Characterization of novel murine monoclonal antibodies directed against the extracellular domain of human HER2 tyrosine kinase receptor

HER2 proto-oncogene encodes a transmembrane receptor tyrosine kinase overexpressed in a variety of solid tumors. Several mouse monoclonal antibodies (MAbs) have been developed that recognize the extracellular part of HER2; of them two MAbs were humanized and employed for targeted immunotherapy. In this study we aimed to produce murine MAbs that specifically recognize the extracellular domain of human HER2. BALB/c mice were first primed with HER2-transfected NIH-3T3 cells and then boosted with recombinant extracellular part of HER2. Splenocytes from hyperimmunized mice were fused with myeloma cells and growing hybridomas were selected and screened for HER2 reactivity by an indirect ELISA. HER2-specific hybridomas were selected, cloned by limiting dilution assay, and further characterized by Western blotting and flow cytometry techniques. All clones showed positive reactivity to HER2 with binding affinity, ranging from 1.9×10(8) to 5×10(9), and stained HER2-transfected cells and malignant cells overexpressing HER2. None of the MAbs inhibited the binding of trastuzumab (Herceptin(?)) to HER2, indicating recognition of distinct epitopes by these MAbs. Based on these findings, our MAbs could be potentially used for selective targeting of HER2-expressing malignancies.     

Relationship between cerebrospinal fluid biomarkers and structural brain network properties in Parkinson's disease

Background: Pathological accumulation of α‐synuclein, amyloid‐β₄₂, and tau proteins in the brain is considered critical for development of various neurodegenerative diseases. Objectives: We investigated the association between CSF levels of these biomarkers, brain structural connectivity, and the UPDRS in PD. Methods: Diffusion tensor images and CSF biomarkers (α‐synuclein, amyloid‐β₄₂, total tau, and phosphorylated tau181) from 132 drug‐naïve, nondemented PD patients and 61 healthy controls were obtained from the Parkinson's Progression Markers Initiative database. After network reconstruction of structural connectivity patterns, global interconnectivity measures (including global efficiency, clustering coefficient, and characteristic path length) and local efficiency were calculated. Network properties and CSF biomarkers were compared between PD patients and healthy controls. The association of CSF biomarkers with network properties and UPDRS‐III score was investigated. Results: Global measures (but not local efficiency) and CSF α‐synuclein were significantly lower in PD patients. Global efficiency and clustering coefficient correlated positively with α‐synuclein, Aβ₄₂, and total tau CSF levels. Furthermore, these CSF biomarkers showed no significant association with the UPDRS‐III score. Conclusions: This study examined the association of CSF biomarkers that reflect the brain pathology, with structural brain connectivity and UPDRS‐III in PD. Our results revealed an association between the abnormal aggregation of α‐synuclein, Aβ₄₂, and tau proteins and structural connectivity disruption in PD patients. In summary, a combination of structural imaging and measurement of CSF biomarkers provide a better understanding of the pathogenesis of PD. © 2018 International Parkinson and Movement Disorder Society     

Outcome of term breech births: 10-year experience at a district general hospital

OBJECTIVE: To review the short and long term outcomes among singleton infants with breech presentation at term delivered in a geographically defined population over a 10-year period. DESIGN: Retrospective, cohort study. SETTING: District General Hospital. POPULATION: 1433 term breech infants alive at the onset of labour and born between January 1991 and December 2000. METHODS: Data abstracted from birth registers, neonatal discharge summaries and the child health database system were used to compare the short and long term outcomes of singleton term breech infants born by two different modes of delivery (prelabour caesarean section and vaginal or caesarean section in labour). Fisher's exact test was used to compare the categorical variables. MAIN OUTCOME MEASURES: Short term outcomes: perinatal mortality, Apgar scores, admission to the neonatal unit, birth trauma and neonatal convulsions. Long term outcomes: deaths during infancy, cerebral palsy, long term morbidity (development of special needs and special educational needs). RESULTS: Of 1433 singleton term infants in breech presentation at onset of labour, 881 (61.5%) were delivered vaginally or by caesarean section in labour and 552 (38.5%) were born by prelabour caesarean section. There were three (0.3%) non-malformed perinatal deaths among infants born by vaginal delivery or caesarean section in labour compared with none in the prelabour caesarean section cohort. Compared with infants born by prelabour caesarean section, those delivered vaginally or by caesarean section in labour were significantly more likely to have low 5-minute Apgar scores (0.9% vs 5.9%, P < 0.0001) and require admission to the neonatal unit (1.6% vs 4%, P= 0.0119). However, there was no significant difference in the long term morbidity between the two groups (5.3% in the vaginal/caesarean section in labour group vs 3.8% in the prelabour caesarean group, P= 0.26); no difference in rates of cerebral palsy; and none of the eight infant deaths were related to the mode of delivery. CONCLUSIONS: Vaginal breech delivery or caesarean section in labour was associated with a small but unequivocal increase in the short term mortality and morbidity. However, the long term outcome was not influenced by the mode of delivery.     

