Electrophysiological Correlates of Reward Anticipation in Subjects with Schizophrenia: An ERP Microstate Study.

The current study aimed to investigate alterations of event-related potentials (ERPs) microstate during reward anticipation in subjects with schizophrenia (SCZ), and their association with hedonic experience and negative symptoms. EEG data were recorded in thirty SCZ and twenty-three healthy controls (HC) during the monetary incentive delay task in which reward, loss and neutral cues were presented. Microstate analysis and standardized low-resolution electromagnetic tomography (sLORETA) were applied to EEG data. Furthermore, analyses correlating a topographic index (the ERPs score), calculated to quantify brain activation in relationship to the microstate maps, and scales assessing hedonic experience and negative symptoms were performed. Alterations in the first (125.0-187.5 ms) and second (261.7-414.1 ms) anticipatory cue-related microstate classes were observed. In SCZ, reward cues were associated to shorter duration and earlier offset of the first microstate class as compared to the neutral condition. In the second microstate class, the area under the curve was smaller for both reward and loss anticipation cues in SCZ as compared to HC. Furthermore, significant correlations between ERPs scores and the anticipation of pleasure scores were detected, while no significant association was found with negative symptoms. sLORETA analysis showed that hypo-activation of the cingulate cortex, insula, orbitofrontal and parietal cortex was detected in SCZ as compared to HC. Abnormalities in ERPs could be traced already during the early stages of reward processing and were associated with the anticipation of pleasure, suggesting that these dysfunctions might impair effective evaluation of incoming pleasant experiences. Negative symptoms and anhedonia are partially independent results.

8-Hydroxyquinoline-5-sulfonamides are promising antifungal candidates for the topical treatment of dermatomycosis.

AIM: The purpose of this study was to uncover insights into the mechanism of action of the 8-hydroxyquinoline derivatives PH151 and PH153. In addition, with the future perspective of developing a topical drug for the treatment of candidiasis and dermatophytosis, the antifungal activity of a nanoemulsion formulation containing the most active compound (PH151) is also presented here. METHODS AND RESULTS: Sorbitol protection assay and scanning electron microscopy indicate that the 8-hydroxyquinoline derivatives act on the cell wall of Candida sp. and dermatophytes and they inhibit the pseudohyphae formation of C. albicans. These findings demonstrate a strong effect of these compounds on C. albicans morphogenesis, which can be considered a potential mode of action for this molecule. Besides, the nanoemulsion formulation MIC values ranged from 0·5 to 4 µg ml-1 demonstrating the significant antifungal activity when incorporated into a pharmaceutical formulation. CONCLUSIONS: Taken together, the results support the potential of these molecules as promising antifungal candidates for the treatment of candidiasis and dermatophytosis. SIGNIFICANCE AND IMPACT OF THE STUDY: There is an emerging need to fill the pipeline with new antifungal drugs due to the limitations presented by the currently used drugs. In this study, we have described a novel formulation with a 8-hydroxyquinoline-5-sulfonamide derivative which has presented a great potency in providing a finished product. Furthermore, the derivative has shown a selective mechanism of action confirming its potential to be developed into a new drug candidate.

Weak-field H3O+ ion cyclotron resonance alters water refractive index.

Heretofore only observed in living systems, we report that weak-field ion cyclotron resonance (ICR) also occurs in inanimate matter. Weak magnetic field (50 nT) hydronium ICR at the field combination (7.84 Hz, 7.5 µT) markedly changes water structure, as evidenced by finding an altered index of refraction exactly at this combined field. This observation utilizes a novel technique which measures the scattering of a He-Ne laser beam as the sample is exposed to a ramped magnetic field frequency. In addition to the hydronium resonance, we find evidence of ICR coupling to a more massive structure, possibly a tetrahedral combination of three waters and a single hydronium ion. To check our observations, we extended this technique to D2O, successfully predicting the specific ICR charge-to-mass ratio for D3O+ that alters the index of refraction.

Lorentz force in water: evidence that hydronium cyclotron resonance enhances polymorphism.

