Chalcones induce apoptosis, autophagy and reduce spreading in osteosarcoma 3D models.

Osteosarcoma is the most common primary bone malignancy with a challenging prognosis marked by a high rate of metastasis. The limited success of current treatments may be partially attributed to an incomplete understanding of osteosarcoma pathophysiology and to the absence of reliable in vitro models to select the best molecules for in vivo studies. Among the natural compounds relevant for osteosarcoma treatment, Licochalcone A (Lic-A) and chalcone derivatives are particularly interesting. Here, Lic-A and selected derivatives have been evaluated for their anticancer effect on multicellular tumor spheroids from MG63 and 143B osteosarcoma cell lines. A metabolic activity assay revealed Lic-A, 1i, and 1k derivatives as the most promising candidates. To delve into their mechanism of action, caspase activity assay was conducted in 2D and 3D in vitro models. Notably, apoptosis and autophagic induction was generally observed for Lic-A and 1k. The invasion assay demonstrated that Lic-A and 1k possess the ability to mitigate the spread of osteosarcoma cells within a matrix. The effectiveness of chalcone as a natural scaffold for generating potential antiproliferative agents against osteosarcoma has been demonstrated. In particular, chalcones exert their antiproliferative activity by inducing apoptosis and autophagy, and in addition they are capable of reducing cell invasion. These findings suggest Lic-A and 1k as promising antitumor agents against osteosarcoma cells.

The blue globular pattern in dermoscopy.

BACKGROUND: Seborrheic keratosis (SK) is a frequent benign epithelial skin tumor. Generally its diagnosis is clinical, however SK can sometimes clinically simulate a melanocytic lesion; therefore we need dermoscopy to reach a correct diagnosis. Milia-like cysts and comedo-like openings are the common dermoscopic features of SK, but it is not a rare finding that SK can display one or more dermoscopic patterns suggestive of a melanocytic origin. OBJECTIVES: We describe a case series of SKs with a blue globular pattern simulating a melanocytic lesion. METHODS: We retrospectively evaluated 224 SKs seen during 2011 at the Dermatoscopy Unit of the Department of Dermatology, University of Rome 'Sapienza'. RESULTS: Five SKs showed a blue globular pattern, without the SK main features generally seen in dermoscopy; globules were multiple, round or oval, well-demarcated, small and medium-sized, blue-colored and equally distributed within the lesion. Histopathologic examination was consistent with acanthotic SK. CONCLUSIONS: Identification of the blue globular pattern can be helpful for the dermoscopic diagnosis of SK, especially when its common dermoscopic features are absent.

Metastatic volume: an old oncologic concept and a new prognostic factor for stage IV melanoma patients.

BACKGROUND: The last melanoma staging system of the 2009 American Joint Committee on Cancer takes into account, for stage IV disease, the serum levels of lactate dehydrogenase (LDH) and the site of distant metastases. OBJECTIVE: Our aim was to compare the significance of metastatic volume, as evaluated at the time of stage IV melanoma diagnosis, with other clinical predictors of prognosis. METHODS: We conducted a retrospective multicentric study. To establish which variables were statistically correlated both with death and survival time, contingency tables were evaluated. The overall survival curves were compared using the Kaplan-Meier method. RESULTS: Metastatic volume and number of affected organs were statistically related to death. In detail, patients with a metastatic volume >15 cm(3) had a worse prognosis than those with a volume lower than this value (survival probability at 60 months: 6.8 vs. 40.9%, respectively). The Kaplan-Meier method confirmed that survival time was significantly related to the site(s) of metastases, to elevated LDH serum levels and to melanoma stage according to the latest system. CONCLUSION: Our results suggest that metastatic volume may be considered as a useful prognostic factor for survival among melanoma patients.

The International Physical Activity Questionnaire-long form overestimates self-reported physical activity of Brazilian adults.

