Structured robot-assisted surgery training curriculum for residents in Urology and impact on future surgical activity.

To gain insight into the availability of training for robot assisted surgery (RAS) and the possibility to perform RAS during Dutch residency curriculum and to analyze the effects on surgical skills by the introduction of an advanced course in RAS for residents. A combination of a validated snap shot survey and a prospective cohort study. Structured advanced RAS training including virtual reality (VR) simulation, dry and wet lab facility at ORSI academy (Belgium). A snap-shot survey has been sent to all the residents and specialists in Urology graduated during the years 2017-2020 in Netherlands. Among residents, only last year residents (5th and 6th year) have been considered for the RAS training. Although most of the residents (88.2%) and young urologists (95%) were asked to follow a basic training or meet basic requirements before starting RAS, the requirements set by the educators were different from center to center. Some of them were required to attend only an online course on RAS, whereas others were asked to achieve threshold scores at VR simulator and participate in a standardized course at a training institute. The attendance to a structured advanced course in RAS showed a significant increase in surgical skills. Our study shows residents in urology are allowed to perform RAS during their residency though the criteria for starting RAS differ significantly amongst the teaching hospitals. To guarantee a basic level of skills and knowledge a structured, (multi-step) training and certification program for RAS should be implemented.

Effectiveness and safety of cholinesterase inhibitors in elderly subjects with Alzheimer's disease: a "real world" study.

Clinical trials have demonstrated the efficacy of cholinesterase inhibitors (ChEI) in improving cognitive status and disability in subjects with mild to moderate Alzheimer's disease (AD). However, little is known about the effectiveness of ChEI in clinical practice, and no large clinical trials comparing different ChEI are available at present. Aim of this study was to evaluate safety and effectiveness of ChEI in a sample of elderly outpatients diagnosed with mild to moderate AD. We selected 407 subjects for ChEI treatment (donepezil,rivastigmine or galantamine). Their cognitive function was evaluated by means of the mini mental state examination (MMSE), and the global functional status was estimated by using the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales at baseline (To), then after 1 (T1), 3 (T2) and 9 months (T3), respectively. T3 follow-up was completed by 212 subjects. The patients were considered as responders (R), if the MMSEscore at T2 was unchanged or improved, if compared to that of T0. In 35 patients (8.6 %)treatment was withdrawn because of mostly gastrointestinal adverse events. Compared to the other drugs, donepezil was associated with a lower incidence of withdrawals due to adverse events. Subjects who completed T3 follow-up (age 78 +/- 6 years, MMSE scores 18.8 +/- 3.9) showed an increase at T2 of 0.7 +/- 2.7 (p = 0.001) and a decrease at T3 of -0.6 +/- 3.4 (p = 0.008) in the MMSE scores, as compared to To . The ADL and IADL scores did not show significant changes at T2; however, both decreased significantly at T3. The patients Rat-T2 showed a better cognitive and functional outcome at T3 , compared to the nonresponders(NR-at-T2), displaying values of MMSE R-at-T2 0.4 +/- 3.1 vs. NR-at-T2 -3.0 +/- 2.5, p = 0.001, and ADL values of -0.3 +/- 1.2 vs. -0.7 +/- 1.3, p = 0.03, respectively. No significant difference was found in the changes of MMSE scores between donepezil and rivastigmine (galantamine was not included in the comparison due to the small number of treated subjects). In conclusion, in this sample of elderly subjects with mild to moderate AD,treated with ChEI, a small but significant decline in cognitive and functional status was observed after 9 months. Subjects who showed a good response to treatment after 3 months, had a better cognitive and functional outcome at 9 months. No significant difference in cognitive outcome was found between drugs, while donepezil was better tolerated.

Carbonic anhydrase inhibitors: sulfonamides as antitumor agents?

