Ratiometric Two-Photon Near-Infrared Probe to Detect DPP IV in Human Plasma, Living Cells, Human Tissues, and Whole Organisms Using Zebrafish.

DPP IV, otherwise known as CD26 lymphocyte T surface antigen, is a transmembrane glycoprotein also found in circulation in the blood. It plays an important role in several processes like glucose metabolism and T-cell stimulation. Moreover, it is overexpressed in renal, colon, prostate, and thyroid human carcinoma tissues. It can also serve as a diagnostic in patients with lysosomal storage diseases. The biological and clinical importance of having readouts for the activity of this enzyme, in physiological and disease conditions, has led us to design a near-infrared (NIR) fluorimetric probe that also has the characteristics of being ratiometric and excitable by two simultaneous NIR photons. The probe consists of assembling an enzyme recognition group (Gly-Pro) (Mentlein, 1999; Klemann et al., 2016) on the two-photon (TP) fluorophore (derivative of dicyanomethylene-4H-pyran, DCM-NH2) disturbing its NIR characteristic internal charge transfer (ICT) emission spectrum. When the dipeptide group is released by the DPP IV-specific enzymatic action, the donor-acceptor DCM-NH2 is restored, forming a system that shows high ratiometric fluorescence output. With this new probe, we have been able to detect, quickly and efficiently, the enzymatic activity of DPP IV in living cells, human tissues, and whole organisms, using zebrafish. In addition, due to the possibility of being excited by two photons, we can avoid the autofluorescence and subsequent photobleaching that the raw plasma has when it is excited by visible light, achieving detection of the activity of DPP IV in that medium without interference.

Ten years-experience of sunitinib in the treatment of advanced pan-NETs: an update on safety profile.

INTRODUCTION: Sunitinib still represents a milestone in the treatment for progressive, well-differentiated, advanced panNETs. AREAS COVERED: We performed an evidence reappraisal to critically discuss its safety profile. We included nine studies, five clinical trials and four real-world (RW) studies. Within non-real-world (NRW) studies, diarrhea was the most frequent clinical AE. With regard to G3-4 AEs, fatigue and hypertension were the two most frequent, while neutropenia was the most recurrent hematological one. Considering four real-world trials, hand-foot-syndrome (HFS) was the most frequent clinical any-grade AE of any grade and neutropenia was the most common G3-4. Alongside to the AEs rate, the discontinuation rate of sunitinib due to TRAEs was variable among all the nine selected studies, ranging from 10% to 35% in the NRW setting and from 7% to 31% in the RW setting. Conversely, temporary interruption is an accepted strategy to reduce toxicity, even though not specifically tested in pan-NET. EXPERT OPINION: Till now, sunitinib continues to be one of the main therapeutic options for patients with well differentiated advanced panNETs, potentially covering any line of treatment. Therefore, tolerability plays a crucial role to increase adherence to therapy and maximize QoL.

Gastroenteropancreatic grade 3 neuroendocrine tumors: a single entity or a heterogeneous group? A retrospective analysis.

PURPOSE: Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed. PATIENTS AND METHODS: We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes. RESULTS: Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68Gallium(68Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose (18FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048). CONCLUSION: Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed.

Should temozolomide be used on the basis of O6-methylguanine DNA methyltransferase status in patients with advanced neuroendocrine tumors? A systematic review and meta-analysis.

BACKGROUND: Temozolomide (TEM) is an active treatment in metastatic neuroendocrine tumors (NETs). Patients affected by glioblastoma multiforme or advanced melanoma treated with TEM who have deficiency of O6-methylguanine DNA methyltransferase (MGMT) have a better responses and survival. However, the predictive role of MGMT in patients with NETs treated with TEM is still debated. METHODS: We conducted a systematic review of the literature and meta-analysis, based on PRISMA methodology, searching in the main databases (PubMed, Embase, Scopus, Web of Science, Cochrane Library and clinical trial.gov) and the proceedings of the main international congresses, until April 26, 2021. RESULTS: Twelve out of 616 articles were selected for our analysis, regarding a total of 858 NET patients treated with TEM-based chemotherapy. The status of MGMT had been tested in 513 (60%) patients, using various methods. The pooled overall response rate (ORR) was higher in MGMT-deficient compared with MGMT-proficient NETs, with a risk difference of 0.31 (95% confidence interval, CI: 0.13-0.50; p < 0.001; I2: 73%) and risk ratio of 2.29 (95% CI: 1.34-3.91; p < 0.001; I2: 55%). The pooled progression free survival (PFS) (hazard ratio, HR = 0.56; 95% CI: 0.43-0.74; p < 0.001) and overall survival (OS) (HR = 0.41; 95% CI: 0.20-0.62; p = 0.011) were longer in MGMT-deficient versus MGMT-proficient NETs. CONCLUSIONS: Our meta-analysis suggested that MGMT status may be predictive of TEM efficacy. However, due to the high heterogeneity of the evaluated studies the risk of biases should be considered. On this hypothesis future homogeneous prospective studies are warranted.