There is an ongoing question regarding the structure forming capabilities of water at ambient temperatures. To probe for different structures, we studied effects in pure water following magnetic field exposures corresponding to the ion cyclotron resonance of H3O(+). Included were measurements of conductivity and pH. We find that under ion cyclotron resonance (ICR) stimulation, water undergoes a transition to a form that is hydroxonium-like, with the subsequent emission of a transient 48.5 Hz magnetic signal, in the absence of any other measurable field. Our results indicate that hydronium resonance stimulation alters the structure of water, enhancing the concentration of EZ-water. These results are not only consistent with Del Giudice's model of electromagnetically coherent domains, but they can also be interpreted to show that these domains exist in quantized spin states.

Cervical pessary for preterm birth prevention after an episode of arrested preterm labor: a retrospective cohort study with targeted maximum likelihood estimation of the average treatment effect.

OBJECTIVE: To evaluate whether cervical pessary effectively reduces the preterm birth < 37 weeks rate in patients who have not delivered after an episode of arrested preterm labor. PATIENTS AND METHODS: Retrospective cohort study was conducted on singleton pregnant patients admitted to our institution between January 2016 and June 2021 for threatened preterm labor and who had a cervical length < 25 mm. Women in whom a cervical pessary was placed were considered as exposed, while women in whom expectant management was preferred were considered as unexposed. The primary outcome was the rate of preterm birth before 37 weeks. A targeted maximum likelihood estimation was used to estimate the average treatment effect of cervical pessary by adjusting for a-priori-defined confounders. RESULTS: A cervical pessary was placed in 152 (36.6%) patients (exposed), while the remaining 263 (63.4%) were managed expectantly (unexposed). The adjusted average treatment effect was -14% (-18 to -11%), -17% (-20 to -13%), and -16% (-20 to -12%) for preterm birth < 37 weeks, < 34 weeks, and < 32 weeks, respectively. The average treatment effect for adverse neonatal outcomes was -7% (-8 to -5%). No difference in gestational weeks at delivery between exposed and unexposed emerged when gestational age at first admission was > 30.1 gestational weeks. CONCLUSIONS: The positioning of a cervical pessary placement may be evaluated to reduce the risk of a subsequent preterm birth after an episode of arrested preterm labor in pregnant patients with onset of symptoms before 30 gestational weeks.

Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques.

Prolonged antiretroviral therapy (ART) is not likely to eradicate human immunodeficiency virus type I (HIV-I) infection. Here we explore the effect of therapeutic immunization in the context of ART during primary infection using the simian immunodeficiency virus (SIV251) macaque model. Vaccination of rhesus macaques with the highly attenuated poxvirus-based NYVAC-SIV vaccine expressing structural genes elicited vigorous virus-specific CD4 + and CD8+ T cell responses in macaques that responded effectively to ART. Following discontinuation of a six-month ART regimen, viral rebound occurred in most animals, but was transient in six of eight vaccinated animals. Viral rebound was also transient in four of seven mock-vaccinated control animals. These data establish the importance of antiretroviral treatment during primary infection and demonstrate that virus-specific immune responses in the infected host can be expanded by therapeutic immunization.

50 Hz extremely low frequency electromagnetic fields enhance protein carbonyl groups content in cancer cells: effects on proteasomal systems.

Electromagnetic fields are an assessed cause of prolonging free radicals lifespan. This study was carried out to investigate the influence of extremely low frequency electromagnetic fields on protein oxidation and on the 20S proteasome functionality, the complex responsible for the degradation of oxidized proteins. Caco 2 cells were exposed, for 24-72 hours, to 1 mT, 50 Hz electromagnetic fields. The treatment induced a time-dependent increase both in cell growth and in protein oxidation, more evident in the presence of TPA, while no changes in cell viability were detected. Exposing the cells to 50 Hz electromagnetic fields caused a global activation of the 20S proteasome catalytic components, particularly evident at 72 hours exposure and in the presence of TPA. The finding that EGCG, a natural antioxidant compound, counteracted the field-related pro-oxidant effects demonstrates that the increased proteasome activity was due to an enhancement in intracellular free radicals.

Identification and characterization of a novel expandable adult stem/progenitor cell population in the human exocrine pancreas.