Design of a birdcage array for lower extremity angiography

PURPOSE: To investigate the application of a coil array consisting of multiple birdcages for bolus chase magnetic resonance angiography (MRA) of the lower extremities. MATERIALS AND METHODS: The prototype consisted of four birdcage coils; two adjacent birdcages for thigh imaging, and two for calf imaging. Decoupling between adjacent coils was achieved using shared capacitors. Bench measurements and MR images were used to evaluate the decoupling scheme. Image signal-to-noise ratios (SNR) were compared between the birdcage array and four commercially available coils. Contrast-enhanced imaging experiments were performed on 10 volunteers and parallel imaging was simulated. This study was approved by the local institutional review board and written informed consent was obtained from each volunteer. RESULTS: Capacitive decoupling resulted in a reduction in signal leakage. The calf birdcages provided an 84% SNR improvement over a four element array, while the thigh birdcages provided a 53% improvement. Angiographic images illustrated the utility of the coil for peripheral MRA. Parallel imaging was demonstrated with a two-fold reduction factor. CONCLUSION: Birdcage coils were demonstrated to be valuable for lower extremity imaging due to their homogenous sensitivity, good SNR, and cylindrical geometry. Coupling was controlled using shared capacitors that allowed a single birdcage to encompass each leg individually, providing a novel approach to signal reception for peripheral imaging.     

The Stolzalpe technique: a modified Watson-Jones approach

We report our experiences with minimally invasive total hip replacement performed via a modified Watson-Jones approach with a special positioning technique (the "Stolzalpe technique"). With the patient placed in the conventional supine position, the contralateral leg is held in a gynaecological footrest to allow hyperextension, adduction and external rotation of the leg during femoral preparation. The first 117 patients operated with this technique were compared with a conventionally operated group. The patients operated with the Stolzalpe technique had superior results for nearly all study criteria, including time of operation, time of postoperative intensive care, blood loss, complications and Harris Hip Score. The Stolzalpe technique appears to be the best possible compromise between patient comfort and the surgical demands of proper implant positioning, minimization of anaesthetic risk, and reducing the time required for draping and positioning.     

Fracture of the alumina-bearing couple delta ceramic liner

The fracture rate of third-generation ceramic liners is greatly reduced compared with first- and second-generation liners because of improvements in the design and manufacturing process. Fractures of the alumina-bearing couple are rare for the same reason.This article describes a case of a fracture of an alumina-bearing couple delta ceramic liner without trauma history that was treated with ceramic-on-polyethylene revision total hip arthroplasty. A 57-year-old man was admitted to the hip ward because of an alumina-bearing couple delta ceramic liner fracture. He underwent hip replacement by anterior approach 18 months previously in the same center because of left hip primary osteoarthritis. He received a 54×36-mm modular press-fit cup ceramic alumina-bearing couple delta insert. Probable causes of such fractures are manufacture production failure and edge loading based on cup inclination, but in our patient, inacceptable range of motion, failure of the locking mechanism during implantation insertion, or cracking were possible causes of fracture.Although the fracture rate of third-generation alumina-bearing couples is low, we believe that it may not be possible to eliminate the actual risk of alumina head fracture. Patients should be informed about the potential for this complication before receiving an alumina-bearing couple.     

Short Versus Long Course of Antibiotics for Catheter-Associated Urinary Tract Infections in Patients With Spinal Cord Injury: A Randomized Controlled Noninferiority Trial

Objective

To assess the applicability of a short-course regimen of antibiotics for managing catheter-associated urinary tract infection (CA-UTI) in patients with spinal cord injury (SCI).

Design

Randomized, controlled, noninferiority trial.

Setting

Medical center.

Participants

Patients with SCI who had CA-UTI (N=61).

Interventions

Patients were randomized to receive either a 5-day regimen of antibiotics after catheter exchange (experimental group) or a 10-day regimen of antibiotics with catheter retention (control group). Noninferiority was prespecified with a margin of 10%.

Main Outcome Measure

Clinical cure at the end of therapy.

Results

Of the 61 patients enrolled in this study, 6 patients were excluded because of bacteremia or absence of urinary symptoms. All patients (100%) achieved clinical cure at the end of therapy. The rates of microbiologic response were 82.1% in the experimental group and 88.9% in the control group (upper boundary 95% confidence interval (CI) for difference, 26%). The rates of resolution of pyuria were 89.3% in the experimental group and 88.9% in the control group (upper boundary 95% CI for difference, 16%). Patients in the experimental group had higher rates of CA-UTI recurrence than the control group. The rates of new CA-UTI, diarrhea, and Clostridium difficile colitis were similar in the 2 treatment arms.

Conclusions

The primary endpoint of the study was met, indicating that the 5-day regimen with catheter exchange was noninferior to the 10-day regimen with catheter retention on the basis of clinical cure. Criteria for noninferiority on the basis of microbiologic response and resolution of pyuria were not met.     

Copper-free Sonogashira cross-coupling reactions: an overview

The Sonogashira reaction is a cross-coupling reaction of a vinyl or aryl halide with a terminal alkyne to form a C–C bond. In its original form, the Sonogashira reaction is performed with a palladium species as a catalyst while co-catalyzed by a copper species and a phosphine or amine. The reaction is conducted under mild conditions, i.e., room temperature, aqueous solutions, and the presence of mild bases. Undeniably, the Sonogashira reaction is among the most competent and efficient reactions widely used in organic synthesis. This named reaction has proved useful in many organic synthesis areas, including the synthesis of pharmaceuticals, heterocycles, natural products, organic compounds, complex molecules having biological activities, nanomaterials, and many more materials that we use in our daily lives. The presence of transition metals as a catalyst was indeed essential in the Sonogashira reaction. However, recently, the reaction has been successfully conducted without copper as a co-catalyst and phosphines or amines as bases. In this critical review, we have focused on developments in the Sonogashira reaction successfully performed in the absence of copper complexes, phosphines or amines, which could be of particular advantage in implementing green chemistry principles and making the reactions more achievable from an economic viewpoint.

The Sonogashira reaction is a cross-coupling reaction of a vinyl or aryl halide with a terminal alkyne to form a C–C bond.