Lung carcinoids with high proliferative activity: Further support for the identification of a new tumor category in the classification of lung neuroendocrine neoplasms.

Highly proliferative lung carcinoids (HPLC) have been recently reported but information about this subset remains scarce. OBJECTIVES: Clinical and pathological data of 630 patients with lung carcinoids (LC) referred to Gustave Roussy Institute (GR) and European Institute of Oncology (IEO) were retrospectively reviewed to select HPLC and analyze their frequency, behavior and compare their outcome to conventional LC with Ki-67 ≤ 20 % and mitotic count (MC)≤10/2 mm2. MATERIALS AND METHODS: Selection criteria were: diagnosis of LC confirmed by local pathologist, and available clinical and follow-up data. Patients with Ki-67 > 20 % and/or MC > 10/ 2 mm2 in primary or metastatic specimens were identified as HPLC. RESULTS: 30/514 patients (6%) met the selection criteria of HPLC. Based on primary tumor evaluation, 22/25 (88 %) were classified as atypical carcinoids (AC). Median MC was 4.5/2 mm2 (1-11) 6/2 mm2 (3-15) in primary tumors and metastasis, respectively. Median Ki-67 was respectively 23 % (15-65) and 25 % (8-60). Recurrence rate was 66 % (12/18) in HPLC and 9 % (33/352) in conventional LC. Median RFS was 24 (10-NR) months in HPLC, 288 (141-NR) months in LC with Ki-67 index≤5 % and NR (148-NR) months in LC with Ki-67 6-20% (p < 001). Median OS was 203 (83-NR) months in LC with Ki-67 index≤5%, 101 (79-NR) months in LC with Ki-67 index 6-20 % and 53 (39-NR) months in HPLC (p = 002). Among 20 metastatic patients with HPLC, median PFS under platinum-based chemotherapy, everolimus, alkylating-based chemotherapy, FOLFOX and PRRT was 5.1 (95 % CI 0.7-9.4), 12.1(95 %CI 0.3-24), 6.8 (95 % CI 0-14.9), 10.2 (95 % CI 0.4-19.9) and 14.2 months (95 % CI 0-30) respectively. Best response was stable disease (SD) under platinum-based chemotherapy and partial response (PR) under alkylating-based chemotherapy and FOLFOX. CONCLUSION: This study confirms the existence and rarity of HPLC. Their characteristics and clinical behavior are more similar to LC rather than neuroendocrine carcinomas (NECs), suggesting that this entity could be managed accordingly.

SARS-CoV-2-related pneumonia can be successfully managed in patients with metastatic neuroendocrine tumors: a critical point of view.

Primary neuroendocrine tumors of the thymus are extremely rare. In patients with advanced disease, tumor growth control, and sometimes also syndrome control are the main goals of systemic therapy. Unfortunately, no standard therapies are available in clinical practice; therefore, clinical studies are strongly recommended. Axitinib (AXI) is a tyrosine kinase inhibitor, currently under investigation in an international phase II/III trial including thymic neuroendocrine tumors. Over the past 5 months, the entire world has been facing a devastating medical emergency brought about by a pandemic due to a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, in late 2019. Since then, health professionals have been expending all their efforts on trying to provide the best available treatments for patients involved. Patients with cancer, especially those with thoracic involvement, are at higher risk of coronavirus disease 19 (COVID-19) and its complications because of their immunosuppressive status caused by the cancer and the anticancer therapies. As it remains unclear how to optimally manage such patients, we wished to report our experience with a patient with a metastatic neuroendocrine tumor of the thymus infected with SARS-CoV-2 in the hope that it may provide some insights and reflections on the management of cancer patients during this challenging time in our history.

Complications of the "Nuss Procedure" In Pectus Excavatum.