It is a general opinion that tissue-specific stem cells are present in adult tissues but their specific properties remain elusive. They are rare in tissues and heterogeneous; in addition, their identification and the characterization of their progeny has encountered technical difficulties. In particular, the existence of pancreatic stem cells remains elusive because specific markers for their identification are not available. We established a method for the isolation of a population of stem/progenitor cells from the human exocrine pancreas, and propose it as a model for other human compact organs. We also used markers that identified and finally characterized these cells. Spheroids with self-replicative potential were obtained from all specimens. The isolated population contained a subset of CD34+ CD45- cells and was able to generate, in appropriate conditions, colonies that produce insulin. We obtained evidence that most freshly isolated spheroids, when co-cultured with the c-kit positive neuroblastoma cell line LAN 5, produced a c-kit positive progeny of cells larger in their cytoplasmic content than the original spheroid population, with elongated morphology resembling the neuronal phenotype. We identified a novel predominant functional type of stem/progenitor cell within the human exocrine pancreas, able to generate insulin-producing cells and potentially non-pancreatic cells.

Clastogenicity and aneuploidy in newborn and adult mice exposed to 50 Hz magnetic fields.

PURPOSE: To detect possible clastogenic and aneugenic properties of a 50 Hz, 650 muT magnetic field. MATERIALS AND METHODS: The micronucleus test with CREST (Calcinosis, Raynaud's phenomenon, Esophageal dismotility, Sclerodactility, Telangectasia) antibody staining was performed on liver and peripheral blood sampled from newborn mice exposed to an ELF (Extremely Low Frequency) magnetic field during the whole intra-uterine life (21 days), and on bone marrow and peripheral blood sampled from adult mice exposed to the same magnetic field for the same period. RESULTS: Data obtained in newborn mice show a significant increase in micronuclei frequencies. In absolute terms, most of the induced micronuclei were CREST-negative (i.e., formed by a chromosome fragment). However, in relative terms, ELF exposure caused a two-fold increase in CREST-negative micronuclei and a four-fold increase in CREST-positive micronuclei (i.e., formed by a whole chromosome). No significant effect was recorded on exposed adults. CONCLUSIONS: These findings suggest the need for investigation of aneugenic properties of ELF magnetic fields in order to establish a possible relationship to carcinogenesis.

Delayed allergy to aminopenicillins: clinical and immunological findings.

Aminopenicillins are the most used beta-lactam antibiotics. Morbilliform or maculopapular rashes are rather frequent during therapy with aminopenicillins. The pathogenesis of these reactions is often due to a cell-mediated allergy. The aim of this work is to characterize patients with cell-mediated allergy to aminopenicillins and to identify alternative beta-lactam drugs that can be safely administered to these patients. We studied 27 subjects affected by cell-mediated allergy to aminopenicillins. The diagnosis was made on the basis of positivity of patch tests with aminopenicillins. These patients then underwent an allergological evaluation (skin and patch tests, oral and/or intramuscular challenge tests) with a wide spectrum of beta-lactam antibiotics. Our work highlights the following main characteristics of cell-mediated allergy to aminopenicillins: time elapsing between drug administration and onset of symptoms of about 2 days; the maculopapular rash and delayed appearance of urticaria/angioedema were the most typical symptoms (82.8 percent of cases); a cross-reactivity with aminocephalosporins is usually absent, or it is limited to cephalexin (in our study, in fact, just 3 out of 20 patients challenged with cephalexin showed a positive oral challenge test); all the beta-lactams, other than aminopenicillins, are well tolerated. Patch tests represent a specific diagnostic tool with a good predictive value of identifying alternative drugs that can be safely administered to patients with beta-lactam allergy. Our patients could tolerate other beta-lactam drugs after a complete allergological evaluation. On the basis of our study, cell-mediated allergy to aminopenicillins should be considered a well-defined nosologic entity.

Diagnostic value and learning curve of transbronchial needle aspiration in thoracic surgery.