Novel sulfonamide inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) were prepared by reaction of aromatic or heterocyclic sulfonamides containing amino, imino, or hydrazino moieties with N,N-dialkyldithiocarbamates in the presence of oxidizing agents (sodium hypochlorite or iodine). The N,N-dialkylthiocarbamylsulfenamido-sulfonamides synthesized in this way behaved as strong inhibitors of human CA I and CA II (hCA I and hCA II) and bovine CA IV (bCA IV). For the most active compounds, inhibition constants ranged from 10(-8) to 10(-9) M (for isozymes II and IV). Three of the derivatives belonging to this new class of CA inhibitors were also tested as inhibitors of tumor cell growth in vitro. These sulfonamides showed potent inhibition of growth against several leukemia, non-small cell lung, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines. With several cell lines. GI50 values of 10-75 nM were observed. The mechanism of antitumor action with the new sulfonamides reported here remains obscure, but may involve inhibition of CA isozymes which predominate in tumor cell membranes (CA IX and CA XII), perhaps causing acidification of the intercellular milieu, or inhibition of intracellular isozymes which provide bicarbonate for the synthesis of nucleotides and other essential cell components (CA II and CA V). Optimization of these derivatives from the SAR point of view, might lead to the development of effective novel types of anticancer agents.

Carbonic anhydrase inhibitors. metal complexes of 5-(2-chlorophenyl)-1,3,4-thiadiazole-2-sulfonamide with topical intraocular pressure lowering properties: the influence of metal ions upon the pharmacological activity.

Metal complexes of a sulfonamide possessing strong carbonic anhydrase (CA) inhibitory properties, 5-(2-chlorophenyl)-1,3,4-thiadiazole-2-sulfonamide (chlorazolamide) have been obtained from the sodium salt of the sulfonamide and the following metal ions: Mg(II), Zn(II), Mn(II), Cu(II), Co(II), Ni(II), Be(II), Cd(II), Pb(II), Al(III), Fe(III) and La(III). The original sulfonamide and its complexes were assayed for the in vitro inhibition of three CA isozymes, CA I, II, and IV, some of which play a critical role in ocular fluid secretion. All these compounds (the sulfonamide and its metal complexes) behaved as powerful inhibitors against the three investigated isozymes. The parent sulfonamide possessed an extremely weak topical pressure lowering effect when administered as a 1-2% suspension into the rabbit eye, but some of its metal complexes, such as the Mg(II), Zn(II), Mn(II) and Cu(II) derivatives, lower intraocular pressure (IOP) in experimental animals very well. Ex vivo data showed a 99.5-99.9% CA II inhibition in ocular fluids and tissues of rabbits treated with these agents, proving that the observed IOP lowering is due to CA inhibition. The influence of the different metal ions upon the efficiency of the obtained complexes as pressure lowering drugs are discussed, leading to the possibility of designing more selective/potent pharmacological agents from this class.

Regional differences in the electrically stimulated release of endogenous and radioactive adenosine and purine derivatives from rat brain slices.

The release of both radioactive and endogenous purines was investigated in rat brain cortical, hippocampal and striatal slices at rest and following stimulation with electrical fields. Purines were labelled by incubating the slices with 3H-adenine. The purine efflux at rest and that evoked by electrical stimulation (10 Hz. 5 min) was analyzed by HPLC with ultraviolet absorbance detection. Both radioactive and endogenous purines in the effluent consisted mainly of hypoxanthine, xanthine, inosine and adenosine. No qualitative differences in the composition of the released purines were found in the three areas investigated. Electrical stimulation evoked a net increase in both radioactive and endogenous purine release. However the increase in 3H-adenosine following electrical stimulation was twice as large as that of endogenous adenosine. The electrically evoked release of both radioactive and endogenous purines was greatest in hippocampal slices and progressively smaller in cortical and striatal slices. In the three areas the addition of 0.5 microM tetrodotoxin to the superfusing Krebs solution brought about a similar (83-100%) reduction in evoked 3H-purine and endogenous purine release. Superfusion of the slices with calcium-free Krebs solution containing 0.5 mM EGTA reduced evoked release of 3H-purines by 58-60% and that of endogenous purine components by 54-89%. The results demonstrate similar characteristics for both radioactive and endogenous purine release but indicate that the most recently synthetized adenosine is the most readily available for release. The features of the electrically evoked purine release support a neuronal origin of adenosine and derivatives and are consistent with the hypothesis of discrete regional differences in adenosine neuromodulation.