During the pediatric age range, one the most frequent deformities of the chest wall are Pectus Excavatum (PE). Currently the treatment of choice for PE is surgical intervention following the Nuss procedure. In this study, we present a description of the complications associated with surgical treatment of PE with the Nuss technique, in patients with symmetrical or asymmetrical deformity, in different stages of disease severity. The study was conducted in collaboration with the Pediatric Hospital "Istituto G. Gaslini" of Genoa. We analyzed a cohort of 402 patients (334 males and 68 females), who underwent corrective surgery between 2005 and 2018. Within this group of patients, we observed 82 cases with complications (20.39%), 20 of which were intraoperative (4.98%) and 62 post-operative (15.42%). For the evaluation of complications, this group was arbitrarily divided into patients with symmetric and asymmetric Pectus and in patients with mild, moderate and severe Pectus using Haller's index. Although a small group of patients presented complications, overall results from data analysis show that the Nuss technique represents the preferred surgical procedure for the treatment of PE, in agreement with literature. Furthermore, in our results show no correlation between asymmetry or severity of PE with complication related to the surgery.

Papillary Thyroid Carcinoma in Paediatric Age.

In children, differentiated thyroid carcinoma is a rare condition. Early diagnosis is not always easy, because of the lack of clinical symptoms, but it has a pivotal role in performing a correct therapeutic process. The study describes three cases of papillary thyroid carcinoma. None of the three patients had a positive familiarity or exposure to risk factors. In two cases, the tumor occurred as a non-injurious swelling in the anterior cervical region, in the other case it occurred with a latero-cervical lymphadenopathy that had been persistent for a year. In the first two patients we made a certain diagnosis by the needle aspiration of the thyroid nodule; in the other case the diagnosis was made by surgical exeresis and histological analysis of the lymph nodes. We also performed blood chemistry and hormonal tests, neck ultrasound, chest x-ray. The three children underwent total thyroidectomy and two of them also underwent right-sided cervical lymph node exeresis because there was the presence of metastasis. In our experience, the best therapeutic strategy for children with differentiated thyroid carcinoma is the total thyroidectomy, followed or not by latero-cervical lymph node exeresis and radioiodiotherapy. The removal of the whole gland reduces the risk of relapse.

Laparoscopic Repair of Paediatric Indirect Inguinal Hernia: Modified Flip Flap Technique.

In paediatric age, indirect inguinal hernia represents more than 95% of the hernial disease. It is a congenital type, in contrast with adulthood in which acquired forms are more frequently found (1). The laparoscopic correction of indirect inguinal hernia is one of the most common surgeries performed in paediatric age. In recent years, various techniques have been introduced for the videolaparoscopic correction of this disease. The aim of this study is to provide an assessment of the efficacy and safety of the execution of a modified Flip-Flap technique, using tissue glue for filling of Peritoneal-vaginal duct (DPV), performed in order to ensure greater suture tightness and reduce the incidence of postoperative hydrocele. author1, author2, author 2, author1, author1, author 2 The Authors present a retrospective review of their record of cases, considering a total of 187 patients aged between 18 months and 14 years. For the correction of the hernial defect, the modified VLS Flip-Flap technique was carried out. The evaluation of safety, efficacy, operating time, relapse rate and development of short-term complications (such as postoperative hydrocele, scrotal hematoma or ecchymosis, atrophy or iatrogenic testicle ascension) was considered in a mean follow-up of 6 months. The Authors suggest that this variant of the peritoneal Flip-Flap technique is simple to perform; its safety, reproducibility and effectiveness is proven and has a percentage of relapses and complications overlapping with the "open" approach and superior to other laparoscopic techniques.

Surgical VLS Therapy of Oesophageal Achalasia in Pediatric Age: Four Case Reports.

The Authors present a retrospective review of their record of cases, characterized by 4 cases of achalasia in which it was performed a Heller myotomy with front fundoplication (Thall) in laparoscopic approach in the period from 2012 to 2019. In paediatric achalasia, the laparoscopic Heller myotomy seems to be the best treatment because of its multiple advantages offered by the minimally invasive technique. First of all, thanks to the video-technique, which allows a complete and extended myotomy, the accuracy of this operation is maximized; moreover, the post-operative pain is widely reduced, thanks to the minimal dissection and traction of the tissues; finally, but not negligible, this approach ensures a better aesthetic result than the classic open technique. With regard to the front fundoplication, the Authors suggest that it is mandatory because, even if it extends the operating time, it ensures a natural protection to the myotomy herniated mucosa and avoids gastro-oesophageal reflux, which often occurs after the surgical correction, thus obliging to perform a reoperation.