OBJECTIVE: To explore issues associated with measuring physical activity using the International Physical Activity Questionnaire (IPAQ)-long form in adults living in a mid-sized Brazilian city. METHODS: A stratified random sampling procedure was used to select a representative sample of adults living in Rio Claro. This yielded 1572 participants who were interviewed using the IPAQ-long form. The data were analysed using standard statistical procedures. RESULTS: Overall, 83% of men and 89% of women reported at least 150 min of combined moderate and/or vigorous physical activity per week. Reliable values of leisure and transportation-related physical activity were observed for both males and females. With regard to the household and work-related physical activity domains, both males and females reported unusually high levels of participation. CONCLUSION: The IPAQ-long form appears to overestimate levels of physical activity for both males and females, suggesting that the instrument has problems in measuring levels of physical activity in Brazilian adults. Accordingly, caution is warranted before using IPAQ data to support public policy decisions related to physical activity.

Antibacterial activity of methyl aminolevulinate photodynamic therapy in the treatment of a cutaneous ulcer.

We describe a 79-year-old female with a chronic venous ulceration infected by Staphylococcus aureus and Enterococcus faecalis and not responsive to conventional treatments. The patient was treated with Methyl-Aminolaevulinate Photodynamic Therapy (MAL-PDT). After four weeks the cutaneous swabs become negative and we observed a significant clinical improvement. Therefore we suppose that MALPDT could represent a valid therapeutic option in the treatment of infected chronic ulcers.

Consensus conference on laparoscopic appendectomy: development of guidelines.

AIM: Laparoscopic appendectomy (LA) is not yet unanimously considered the gold standard treatment for appendicitis, despite the increasing use of advanced laparoscopic operations and the high incidence of the disease. METHOD: Due to the results of an audit which classified LA as widespread in Italy, a Consensus Conference was organized, in order to give evidence-based answers to the most debated problems regarding the operation. After researching the literature, a panel of 20 experts were selected and interviewed on hot topics; a subsequent discussion using the Delphi methodology was utilized in the course of the consensus conference and submitted to the evaluation of an audience of surgeons. RESULTS: Checkpoint statements were formulated whenever an agreement was reached. A level of evidence was then assigned to single statements and the process revised by two external reviewers. CONCLUSION: Consensus development guidelines are herein reported and regard diagnostic pathway, diagnostic laparoscopy, indications, behaviour in case of innocent appendix, technical aspects, learning curve; however, some questions remain unsolved due to the lack of evidence.

Reduced Neural Satiety Responses in Women Affected by Obesity.

Overweight and obesity are major risk factors for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity rates are on the rise worldwide with women more frequently affected than men. Hedonic responses to food seem to play a key role in obesity, but the exact mechanisms and relationships are still poorly understood. In this study, we investigate the perceived pleasantness of food rewards in relation to satiety and calories consumed during an ad libitum meal in women. Using functional magnetic resonance imaging (fMRI) and a milkshake consumption task, we studied how experienced food values are encoded in women with healthy weight, overweight or obesity. Participants rated the pleasantness and intensity of high and low caloric milkshakes in the fMRI scanner during both the fasted and fed states. We found differences in the neural responses and experienced pleasantness of high and low caloric milkshakes depending on satiety and Body Mass Index (BMI). Women with both high ad libitum consumption levels and high BMI reported greater experienced pleasantness for milkshakes. In contrast, among women with low ad libitum consumption levels, greater BMI was associated with less experienced pleasantness. At the neural level, satiety affected women with obesity to a lesser degree than women with healthy weight. Thus, having obesity was associated with altered relationships between food consumption and the hedonic responses to food rewards as well as reduced satiety effects in women.

Bromhidrosis induced by sphingomonas paucimobilis: a case report.

Bromhidrosis is a clinical disorder characterized by excessive or abnormal foul axillary odour due to the interaction of apocrine glands with micro-organisms which causes a serious personal and social handicap for affected people. We present the case of a 50-year-old caucasian female with bromhidrosis. The patient referred that this symptom had begun two months previously. Her past treatments included antibacterial soap, topical antibacterial agents and perfumes, but none of these relieved the patient of the odour. A cultural examination of axillary smear was carried out and it revealed the presence of ciprofloxacin sensible Sphingomonas paucimobilis. Therefore the patient was treated with ciprofloxacin and after 1 week the infection resolved completely.

[Depressive symptoms and motor condition in Parkinson's disease patients]. / Síntomas depresivos y trastorno motor en pacientes con enfermedad de Parkinson.

