Developing and validating ultrasound-based radiomics models for predicting high-risk endometrial cancer.

OBJECTIVES: The primary aim of this study was to develop and validate radiomics models, applied to ultrasound images, capable of differentiating from other cancers high-risk endometrial cancer, as defined jointly by the European Society for Medical Oncology, European Society of Gynaecological Oncology and European Society for Radiotherapy & Oncology (ESMO-ESGO-ESTRO) in 2016. The secondary aim was to develop and validate radiomics models for differentiating low-risk endometrial cancer from other endometrial cancers. METHODS: This was a multicenter, retrospective, observational study. From two participating centers, we identified consecutive patients with histologically confirmed diagnosis of endometrial cancer who had undergone preoperative ultrasound examination by an experienced examiner between 2016 and 2019. Patients recruited in Center 1 (Rome) were included as the training set and patients enrolled in Center 2 (Milan) formed the external validation set. Radiomics analysis (extraction of a high number of quantitative features from medical images) was applied to the ultrasound images. Clinical (including preoperative biopsy), ultrasound and radiomics features that were statistically significantly different in the high-risk group vs the other groups and in the low-risk group vs the other groups on univariate analysis in the training set were considered for multivariate analysis and for developing ultrasound-based machine-learning risk-prediction models. For discriminating between the high-risk group and the other groups, a random forest model from the radiomics features (radiomics model), a binary logistic regression model from clinical and ultrasound features (clinical-ultrasound model) and another binary logistic regression model from clinical, ultrasound and previously selected radiomics features (mixed model) were created. Similar models were created for discriminating between the low-risk group and the other groups. The models developed in the training set were tested in the validation set. The performance of the models in discriminating between the high-risk group and the other groups, and between the low-risk group and the other risk groups for both validation and training sets was compared. RESULTS: The training set comprised 396 patients and the validation set 102 patients. In the validation set, for predicting high-risk endometrial cancer, the radiomics model had an area under the receiver-operating-characteristics curve (AUC) of 0.80, sensitivity of 58.7% and specificity of 85.7% (using the optimal risk cut-off of 0.41); the clinical-ultrasound model had an AUC of 0.90, sensitivity of 80.4% and specificity of 83.9% (using the optimal cut-off of 0.32); and the mixed model had an AUC of 0.88, sensitivity of 67.3% and specificity of 91.0% (using the optimal cut-off of 0.42). For the prediction of low-risk endometrial cancer, the radiomics model had an AUC of 0.71, sensitivity of 65.0% and specificity of 64.5% (using the optimal cut-off of 0.38); the clinical-ultrasound model had an AUC of 0.85, sensitivity of 70.0% and specificity of 80.6% (using the optimal cut-off of 0.46); and the mixed model had an AUC of 0.85, sensitivity of 87.5% and specificity of 72.5% (using the optimal cut-off of 0.36). CONCLUSIONS: Radiomics seems to have some ability to discriminate between low-risk endometrial cancer and other endometrial cancers and better ability to discriminate between high-risk endometrial cancer and other endometrial cancers. However, the addition of radiomics features to the clinical-ultrasound models did not result in any notable increase in performance. Other efficacy studies and further effectiveness studies are needed to validate the performance of the models. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Comparison between MIBI-based radiopharmaceuticals for parathyroid scintigraphy: quantitative evaluation and correlation with clinical-laboratory parameters.