Minimally Invasive Treatment of Urolithiasis in Children: Evaluation of the Use of Flexible Ureterorenoscopy and Laser Lithotripsy.

Urolithiasis is a multifactorial disease; in recent years, its incidence has gradually increased in pediatric age. Among the factors involved in urolithiasis pathophysiology, urinary tract anomalies and metabolic diseases are the most relevant, although ethnicity and environmental factors may have an important role. The advances in technology and miniaturization of endoscopic devices have permitted the use of Retrograde Intrarenal Surgery (RIRS) to treat kidney and ureteral stones. Nowadays, flexible ureterorenoscopy and laser lithotripsy, which are techniques that have been applied in the management of adult upper urinary tract disorders, are also used in children as a minimally invasive treatment of urolithiasis with encouraging, effective and safe results. The Authors report a retrospective review of their record of cases considering 21 pediatric urolithiasis treatment procedures performed between October 2017 and April 2019 in a total of 17 patients (10 males and 7 females). Six procedures involved the use of the flexible ureterorenoscope (FURS) while in 15 procedures the application of the laser fiber was used (FURSL). A case of laser lithotripsy for bladder stone was included. The average age of patients was 10.5 years (2-18 years). The renal pelvis dilatation pretreatment was evaluated in post-operative follow-up. From the evaluation of the sample in analysis, the use of RIRS has good results in the treatment of paediatric urolithiasis, emerging as a valid option in the management of the paediatric population in terms of efficacy and safety, with an improvement in patient outcomes.

Molecular and supramolecular recognition patterns in ternary copper(II) or zinc(II) complexes with selected rigid-planar chelators and a synthetic adenine-nucleoside.

Four ternary metal-complexes with Cu(II) or Zn(II), 2,6-pyridine-dicarboxylate (pdc) or glycyl-glycinate (GG) and the synthetic nucleoside 9-(2-hydroxyethyl)adenine (9heade) have been synthesized and studied by single-crystal X-ray diffraction and other physical methods. Relevant supramolecular assemblies found in the solid state structures have been further studied using density functional theory (DFT) calculations. In addition, the energetic features of the non-covalent interactions as well as the cooperativity effects have been calculated and characterized using the non-covalent interaction plot computational tool. Compounds trans-[Cu(pdc)(9heade)(H2O)2]·3H2O (1a) and [Cu(pdc)(9heade)(H2O)]·H2O (1b), trans-[Zn(pdc)(9heade)(H2O)2] (2), share the same molecular recognition pattern consisting in the cooperation of the metal-N7(9heade) bond and an interligand (9heade)N6-H···O(pdc) interaction, regardless of the nature of the metal, the coordination environment and the water content. At a supramolecular level, these compounds exhibit pairs of complex molecules linked by H-bonds and interesting anion-π/π-π/π-anion assemblies (in 1a and 1b) or the unprecedented π-π interactions (in 2), involving the purine moieties or the exocyclic -6NH2 purine groups, respectively. Compound 3, {[Cu(GG)(9heade)(H2O)·Cu(GG)(µ2-9heade)]·8H2O}n, consists in asymmetric dinuclear complex units (Cu···Cu 7.83 Å) that connect with adjacent ones by pairs of very weak Cu-O(carboxylate) bonds (Cu···Cu 3.81 Å) building a polymeric chain. The supramolecular transition from a single molecule to dinuclear units and finally a polymeric chain is also observed in the electron paramagnetic resonance spectra and discussed from a structural point of view as well as by DFT calculations. The unprecedented N7 and µ-N7,O(ol) metal binding patterns of 9heade differs from that recently reported (µ-N1,N7) in a Cd(II) polymer.

Laparoscopic Splenectomy: Postero-Lateral Approach.