AIM: Transbronchial needle aspiration (TBNA) is particularly indicated in diagnosing mediastinal masses or lymphoadenopathy proximal to the airways. Nowadays TBNA has not been widely accepted among pulmonologist and thoracic surgeons. Since its correct management could reduce patient morbidity we adopted this method. Here is presented an overview of our experience over a 18-months training period. METHODS: Fifty patients underwent TBNA. They presented non diagnosed paratracheal or peribronchial lymphadenopathy or masses of >1 cm. TBNA has been considered in order to spare patients the need for more invasive diagnostic procedures. TBNA has been performed with flexible bronchoscope and 19-gauge or 21-gauge needle. RESULTS: We made diagnosis of disease in 25 of 41 patients whose adequate sampling was obtained. 16 cases showed absence of disease despite criteria for adequacy have been confirmed, 9 cases presented an inadequate specimen. The overall diagnostic yield and sensitivity were 50% and 86%. The overall accuracy was 76%. Considering the last 6 months of the training period diagnostic yield increased from 18.7% to 88.2% (P<0.001),accuracy from 56.2% to 88.2% (P=0.04) and frequency of inadequacy decreased from 43.7% to 11.7% (P=0.046). CONCLUSIONS: TBNA resulted a successful diagnostic tool in selected cases as it is safe and permits to spare patients the need for more invasive procedures. These data revealed that experience is mandatory in order to achieve acceptable RESULTS: We think that an experienced operator should require a training period of approximately 50 procedures to obtain a good technique proficiency.

Detection of epidermal growth factor receptor mRNA in peripheral blood: a new marker of circulating neoplastic cells in bladder cancer patients.

Despite the large number of studies performed in solid tumors, few attempts at molecular detection of urothelial cells in blood have been made. Specifically, only uroplakin II (UP-II) and cytokeratin 20 (CK-20) have been suggested as tumor markers in the blood of bladder cancer patients. Epidermal growth factor receptor (EGFR) mRNA expression was found in the blood of patients with some types of carcinoma; nevertheless, its expression has been never investigated in the blood of patients with urothelial tumors. We used a EGFR-based reverse transcription-PCR assay for the detection of tumoral cells in the blood of 27 patients with bladder cancer, in 30 healthy donors, and in 9 patients with cystitis. EGFR expression was compared with that of known markers of circulating epithelial cells, CK-19 and CK-20, and to a urothelial-specific marker, UP-II. Analysis by reverse transcription-PCR and Southern blot hybridization showed no evidence of EGFR and UP-II mRNA expression in any of the samples used as controls. Analysis of healthy donors showed mRNA expression for CK-19 and CK-20 in 6 of 30 and in 4 of 30 samples, respectively. All patients with cystitis resulted negative for EGFR expression, whereas 3 of 9, 2 of 9, and 3 of 9 were found expressing CK-19, CK-20, and UP-II, respectively. Among blood samples from tumoral patients, 74% had EGFR mRNA and 41% had positive signals for CK-19, whereas positivity for CK-20 and UP-II was found in 15% and 37% of patients, respectively. These results seem to indicate that EGFR mRNA in the blood may be a useful tumor marker in bladder cancer patients, as well as in other patients with epithelial tumors.

Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer. The Italian Prostatic Cancer Project (PONCAP) Study Group.

From March 1987 to December 1990, 373 patients with stage C and D prostate cancer were randomized to receive either goserelin acetate alone or goserelin acetate plus flutamide. At a median follow-up time of 24 months, there was no significant difference in the response rate, progression-free and overall survival between the two treatment groups. In particular, median time to progression was 18 months in the goserelin arm and 24 months in the combined treatment arm (P = 0.09). However, median time to progression in stage D patients was 12 months in both treatment groups. Median time to death was 32 and 34 months, respectively. The combination regimen produced a more rapid normalisation of prostatic acid phosphatase levels and a prompt relief of bone pain. However, significantly more patients in the combination arm experienced treatment-related side-effects such as diarrhoea and increases in transaminase levels. The concurrent use of goserelin acetate and flutamide does not seem to significantly improve the results that can be achieved with goserelin acetate alone.

Radiofrequency exposure near high-voltage lines.