INTRODUCTION: Complex relations between brain and psychopathology have attracted the interest of researchers, aiming to clarify the neurobiological mechanisms of depression in Parkinson's disease, obviously in addiction to mental features. AIMS: The association of motor impairment and decline of personal autonomy with severity of depressive symptoms was the hypothesis of the present study. Aiming to check this hypothesis, the objective of this study consisted in investigating relationships between the severity of depressive symptoms and motor characteristics of Parkinson's disease. PATIENTS AND METHODS: Thirty patients (53 to 80 year-old) with medical diagnosis of idiopathic Parkinson's disease in initial clinic stages were studied. The Unified Parkinson's Disease Rating Scale, Hoehn-Yahr Scale, and Schwab & England Scale were used to assess the clinic signs and symptoms. The depressive symptoms were identified by complete anamnesis, examination of mental condition, and the Hamilton Rating Scale for Depression and the Anxiety and Depression Scale. Statistical analysis was performed by Pearson's correlation and multiple regression analysis. RESULTS: A significant correlation of severity of depression symptoms with disease stage (p < 0.02), with motor signs (p < 0.008), and with functional performance (p < 0.007) was found. CONCLUSION: There was significant association between motor impairment and severity of depressive symptoms, and between depression and early disease onset or prolonged duration of Parkinson's disease.

SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues.

In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3, 4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4-tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.

Acetylcholinesterase inhibitors: SAR and kinetic studies on omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl derivatives.

In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure-activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC(50) value for the AChE inhibition of 0.32 +/- 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC(50) value of 3.3 +/- 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.

A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase.

Aromatase (P450arom) is a target of pharmacological interest for the treatment of breast cancer. In this paper, we report the design, synthesis, and in vitro biological evaluation of a series of new (di)benzopyranone-based inhibitors of this enzyme. The design of the new compounds was guided by a CoMFA model previously developed for a series of nonsteroidal aromatase inhibitors. Both the chromone and the xanthone nuclei were taken as molecular skeletons, and the functions supposed to be critical for binding to the aromatase active site - a heterocyclic ring (imidazole or 1,3,4-triazole) linked to the aromatic moiety by a methylene unit and an H-bond accepting function (CN, NO(2), Br) located on the aromatic ring at a suitable distance from the heterocyclic nitrogen carrying the lone pair--were attached to them. The chromone, xanthone, and flavone derivatives were prepared by conventional synthetic methods from the appropriate methyl analogues. Aromatase inhibitory activities were determined by the method of Thompson and Siiteri, using human placental microsomes and [1 beta,2 beta-(3)H]testosterone as the labeled substrate. All the compounds were also tested on 17 alpha-hydroxylase/C17,20-lyase (P450 17), an enzyme of therapeutic interest for the treatment of prostatic diseases. The goal to find new potent inhibitors of aromatase was reached with the xanthone derivatives 22d,e (IC(50) values 43 and 40 nM, respectively), which exceeded the potency of the known reference drug fadrozole and also showed high selectivity with respect to P450 17. Moreover, compounds 22g-i based on the same xanthonic nucleus showed fairly high potency as P450 17 inhibitors (IC(50) values 220, 130, and 42 nM, respectively). Thus, they might be new leads for the development of drug candidates for androgen-dependent diseases.

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.

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.

Laparoscopic diagnosis of gallbladder agenesis.

In this article, we report two cases of gallbladder agenesis that were incorrectly diagnosed as cholelithiasis on preoperative sonography. In the first case, the diagnosis was made by laparoscopic surgery and confirmed by postoperative CT scan. The second case was confirmed by laparoscopic abdominal examination and by laparoscopic sonography. Both patients had undergone preoperative IV cholangiography. Preoperative cholangiography and laparoscopic exploration completed by laparoscopic sonography should be considered adequate modalities for the diagnosis of gallbladder agenesis, without the need for laparotomy and thorough postoperative workup.

Laparoscopically assisted treatment of acute abdomen in systemic lupus erythematosus.