In paediatric population, the laparoscopic splenectomy has been preferred to the open surgery during the last years. Due to the improvement of the technique and the devices, the indications to the laparoscopic splenectomy have been increased, even though there is still a variety of conditions in which the execution of this technique is arduous. During the preoperative consult there is the need to carefully evaluate the existence of cholecystic lithiasis, the haemoglobin level in patients with SCA, platelet count in children with ITP and the vaccination status. An anterior and a lateral or hanging spleen approach are primarily used for laparoscopic splenectomy. In the last four years, near the Section of Pediatric Surgery of the Department of Pediatrics, Obstetrics and Medicine of the Reproduction of Siena University, 8 cases of splenomegaly have been treated, 7 by lateral videolaparoscopic splenectomy (5 males and 2 females, with medium age of 10,5 years) and 1 by anterior approach (10 years). The advantages shown by these techniques allow the laparoscopic splenectomy to be considered as a valid alternative to the open surgery. In children's laparoscopic splenectomy, the rate of complications is considerably low and the the major problem is the intraoperative hemorrhage. With increasing surgical experience, the minimally invasive approach appears to be superior in terms of faster postoperative recovery, shorter hospital stay, perioperative and postoperative advantages. Therefore, the laparoscopic technique may soon be accepted as the standard method in patients requiring splenectomy.

Pre and Post-Operative Ph-Metry in Videolaparoscopic Surgery for Gastro Oesophageal Reflux Disease.

Gastro-oesophageal reflux is common in children, especially in the first year of life, and it may be regarded as physiological. Good functioning of the lower oesophageal sphincter depends largely on the anatomical relationships between oesophagus, stomach and diaphragm hiatus. Relative immaturity of these structures in newborn babies and young children is a risk factor in reflux disease, which may result in a wide variety of typical and/or atypical symptoms and, sometimes, serious complications such as oesophagitis and stenosis. Reflux disease may be diagnosed and studied, basing on morphological and functional aspects and, since the advent of pH-metry, it is possible to personalise the therapeutic approach to children with reflux. Surgical treatment of reflux disease in children has recently been improved due to a mini-invasive surgical approach. Absolute indications are recurrent pneumonia, intractable pain due to oesophagitis and retarded growth, often in association with neurological impairment. In the last three years, 18 children with reflux disease underwent videolaparoscopic surgery in our department, 14 by the Nissen and 4 by the Toupet technique. Post-operative pH-metry always showed a reduction in exposure of the distal oesophagus to acid (integral of H+) and an improvement in oesophageal clearance (short refluxes percentage) indicative of good functioning of the gastro-oesophageal junction. PH-metry proved to be an invaluable technique for planning therapeutic strategy. In follow-up evaluations, it enabled us to monitor functioning of the gastro-oesophageal junction and to avoid other more difficult and invasive tests in patients with severe neurological impairment.

Congenital Cystic Adenomatoid Malformation of the Lung Tipe II: Three Cases Report.

Congenital cystic adenomatoid malformation (CCAM) is a rare congenital lung lesion. It may appear since birth (30-35%) with difficulty breathing or may have a late onset (60-65%) with recurring pulmonary infections or growth failure; in a small percentage of cases, the lesion can be completely asymptomatic. Fetal or post-natal surgery can be used as surgical treatment of these lesions. Postnatal surgery consists of a lobectomy, bilobectomy or pneumonectomy, based on the size of the lesion. The best age to undergo this surgery is around 2 years, but only if the injury is stable and the child has no complications. The study describes three cases of CCAM, observed at the Pediatric Surgery Section of the University of Siena. We analyzed those 3 cases whose approach was defined by the onset of symptoms, age and clinical condition of patients. In the first case the surgery was performed a few hours after birth due to the worsening of the clinical conditions; in the other two cases it was delayed because the patients were asymptomatic. The purpose of this study is to review the management of patients with CCAM in relation to clinical onset and the type of injury.

δ13 C values in archaeological 14 C-AMS dated charcoals: assessing mid-Holocene climate fluctuations and human response from a high-resolution isotope record (Arslantepe, Turkey).

RATIONALE: Past climate has always influenced human adaptation to the environment. In order to reconstruct palaeoclimate fluctuations and their role in the evolution of Near Eastern societies during the mid-Holocene, high-resolution Δ13 C records from fossil wood remains at the archaeological site of Arslantepe (eastern Turkey) have been developed. METHODS: After chemical treatment, δ13 C values were measured by sample combustion flow using a FLASH EA-CHNS instrument interfaced with a Delta V isotope ratio mass spectrometer via a CONFLO III. Two replicates per sample were analysed. The measurement precision was evaluated by propagating variations of the δ13 C values of samples and V-PDB standards, whereas the accuracy was checked by a quality control sample. To account for changes in atmospheric CO2 , Δ13 C values were calculated. In addition, 14 C/12 C ratios were measured by means of ann AMS system (3 MV tandem accelerator). RESULTS: Mean Δ13 C curves of deciduous Quercus and Juniperus from archaeological levels between 4700 and 2000 BC (Arslantepe periods VIII-VI D) were produced, where the isotope values were ordered by the available RC ages. Interspecific variations of evergreen vs deciduous plants were postulated for the juniper Δ13 C values being higher than 3‰. The seasonal rainfall amount was recorded by the juniper remains, while the water table levels were obtained from the oak samples. CONCLUSIONS: The local climate experienced times of enhanced/reduced precipitation in concert with regional trends. Anomalies in the air mass circulation from the Mediterranean basin also produced oscillations of rainfall amount. In such a frame the Rapid Climate Change dry events had a consistent signature in the Arslantepe Δ13 C record, thus potentially contributing to social or organisational changes at the site.