OBJECTIVE: Parathyroid scintigraphy is mandatory for the identification of hyperfunctioning parathyroid glands in hyperparathyroidism (HPT). The use of 99mTc-methoxy-isobutyl-isonitrile (MIBI) as radiopharmaceutical for parathyroid scintigraphy is considered the most valid and useful considering its uptake mechanism. Several MIBI-based radiopharmaceuticals are commercially available (i.e., MediMIBI, TechneMIBI, Stamicis). They seem to have similar physico-chemical characteristics and the choice between them is based on commercial criteria, even though some differences in qualitative scintigraphic results have been appreciated. Aims of the study were: first, to compare the scintigraphic quantitative data of MediMIBI, TechneMIBI, and Stamicis, particularly in the view of a personalized medicine approach; second, to investigate the potential effect of clinical-laboratory data on image quality using one of these radiopharmaceuticals. METHODS: Patients with diagnosis of HPT, who underwent a parathyroid scintigraphy using one of the three MIBI-based radiopharmaceuticals between December 2018 and October 2020, have been retrospectively identified. Parameters derived from regions of interest (ROIs) drawn on three different sites were obtained: a reasonable parathyroid lesion detected, an area in the lateral neck considered as the background, and the hepatic dome as the site of MIBI physiological uptake. Laboratory and clinical data, such as serum calcium, PTH, vitamin D, and creatinine levels, as well as possible drug-mediated interferences were considered. RESULTS: Among 250 patients included, 83 (33.2%) had the parathyroid scintigraphy using MediMIBI, 84 (33.6%) using TechneMIBI and 83 (33.2%) using Stamicis. The ROIs on the parathyroid uptake at early images, on the background, and on the hepatic dome were statistically different among the three groups (p < 0.05). No significant differences were found in the remaining semi-quantitative parameters among the three groups, not even considering clinical-laboratory data. CONCLUSIONS: Some differences in semi-quantitative parameters emerged among MIBI-based radiopharmaceuticals for parathyroid scintigraphy. This might justify the different qualitative scintigraphic results obtained using one or another of the cited radiopharmaceuticals.

Minimally Invasive Approaches in Locally Advanced Cervical Cancer Patients Undergoing Radical Surgery After Chemoradiotherapy: A Propensity Score Analysis.

PURPOSE: Chemoradiation (CT/RT) followed by radical surgery (RS) may play a role in locally advanced cervical cancer (LACC) patients with suboptimal response to CT/RT or in low-income countries with limited access to radiotherapy. Our aim is to evaluate oncological and surgical outcomes of minimally invasive radical surgery (MI-RS) compared with open radical surgery (O-RS). PATIENTS AND METHODS: Data for stage IB2-IVA cervical cancer patients managed by CT/RT and RS were retrospectively analyzed. RESULTS: Beginning with 686 patients, propensity score matching resulted in 462 cases (231 per group), balanced for FIGO stage, lymph node status, histotype, tumor grade, and clinical response to CT/RT. The 5-year disease-free survival (DFS) was 73.7% in the O-RS patients and 73.0% in the MI-RS patients (HR 1.034, 95% CI 0.708-1.512, p = 0.861). The 5-year locoregional recurrence rate was 12.5% (O-RS) versus 15.2% (MI-RS) (HR 1.174, 95% CI 0.656-2.104, p = 0.588). The 5-year disease-specific survival (DSS) was 80.4% in O-RS patients and 85.3% in the MI-RS group (HR 0.731, 95% CI 0.438-1.220, p = 0.228). Estimated blood loss was lower in the MI-RS group (p < 0.001), as was length of hospital stay (p < 0.001). Early postoperative complications occurred in 77 patients (33.3%) in the O-RS group versus 88 patients (38.1%) in the MI-RS group (p = 0.331). Fifty-six (24.2%) patients experienced late postoperative complications in the O-RS group, versus 61 patients (26.4%) in the MI-RS group (p = 0.668). CONCLUSION: MI-RS and O-RS are associated with similar rates of recurrence and death in LACC patients managed by surgery after CT/RT. No difference in early or late complications was reported.

Fusion imaging in preoperative assessment of extent of disease in patients with advanced ovarian cancer: feasibility and agreement with laparoscopic findings.