Many epidemiologic studies suggest a relationship between incidence of diseases like cancer and leukemia and exposure to 50/60 Hz magnetic fields. Some studies suggest a relationship between leukemia incidence in populations residing near high-voltage lines and the distance to these lines. Other epidemiologic studies suggest a relationship between leukemia incidence and exposure to 50/60 Hz magnetic fields (measured or estimated) and distance from the main system (220 or 120 V). The present work does not question these results but is intended to draw attention to a possible concurrent cause that might also increase the incidence of this disease; the presence on an electric grid of radiofrequency currents used for communications and remote control. These currents have been detected on high- and medium-voltage lines. In some cases they are even used on the main system for remote reading of electric meters. This implies that radiofrequency (RF) magnetic fields are present near the electric network in addition to the 50/60 Hz fields. This intensity of these RF fields is low but the intensity of currents induced in the human body by exposure to magnetic fields increases with frequency. Because scientific research has not yet clarified whether the risk is related to the value of magnetic induction or to the currents this kind of exposure produces in the human body, it is reasonable to suggest that the presence of the RF magnetic fields must be considered in the context of epidemiologic studies.

Detection of basic fibroblast growth factor mRNA in urinary bladder cancer: correlation with local relapses.

Natural history of bladder cancer is characterized by high risk of disease progression even for patients with a clinical diagnosis of superficial disease; in these tumors, the occurrence of local relapse is known to be dependent on the angiogenesis rate. Basic fibroblast growth factor (bFGF), has been described to be elevated in urine and serum of patients with bladder cancer. We investigated the expression of bFGF at mRNA level in a panel of 32 transitional cell tumors of the urinary bladder and in normal bladder tissues used as controls. Expression of bFGF was found elevated in most tumors of high stage, where its presence was found correlated with the occurrence of early local relapses. Furthermore, bFGF was found highly expressed in the majority of tumors showing a high bcl-2 expression rate. Our data suggest that bFGF expression could contribute to the progression of disease; it may provide a prognostic indicator in the identification of patients with high risk for occurrence of local relapses.

Follicle-stimulating hormone, testosterone, and hypoxia differentially regulate UDP-glucuronosyltransferase 1 isoforms expression in rat sertoli and peritubular myoid cells.

Uridine diphosphoglucuronosyltransferases (UGTs) are detoxifying enzymes responsible for the metabolism of endogenous and xenobiotics compounds. UGT isoforms are widely distributed in rat tissues showing a constitutive and inducible gene expression. However, little information is available concerning UGTs expression in testis. The UGT1A1, UGT1A2, and UGT1B1 mRNAs expression in whole rat testis, in Sertoli and peritubular myoid cells in basal conditions, and after hormonal and hypoxic stimulation were investigated by reverse transcriptase-polymerase chain reaction (RT-PCR). Constitutive expression of each UGT1 isoform was present in rat testis with higher levels of UGT1A2. UGT transcripts were also detected in Sertoli and peritubular myoid cells. After FSH stimulation, Sertoli cells showed an increase in UGT1B1 mRNA expression, whereas the levels of UGT1A1 and UGT1A2 resulted unmodified. The main effect induced by testosterone was a decrease of UGT1B1 mRNA expression in peritubular myoid cells, whereas in Sertoli cells an increase in UGT1A1 and UGT1B1 was observed. In hypoxic conditions, a reduction in UGTs mRNA levels was detected in both cell types. These findings suggest that rat UGT1 isoforms are regulated in testis by hormonal and environmental factors. Thus, it was speculated that alterations in UGTs expression and/or activity may be involved in the pathogenesis of testis injury.

Tumor targeting potential and metabolism of 5-[125I]iodo-2'-deoxyuridine injected intratumorally in patients with breast cancer.