Antarctic ice sheet discharge driven by atmosphere-ocean feedbacks at the Last Glacial Termination.

Reconstructing the dynamic response of the Antarctic ice sheets to warming during the Last Glacial Termination (LGT; 18,000-11,650 yrs ago) allows us to disentangle ice-climate feedbacks that are key to improving future projections. Whilst the sequence of events during this period is reasonably well-known, relatively poor chronological control has precluded precise alignment of ice, atmospheric and marine records, making it difficult to assess relationships between Antarctic ice-sheet (AIS) dynamics, climate change and sea level. Here we present results from a highly-resolved 'horizontal ice core' from the Weddell Sea Embayment, which records millennial-scale AIS dynamics across this extensive region. Counterintuitively, we find AIS mass-loss across the full duration of the Antarctic Cold Reversal (ACR; 14,600-12,700 yrs ago), with stabilisation during the subsequent millennia of atmospheric warming. Earth-system and ice-sheet modelling suggests these contrasting trends were likely Antarctic-wide, sustained by feedbacks amplified by the delivery of Circumpolar Deep Water onto the continental shelf. Given the anti-phase relationship between inter-hemispheric climate trends across the LGT our findings demonstrate that Southern Ocean-AIS feedbacks were controlled by global atmospheric teleconnections. With increasing stratification of the Southern Ocean and intensification of mid-latitude westerly winds today, such teleconnections could amplify AIS mass loss and accelerate global sea-level rise.

A new surgical technique for the treatment of scaphotrapezial arthritis associated with trapeziometacarpal arthritis: the narrow pseudoarthrosis.

UNLABELLED: We describe a technique for treating Eaton stage IV osteoarthritis of the first ray, which is a development of our previously published technique for treating trapeziometacarpal arthritis. This simple technique is based on a limited resection arthroplasty of the first trapeziometacarpal and the scaphotrapezial joints, with the aim of inducing the formation of a narrow pseudoarthrosis at both sites. A total of 26 consecutive patients were treated for Eaton stage IV arthritis at a mean follow-up of 4.7 years (range 3.2-6.6). There were statistically significant improvements in all clinical parameters: mean appositional and oppositional pinch strength, mean DASH score (65 points pre-operatively to 8.7 points at final follow-up), and in mean visual analogue scale score (8.6 to 0.2 points). Although a larger cohort and a longer follow-up will be necessary to evaluate this new technique fully, these results encourage us to believe that the limited excision arthroplasty of the trapeziometacarpal and scaphotrapezial joints is a viable alternative to the existing surgical treatments for stage IV thumb arthritis. LEVEL OF EVIDENCE: 4.

Imidazoles and benzimidazoles as tubulin-modulators for anti-cancer therapy.

Imidazoles and benzimidazoles are privileged heterocyclic bioactive compounds used with success in the clinical practice of innumerous diseases. Although there are many advancements in cancer therapy, microtubules remain as one of the few macromolecular targets validated for planning active anti-cancer compounds, and the design of drugs that modulate microtubule dynamics in unknown sites of tubulin is one of the goals of the medicinal chemistry. The discussion of the role of new and commercially available imidazole and benzimidazole derivatives as tubulin modulators is scattered throughout scientific literature, and indicates that these compounds have a tubulin modulation mechanism different from that of tubulin modulators clinically available, such as paclitaxel, docetaxel, vincristine and vinblastine. In fact, recent literature indicates that these derivatives inhibit microtubule formation binding to the colchicine site, present good pharmacokinetic properties and are capable of overcoming multidrug resistance in many cell lines. The understanding of the mechanisms involved in the imidazoles/benzimidazoles modulation of microtubule dynamics is very important to develop new strategies to overcome the resistance to anti-cancer drugs and to discover new biomarkers and targets for cancer chemotherapy.