OBJECTIVES: Fusion imaging is an emerging technique that combines real-time ultrasound examination with images acquired previously using other modalities, such as computed tomography (CT), magnetic resonance imaging and positron emission tomography. The primary aim of this study was to evaluate the feasibility of fusion imaging in patients with suspicion of ovarian or peritoneal cancer. Secondary aims were: to compare the agreement of findings on fusion imaging, CT alone and ultrasound imaging alone with laparoscopic findings, in the assessment of extent of intra-abdominal disease; and to evaluate the time required for the fusion imaging technique. METHODS: Patients with clinical and/or radiographic suspicion of advanced ovarian or peritoneal cancer who were candidates for surgery were enrolled prospectively between December 2019 and September 2020. All patients underwent a CT scan and ultrasound and fusion imaging to evaluate the presence or absence of the following abdominal-cancer features according to the laparoscopy-based scoring model (predictive index value (PIV)): supracolic omental disease, visceral carcinomatosis on the liver, lesser omental carcinomatosis and/or visceral carcinomatosis on the lesser curvature of the stomach and/or spleen, involvement of the paracolic gutter(s) and/or anterior abdominal wall, involvement of the diaphragm and visceral carcinomatosis on the small and/or large bowel (regardless of rectosigmoid involvement). The feasibility of the fusion examination in these patients was evaluated. Agreement of each imaging method (ultrasound, CT and fusion imaging) with laparoscopy (considered as reference standard) was calculated using Cohen's kappa coefficient. RESULTS: Fifty-two patients were enrolled into the study. Fusion imaging was feasible in 51 (98%) of these patients (in one patient, it was not possible for technical reasons). Two patients were excluded because laparoscopy was not performed, leaving 49 women in the final analysis. Kappa values for CT, ultrasound and fusion imaging, using laparoscopy as the reference standard, in assessing the PIV parameters were, respectively: 0.781, 0.845 and 0.896 for the great omentum; 0.329, 0.608 and 0.847 for the liver surface; 0.472, 0.549 and 0.756 for the lesser omentum and/or stomach and/or spleen; 0.385, 0.588 and 0.795 for the paracolic gutter(s) and/or anterior abdominal wall; 0.385, 0.497 and 0.657 for the diaphragm; and 0.336, 0.410 and 0.469 for the bowel. The median time needed to perform the fusion examination was 20 (range, 10-40) min. CONCLUSION: Fusion of CT images and real-time ultrasound imaging is feasible in patients with suspicion of ovarian or peritoneal cancer and improves the agreement with surgical findings when compared with ultrasound or CT scan alone. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Neuropsychological profiles in children and young adults with spina bifida.

PURPOSE: A total of 43 Italian children, aged between 6 and 16 years, diagnosed with spina bifida, myelomeningocele, and shunted hydrocephalus have been described clinically and completed a neuropsychological battery in order to evaluate their cognitive, personality, and behavior profile. METHODS: Enrolled children underwent cognitive assessment by means of the Weschler WISC-IV cognitive test and assessment of the attention sustained through the LEITER test. In addition, parents were asked, in order to obtain a personality and behavior profile of the children, to fill in a "CBCL 6-18 years" questionnaire and to fill in a Barthel Index questionnaire. RESULTS: Processing Speed Index of the WISC-IV QI scale was statistically significant (p = 0.027), with the highest value presented by autonomous patients (95.8 ± 12.8) and the lowest by patients using a wheelchair (75.5 ± 19). WISC-IV QI mean value is 98 (±15.7) for lipoma patients and 78.7 (±17.6) for LMMC and MMC patients (p = 0.001). In more detail, Perceptual Reasoning (p < 0.0005), Working Memory (p = 0.01), and Processing Speed Index (p = 0.001) highlighted a significant difference between the groups. The attention sustained subscale of the LEITER presented a mean of 6.9 (±3.1) for lipoma patients and a men value of 4.6 (±3.1) for LMMC and MMC patients (p = 0.024). Patients with hydrocephalus had statistically significant worse cognition and autonomy (Barthel Index) score (p < 0.001) compared with those without hydrocephalus, and normal scores regarding attention and depression scales. CONCLUSION: These results can be useful in planning dedicated therapeutic protocols such as suitable rehabilitation treatments, speech therapy, psychomotor skills, and cognitive enhancement and to develop prevention protocols particularly tailored for children with hydrocephalus who appear to have the more deficient skills.

Efficacy of Sphinkeeper™ implant in treating faecal incontinence.

The primary aim of this prospective study was to assess the efficacy of Sphinkeeper™ (SK) implantation in patients with faecal incontinence. Forty-two patients with faecal incontinence (14 with sphincter defects) underwent SK implantation and were followed up for a mean(s.d.) of 15·9(8·6) months. SK implantation was a safe and effective method that improved patients' quality of life. Implants and incontinence.

Unexpectedly Large Electron Correlation Measured in Auger Spectra of Ferromagnetic Iron Thin Films: Orbital-Selected Coulomb and Exchange Contributions.