The incidence of abdominal pain in patients with systemic lupus erythematosus (SLE) is very high. Most patients do not require surgical treatment (serositis). Some cases such as appendicitis, perforated ulcer, cholecystitis or, rarely, intestinal infarction are surgical. Differential diagnosis is difficult, partly because noninvasive examinations do not provide enough evidence to rule out a diagnosis. On the other hand, in patients with SLE who have acute abdomen, it is dangerous to delay surgery by attempting conservative therapy. In fact, a better survival rate has been associated with early laparotomy. We report a case of acute abdomen in a patient affected by SLE, in which the diagnostic problem was solved by means of laparoscopy and the treatment was laparoscopically assisted. A 45-year-old woman with a 25-year history of SLE was admitted with abdominal pain and fever. Her physical examination revealed a painful right iliac fossa with rebound tenderness. Her WBC count was normal. Abdominal x-ray, ultrasonography, paracentesis, and peritoneal lavage did not provide a diagnosis. A diagnostic laparoscopy was performed, showing segmentary small bowel necrosis. The incision of the umbilical port site was enlarged to allow a small laparatomy, and a small bowel resection was performed. The histopathologic finding was "leucocytoclasic vasculitis, with infarction of the intestinal wall." The patient recovered uneventfully. In conclusion, this case report shows that emergency diagnostic laparoscopy is feasible and useful for acute abdomen in SLE. Currently, this diagnostic possibility could be considered the technique of choice in these cases, partly because, when necessary, it also can allow for mini-invasive treatment therapy.

Scoring system to predict asymptomatic choledocholithiasis before laparoscopic cholecystectomy. A matched case-control study.

BACKGROUND: The purpose of this prospective study was to evaluate if a recently proposed score system based on six preoperative parameters [history of colic pain and/or jaundice, dyspepsia, cholecystitis, ultrasound (US), evidence of common bile duct stones (CBDS), number and size of gallbladder stones at US, level of serum glutamic oxalacetic transaminase and/or alkaline phosphatase is effective in the selection of patients undergoing laparoscopic cholecystectomy (LC) with asymptomatic CBDS and could allow a significant reduction of the total number of preoperative examinations. METHODS: In the case group, 408 patients were categorized into low-, medium-, and high-risk classes and underwent, respectively, no further preoperative assessment of the bile duct, intravenous cholangiography (IVC), and endoscopic retrograde cholangiography (ERC). Intraoperative cholangiography (IOC) was performed whenever the surgeon was in doubt as to biliary anatomy or bile duct clearance. These patients were compared with 408 retrospectively matched patients (control group) undergoing routine preoperative IVC and/or ERC. RESULTS: In the case group, significantly lower numbers of IVC (120 vs 392) and IOC (3 vs 16) were performed ( p < 0.005), whereas no difference in the total number of ERCs was noted. One patient in the control group had retained CBDS detected during follow-up evaluation, whereas none occurred in the case group. CONCLUSION: The proposed scoring system allows selective use of IVC, ERC, and/or IOC in patients undergoing elective LC.

Neuropathy as the only symptom of common carotid artery spontaneous rupture. Case report.

We describe a case of a false aneurysm of the common carotid artery, caused by spontaneous carotid rupture, with atypical clinical presentation. The patient came to the our Hospital complaining of left shoulder pain and functional impairment of her left arm, during the past 20 days. The diagnostic work-up, color Doppler ultrasound, MR and angiography, evidenced a cervical false aneurysm; the electromyography showed denervation of the deltoid muscle, caused by cervical nerve roots compression. The therapeutic stages were initially an endovascular stent placement; then a surgical stage with evacuation for the hematoma and reconstruction of the carotid artery with saphenous graft.

Incidental gallbladder cancer at laparoscopy: a review of two cases.

Early peritoneal seeding and trocar site metastasis from gallbladder cancer have been reported after laparoscopic cholecystectomy. Nevertheless, the role of laparoscopy in gallbladder cancer remains controversial. Two cases of early recurrence of carcinoma of the gallbladder after laparoscopic cholecystectomy are described. In the first case, the use of a gasless technique did not prevent an early, diffuse peritoneal dissemination of the disease. In the second case, despite the use of a retrieval bag to extract the gallbladder, multiple metastases around the gallbladder bed and local peritoneal seeding developed. These cases demonstrate that factors other than bile spillage, CO2 inflation, and the use of a retrieval bag are responsible for early dissemination of gallbladder cancer.

Design of multifunctional compounds for cardiovascular disease: from natural scaffolds to "classical" multitarget approach.

Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required. Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called "privileged structures". Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted.