inability to demonstrate the single layers of the rectal wall. So transrectal ultrasound is now the first choice modalitiy in local staging of rectal cancer. However transrectal ultrasound showed low sensitivity in detecting perirectal lymph nodes metastases and low accuracy in evaluating the patients previously undergone to neoadjuvant chemotherapy or radiotherapy. On the other hand the improvement of MRI sequences and the availability of the endorectal coils allowed to visualize the single layers of the rectal wall so making the endorectal-coil MRI a reliable imaging technique to stage rectal cancer. The results of our work demonstrate a good diagnostic accuracy of endorectal-coil MRI in local staging of rectal cancer, in particular the degree of rectal wall infiltration was well demonstrated, while the perirectal lymph nodes metastases were demonstrated with less accuracy. The long examination time, the costs and the movement-related artefacts are the main limits of MRI. In particular the movement-related artifacts sometime do not allow the visualization of the wall layers so lowering the diagnostic accuracy in demonstrating the tumor wall infiltration. In conclusion, even though endorectal coil MRI proved to be a reliable imaging technique in local staging of rectal cancer, at present we are not able to state what may be its real role in diagnostic evaluation of the patients with rectal cancer, in particular if compared to endorectal ultrasound. Further, comparative studies, based upon larger patients series are probably needed to draw a definitive conclusion.