A set of electron-correlation energies as large as 10 eV have been measured for a magnetic 2 ML Fe film deposited on Ag(001). By exploiting the spin selectivity in angle-resolved Auger-photoelectron coincidence spectroscopy and the Cini-Sawatzky theory, the core-valence-valence Auger spectrum of a spin-polarized system have been resolved: correlation energies have been determined for each individual combination of the two holes created in the four subbands involved in the decay: majority and minority spin, as well as e_{g} and t_{2g}. The energy difference between final states with parallel and antiparallel spin of the two emitted electrons is ascribed to the spin-flip energy for the final ion state, thus disentangling the contributions of Coulomb and exchange interactions.

Ovarian hyperstimulation syndrome: pathophysiology, staging, prediction and prevention.

OBJECTIVE: To identify, appraise and summarize the current evidence regarding the pathophysiology, staging, prediction and prevention of ovarian hyperstimulation syndrome (OHSS). METHODS: Two comprehensive systematic reviews were carried out: one examined methods of predicting either high ovarian response or OHSS and the other examined interventions aimed at reducing the occurrence of OHSS. Additionally, we describe the related pathophysiology and staging criteria. RESULTS: Seven studies examining methods of predicting OHSS and eight more examining methods of predicting high ovarian response to controlled ovarian stimulation were included. Current evidence shows that the best methods of predicting high response are antral follicle count and anti-Müllerian hormone levels, and that a high ovarian response (examined by the number of large follicles, estradiol concentration or the number of retrieved oocytes) is the best method of predicting the occurrence of OHSS. Ninety-seven randomized controlled trials examining the effect of several interventions for reducing the occurrence of OHSS were included. There was high-quality evidence that replacing human chorionic gonadotropin by gonadotropin-releasing hormone agonists or recombinant luteinizing hormone, and moderate-quality evidence that antagonist protocols, dopamine agonists and mild stimulation, reduce the occurrence of OHSS. The evidence for the effect of the other interventions was of low/very low quality. Additionally, we identified and described 12 different staging criteria. CONCLUSIONS: There are useful predictive tools and several preventive interventions aimed at reducing the occurrence of OHSS. Acknowledging and understanding them are of crucial importance for planning the treatment of, and, ultimately, eliminating, OHSS while maintaining high pregnancy rates.

Reentrant surface anisotropy in the antiferromagnetic/ferromagnetic bilayer Mn/Co/Cu(001).

We investigated the magnetic anisotropy energy of monatomic surface-step atoms in antiferromagnetic/ferromagnetic (AF/FM) epitaxial Mn/Co bilayers grown on vicinal Cu(001) surfaces. The step-induced anisotropy of the Co/Cu(001) films was quenched upon submonolayer Mn deposition, but a reentrant uniaxial surface anisotropy was observed for Mn thickness (tMn) between 1 and 2 monolayers, which disappears for Mn thickness above 2 monolayers. In the Mn/Co/Cu(001) system, Mn films undergo a tMn-dependent transition from FM to AF in the 1-2 Mn monolayer thickness range, which entails the coexistence of FM and AF Mn phases in the film. The observation of a sizeable uniaxial anisotropy exclusively in the Mn-thickness range of coexistence of the FM and AF phases points out the crucial role of the boundaries between FM and AF regions within the Mn film. A symmetry-breaking mechanism of a magnetic type, rather than a purely geometric one, is therefore proposed as the origin of the reentrant anisotropy.

Analysis of the learning process for laparoscopic sleeve gastrectomy: CUSUM-curve of 110 consecutive patients with 1-year follow-up.

INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) is the most popular bariatric procedure worldwide. A tremendous recent increase in the number of LSGs has not been driven by an accurate learning process, especially in low volume bariatric centers. The cumulative-sum (CUSUM) method is an effective analysis of the learning process, taking intraoperative and postoperative variables into account. This study was aimed at establishing a CUSUM learning curve for LSG in order to define the number of procedures needed to achieve sufficient surgical skill. METHODS: All LSGs performed by a single general surgeon between September 2014 and November 2017 were considered. We hypothesized that the key t variables related to the LSG learning process (LP) are: operative time (OT), intraoperative complications or difficulties, need for expert assistance, length of hospital stay (LOS), and 3-month postoperative morbidity. All of these parameters are binary variables analyzed with the risk-adjusted CUSUM method. Two groups, learning group (LG) and experienced group (EG), were identified and compared by univariate analysis. Multivariate analysis was performed to identify the variables most closely associated with operative time and surgical success. One-year weight loss outcomes were likewise analyzed. RESULTS: One hundred and ten (110) consecutive LSGs were considered. CUSUM-LSG showed that the mean number of consecutive interventions necessary to reach proficiency in LSG was 58. In multivariate analysis, surgical success was negatively correlated with longer operative time and need for expert assistance. Body mass index was not correlated with surgical success. CONCLUSION: Fifty-eight LSG procedures were required to achieve surgical skill. Operative time and the need for expert assistance were variables most closely associated with surgical success. ACGME COMPETENCY: Practice-based learning and improvement.

4K versus 3D total laparoscopic hysterectomy by resident in training: a prospective randomised trial.

Background: The introduction of ultra-high-definition laparoscopic cameras (4K), by providing stronger monocular depth perception, could challenge the existing 3D technology. There are few available studies on this topic, especially in gynaecological setting. Objectives: Prospective, single institution, randomised clinical trial (NCT04209036). Materials and Methods: The two laparoscopes utilised were the 0°ULTRA Telescopes with 4K technology and the 0°3D-HD by Olympus. The surgeons were all trainees and in their last year of residency and who had obtained the certificate of first or second level of the Gynaecological Endoscopic Surgical Education and Assessment program - GESEA program. Twenty-nine patients with benign uterine pathology were enrolled. Main outcome measures: To compare if the use three-dimensional (3D) versus ultra-high-definition laparoscopic vision system (4K) for total laparoscopic hysterectomy performed by trainees was associated with a shorter operative time. Results: The 3D vision system did not prove to be superior to the 4K vision system. Operators reported significantly more vision-related side effects when using 3D than 4K. Completing the GESEA training program was the only factor with a positive and statistically significant impact on the overall time of the procedure, especially when greater dexterity and tissue handling were required. Conclusions: Neither technology used proved superior to the other, although operators showed a preference for 4K over 3D due to the lower number of visual side effects. Attendance at courses on laparoscopic simulators and training programs allowed trainees to demonstrate excellent surgical skills.

Expression of layer-specific markers in the adult neocortex of BCNU-Treated rat, a model of cortical dysplasia.

The experimental model of cortical dysplasia (CD) obtained by administering carmustine (1-3-bis-chloroethyl-nitrosurea [BCNU]) in pregnant rat uterus mimics the histopathological abnormalities observed in human CD patients: altered cortical layering, and presence of heterotopia and dysmorphic/heterotopic neurons. To investigate further the cortical layering disruption and the neuronal composition of heterotopia in BCNU-exposed cortex, we analyzed the expression pattern of the transcription factors Nurr1, Er81, Ror-beta, and Cux2 (respectively specific markers of layers VI, V, IV and superficial layers) in the cortical areas of BCNU-treated rats by means of in situ hybridization, and compared the findings with those observed in adult control rats. Combining in situ hybridization and immunohistochemistry we also investigated the origin of dysmorphic or heterotopic neurons. The main results of the present study are (i) the analysis of cortical layer thickness revealed that the cortical thinning in the BCNU model was prevalently restricted to the superficial layers; (ii) in cortical and periventricular heterotopia, the prevalent presence of superficial layer neurons in the internal areas, and deeper layer neurons in a more peripheral region, demonstrated a rudimentary pattern of laminar organization in nodule formation; and (iii) the Er81 signal in the dysmorphic and heterotopic pyramidal neurons located in layers I/II showed that they belong to layer V. These results shed light on the disorganization of the laminar architecture of the BCNU model by providing correlations with normal cortical layering and revealing the ontogenesis of heterotopia and heterotopic/dysmorphic neurons. They also provide strong evidence of the usefulness of layer-specific markers in investigating the neuropathology of CD, thus opening up the possibility of expanding their application to human neuropathology.

Growth dynamics of L-cysteine SAMs on single-crystal gold surfaces: a metastable deexcitation spectroscopy study.

We report on a metastable deexcitation spectroscopy investigation of the growth of L-cysteine layers deposited under UHV conditions on well-defined Au(110)- (1 × 2) and Au(111) surfaces. The interaction of He(*) with molecular orbitals gave rise to well-defined UPS-like Penning spectra which provided information on the SAM assembly dynamics and adsorption configurations. Penning spectra have been interpreted through comparison with molecular orbital DFT calculations of the free molecule and have been compared with XPS results of previous works. Regarding adsorption of first-layer molecules at room temperature (RT), two different growth regimes were observed. On Au(110), the absence of spectral features related to orbitals associated with SH groups indicated the formation of a compact SAM of thiolate molecules. On Au(111), the data demonstrated the simultaneous presence, since the early stages of growth, of strongly and weakly bound molecules, the latter showing intact SH groups. The different growth mode was tentatively assigned to the added rows of the reconstructed Au(110) surface which behave as extended defects effectively promoting the formation of the S-Au bond. The growth of the second molecular layer was instead observed to proceed similarly for both substrates. Second-layer molecules preferably adopt an adsorption configuration in which the SH group protrudes into the vacuum side.

Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines.

Identification of genetic copy number changes in glial tumors is of importance in the context of improved/refined diagnostic, prognostic procedures and therapeutic decision-making. In order to detect recurrent genomic copy number changes that might play a role in glioma pathogenesis and/or progression, we characterized 25 primary glioma cell lines including 15 non glioblastoma (non GBM) (I-III WHO grade) and 10 GBM (IV WHO grade), by array comparative genomic hybridization, using a DNA microarray comprising approx. 3500 BACs covering the entire genome with a 1 Mb resolution and additional 800 BACs covering chromosome 19 at tiling path resolution. Combined evaluation by single clone and whole chromosome analysis plus 'moving average (MA) approach' enabled us to confirm most of the genetic abnormalities previously identified to be associated with glioma progression, including +1q32, +7, -10, -22q, PTEN and p16 loss, and to disclose new small genomic regions, some correlating with grade malignancy. Grade I-III gliomas exclusively showed losses at 3p26 (53%), 4q13-21 (33%) and 7p15-p21 (26%), whereas only GBMs exhibited 4p16.1 losses (40%). Other recurrent imbalances, such as losses at 4p15, 5q22-q23, 6p23-25, 12p13 and gains at 11p11-q13, were shared by different glioma grades. Three intervals with peak of loss could be further refined for chromosome 10 by our MA approach. Data analysis of full-coverage chromosome 19 highlighted two main regions of copy number gain, never described before in gliomas, at 19p13.11 and 19q13.13-13.2. The well-known 19q13.3 loss of heterozygosity area in gliomas was not frequently affected in our cell lines. Genomic hotspot detection facilitated the identification of small intervals resulting in positional candidate genes such as PRDM2 (1p36.21), LRP1B (2q22.3), ADARB2 (10p15.3), BCCIP (10q26.2) and ING1 (13q34) for losses and ECT2 (3q26.3), MDK, DDB2, IG20 (11p11.2) for gains. These data increase our current knowledge about cryptic genetic changes in gliomas and may facilitate the further identification of novel genetic elements, which may provide us with molecular tools for the improved diagnostics and therapeutic decision-making in these tumors.

GABA immunoreactivity in the developing rat thalamus and Otx2 homeoprotein expression in migrating neurons.

We investigated the expression of gamma-aminobutyric acid (GABA) in the developing rat thalamus by immunohistochemistry, using light, confocal and electron microscopy. We also examined the relationship between the expression of the homeoprotein Otx2, a transcription factor implicated in brain regionalization, and the radial and non-radial migration of early generated thalamic neurons, identified by the neuronal markers calretinin (CR) and GABA. The earliest thalamic neurons generated between embryonic days (E) 13 and 15 include those of the reticular nucleus, entirely composed by GABAergic neurons. GABA immunoreactivity appeared at E14 in immature neurons and processes laterally to the neuroepithelium of the diencephalic vesicle. The embryonic and perinatal periods were characterized by the presence of abundant GABA-immunoreactive fibers, mostly tangentially oriented, and of growth cones. At E15 and E16, GABA was expressed in radially and non-radially oriented neurons in the region of the reticular thalamic migration, between the dorsal and ventral thalamic primordia, and within the dorsal thalamus. At these embryonic stages, some CR- and GABA-immunoreactive migrating-like neurons, located in the migratory stream and in the dorsal thalamus, expressed the homeoprotein Otx2. In the perinatal period, the preponderance of GABAergic neurons was restricted to the reticular nucleus and several GABAergic fibers were still detectable throughout the thalamus. The immunolabeling of fibers progressively decreased and was no longer visible by postnatal day 10, when the adult configuration of GABA immunostaining was achieved. These results reveal the spatio-temporal features of GABA expression in the developing thalamus and suggest a novel role of Otx2 in thalamic cell migration.