We have previously demonstrated the high tumor targeting potential of the thymidine analogue 125IUdR in experimental animal models following direct intratumoral or locoregional (intracavitary) administration. The aim of the present work was to evaluate the metabolism and selectivity (based on differential cell proliferation kinetics) of 125IUdR incorporation in patients with breast cancer following a similar approach. 125IUdR (4-8 MBq) was injected intratumorally by ultrasound-guided percutaneous injection in 7 patients with breast cancer 24 hours before ablative surgery. Blood and urine samples were collected up to 72 hours after injection and analyzed by HPLC using a C18 reversed-phase column and methanol:water (20:80) as the mobile phase. Following resection, the radioactivity of the tumor and the surrounding tissues was measured in a gamma counter, and microautoradiography was performed on semithin tissue sections to determine the site of tracer incorporation at the cellular level. Activity in plasma peaked at 0.5 to 1 hour after 125IUdR injection (4.96 +/- 1.08% of injected dose/liter), declining thereafter with a mean T1/2 of 11.24 +/- 2.78 hours. By HPLC analysis, undegraded 125IUdR was about 15-30% of total plasma activity, with a biphasic pattern peaking at both 1-3 hours and approximately 12 hours. In addition to free 125I-, about 10% of early plasma activity was constituted by a labeled metabolite (tentatively identified as radio-iodouracil), rising to about 50-60% at later time points. About 70-90% of urinary radioactivity was 125I-, and 5-20% was undegraded 125IUdR in the first 24-hour samples, while the remainder was iodouracil. High tumor/nontumor ratios were obtained (mean 147.4 +/- 125.2, range 27-397) with average tumor/blood ratios at the time of surgery equal to 32.7 +/- 18.6 (range 5-56). An average 0.0244 +/- 0.0189% of the injected dose was present per gram of tumor (range 0.001-0.061% ID/g). Microautoradiography confirmed the high values of tumor/nontumor incorporation ratios and demonstrated the specificity of 125IUdR incorporation mostly in the tumor cell nuclei, with only occasional incorporation by normal-appearing tubular cells. These results suggest the potential of radiolabeled IUdR for tumor targeting in humans, to be used whenever a satisfactory route of locoregional administration allowing for homogeneous tracer distribution within the tumor mass is accessible and in the presence of favorable tumor cell proliferations kinetics.

Value of selective parathormone radioimmunoassay in primary hyperparathyroidism.

Nine cases of primary hyperparathyroidism (PHP) in patients with urinary calculi are reported and discussed. Selective venous catheterization and parathormone (PTH) radioimmunoassay confirmed the diagnosis in all cases, preoperatively discriminated between adenoma and diffuse parathyroid hyperplasia, and permitted exact preoperative localization of 5 of 7 adenomas. The interest of the urologist in PHP and the usefulness of selective PTH radioimmunoassay are discussed and emphasized.

Usefulness of preoperative transcatheter embolization in kidney tumors.

In recent years preoperative transcatheter embolization has been used widely in the management of kidney tumors. However, the effective clinical usefulness of this method has not yet been proved. Forty cases of kidney tumors treated by preoperative embolization and radical nephrectomy are reviewed and compared with a homogeneous group of patients who did not undergo preoperative embolization. Intraoperative blood loss, postoperative complication, and survival rate were statistically evaluated according to tumor stage. Advantages and disadvantages of preoperative transcatheter embolization of kidney tumors are reviewed.

Results of radical cystectomy for primary bladder cancer. Retrospective study of more than 200 cases.

During a seven-year period 202 patients with primary bladder cancer had radical cystectomy with bilateral pelvic lymphadenectomy and urinary diversion. Lymph node metastases were found in 28.7 per cent. No significant differences in overall survival owing to age were apparent. Only extension and grade of histopathologic differentiation of the tumor proved to be an important prognostic factor. The five-year survival rates for pT1, pT2, pT3, and pT4 tumors were 76, 56, 19, and 0 per cent, respectively. In patients with deep invasive (T3 and T4) tumors no significant differences of survival rate depending on N and M categories were found. Nevertheless in pT3 tumors the probability of remaining alive was significantly decreased in those patients with histologic grade 3 compared with grade 2 tumors (P less than 0.01). The prognosis for patients submitted to radical cystectomy for bladder cancer has been classified as good: tumors confined to superficial muscle (pT1 and pT2); intermediate: tumors mildly differentiated infiltrating the deep muscle (pT3/G2); fairly poor: tumors undifferentiated infiltrating deep muscle (pT3/G3); and poor: adjacent invasive bladder tumors (pT4).