Distinct expression pattern of microtubule-associated protein/microtubule affinity-regulating kinase 4 in differentiated neurons.

Protein kinases of the microtubule affinity-regulating kinase (MARK) family were originally discovered because of their ability to phosphorylate tau protein and related microtubule-associated proteins (MAPs), and their role in the establishment of cell polarity in different contexts. Recent papers have indicated that microtubule affinity-regulating kinase 4 (MARK4) is a gene that is finely regulated at transcriptional level and expressed in two spliced isoforms called MARK4L and MARK4S. We here describe the characterization of the mouse orthologue of the human MARK4 gene. Interestingly, MARK4S is predominantly expressed in the brain, whereas MARK4L shows lower transcript levels in this organ. Using MARK4 antibodies specific for each isoform, we found that both isoforms have an identical expression pattern in the mouse CNS, and are present in a number of neuronal populations. We also found that human microtubule affinity-regulating kinase 4S (hMARK4S), whose expression is not detectable in human neural progenitor cells (HNPCs) and NTera2 (NT2) cells, is up-regulated in both cell systems from the very early stages of neuronal differentiation. This indicates that neuronal commitment is marked by MARK4S up-regulation. In conclusion, this study provides the first direct evidence suggesting that MARK4 is a neuron-specific marker in the CNS, and the up-regulation of MARK4S during neuronal differentiation suggests that it plays a specialized role in neurons.

Double-blind study of nimesulide in divers with inflammatory disorders of the ear, nose and throat.

200 divers of either sex, aged 18 to 54 years, entered a double-blind study to compare the efficacy and tolerability of nimesulide 200 mg/day with those of seaprose S 60 mg/day in the treatment of nonbacterial inflammatory disorders of the ear, nose, and throat. At the end of the 1-week treatment period, both drugs were judged to be effective, with improvements and, in most cases, complete remission of all symptoms observed. Nimesulide showed greater clinical efficacy, and both drugs were well tolerated.

Role of TNF-alpha but not NGF in murine hyperalgesia induced by parasitic infection.

Using adult mice infected with the trematode Schistosoma mansoni, we observed that this infection induces both thermal hyperalgesia and an increase in the levels of nerve growth factor in the paws. To explore the mechanism involved in peripheral hypersensitivity during chronic infection, mice were infected with 60 cercariae of S. mansoni and injected 17 weeks later with nerve growth factor, anti-nerve growth factor or with other molecules known to be associated with hyperalgesic processes. The results of these studies showed that antibodies against tumor necrosis factor-alpha, but not against nerve growth factor, reduce thermal sensitivity in schistosome infected mice, suggesting that this cytokine but not NGF plays a crucial role in schistosome-induced thermal hyperalgesia. Treatments with anti-inflammatory drugs support this hypothesis.

Schistosoma mansoni infection enhances the levels of NGF in the liver and hypothalamus of mice.

Schistosoma mansoni infection in adult mice is known to cause granulomas in the liver and intestine. Using a specific enzyme-linked immunoassay, it was found that Schistosoma mansoni infection enhances the level of nerve growth factor in the liver and surprisingly also in the hypothalamus. Exogenous administration of purified NGF antibodies inhibits NGF biological activity both in the hypothalamus and liver and drastically reduces the number of NGF-responsive cells, the mast cells, present in liver granuloma. These findings and those reported by others showing the effect of NGF on cells of the immune system support the hypothesis that this molecule plays a role in neuroendocrine-immune interactions.