Long-Term Lithium Treatment Reduces Glucose Metabolism in the Cerebellum and Hippocampus of Nondemented Older Adults: An [18F]FDG-PET Study

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Vestibular evoked myogenic potentials in Bell’s palsy

The aim of the present study was to evaluate vestibular nerve involvement in patients with Bell’s palsy with ocular and cervical vestibular evoked myogenic potentials (oVEMP and cVEMP). Ten patients who were diagnosed with Bell’s palsy and ten healthy controls were included. All patients underwent VEMP recordings within 6 days after their initial presentation. Patients with Bell’s palsy had greater oVEMP asymmetry ratio comparing to healthy controls (?38.4 ± 28.7 % vs ?1.3 ± 19.3 %, p = 0.005). As well N10 latencies of the oVEMP response were prolonged comparing to healthy controls (11.575 vs 9.72 ms). There was no difference in cVEMP asymmetry ratio or latencies between groups. We found no correlation between House–Brackmann grading scale and oVEMP asymmetry ratio (r = 0.003, p = 0.994). There are three possible explanations for increased oVEMP amplitudes on the affected side: (1) oVEMP response on the ipsilateral eye could be contaminated by facial nerve activity (blink reflex); (2) the amplitude of N10-P33 could be affected through the stapedial reflex; and (3) increased oVEMP amplitude could be the consequence of the vestibular nerve dysfunction itself, with prolonged latencies of the N10 oVEMP further supporting this explanation. The results of this study indicate possible involvement of the superior branch of the vestibular nerve in patients with Bell’s palsy.     

Pretreatment differentiation of renal cell carcinoma subtypes by CT: the influence of different tumor enhancement measurement approaches

Purpose

We conducted a retrospective study to evaluate the influence of different tumor enhancement measurement approaches on the ability of computed tomography (CT) to differentiate between solid forms of clear cell renal cell carcinoma (RCC), other RCC histologic subtypes and oncocytomas. Different RCC subtypes have a diverse range of malignant potential; consequently, the information about RCC subtype obtained using minimally invasive imaging method before the treatment could allow the more accurate therapy planning. Differentiation of ccRCCs from oncocytomas is important because oncocytomas are usually benign tumors which could be treated conservatively.

Methods

CT images of 113 patients with 118 solid renal tumors were evaluated. The imaging protocol consisted pre-contrast and post-contrast images during the arterial and nephrographic phases. Renal tumor attenuation values were measured using region of interest covering as much of the solid enhancing tumor tissue as possible. Tumor attenuation values and tumor enhancement ratios were correlated with histologic subtype. One hundred of tumors were diagnosed as clear cell RCC, nine as non-clear cell RCC and nine as oncocytoma.

Results

Tumor attenuation values of >74 HU on the arterial phase scans significantly correlated with clear cell RCC (Az 0.73). The tumor-to-aorta enhancement ratios calculated on tumor attenuation values measured on the arterial phase scans had a cutoff value of >0.29, which significantly correlated with clear cell RCC (Az 0.79). All ROC curves for differentiating the clear cell RCC from oncocytomas have area under the curve too small (0.5 or less) to have chose cutoff value with sensitivity and specificity that could be applied in clinical work.

Conclusion

Enhancement measurements of renal carcinomas on CT images in the arterial phase can be used as an auxiliary method in the pretreatment differentiation of solid forms of the most frequent RCC subtypes in patients not suitable for core biopsy but who are suitable for minimally invasive treatment methods and/or targeted therapy.     

Electrochemotherapy Treatment of Locally Advanced and Metastatic Soft Tissue Sarcomas: Results of a Non-Comparative Phase II Study

Aims

Our aim was to evaluate the activity, toxicity, and feasibility of electrochemotherapy (ECT) in patients with soft-tissue sarcomas (STS).

Methods

A two-stage phase II trial was conducted between October 2006 and March 2012. Patients (N = 34) with locally advanced or metastatic STS, unsuitable for standard oncological treatments and with maximum 3-cm deep tumors, received an intravenous bolus of bleomycin (15,000 IU/m²), followed by tumor electroporation according to the European Standard Operating Procedures of ECT. Outcome measures included local response according to response evaluation criteria in solid tumors (RECIST), toxicity and tumor control. Feasibility measures included the accuracy of electrode placement and the intensity of electric current flowing in tumor tissue.

Results

Median tumor size was 4.0 cm (range 2–12). Objective response, assessed on 71 target lesions, was 92.2 % (complete 32.3, 95 % CI 28–64). A total of 15 patients received up to four cycles due to incomplete response, but re-treatment did not significantly improve outcome (p = 0.205). After a median follow-up of 19.3 months, 2-year local control rate was 72.5 %. Median time to local failure (N = 11 patients) was 5.1 months. Tumor response (p = 0.041) and control (p = 0.047) correlated with histological grading. Relevant toxicity consisted of G3 skin ulceration and soft tissue necrosis (35 and 23 % of patients, respectively), although this was manageable on an outpatient basis. The accuracy of electrode placement was 47.1 %, and the adequacy of electroporative current 85.3 %.

Conclusions

ECT may represent an active and safe treatment to achieve local control in advanced STS patients with symptomatic disease. Future research challenges include the improvement of electrode placement and voltage delivery together with the containment of soft tissue toxicity.     

Randomized prospective trial comparing two supraglottic airway devices: i-gel™ and LMA-Supreme™ in paralyzed patients

Purpose

Many features can influence the choice of a supraglottic airway device (SAD), including ease of insertion, adequate ventilation pressures and lack of adverse effects. The goal of this randomized prospective trial was to compare the performance of the i-gel? with that of the LMA-Supreme?.

Methods

One hundred adult patients (American Society of Anesthesiologists I-III) scheduled to undergo elective surgery under general anesthesia were randomized to either an i-gel (n = 50) or an LMA-Supreme (n = 50). The primary objective was to compare ventilation pressures. Secondary objectives included time and number of attempts needed to introduce the device, adverse effects, and repositioning. The endoscopic view of the glottic aperture and the position of the drain tubes in relation to the esophagus were also evaluated.

Results

The devices were inserted successfully in 46 (92%) patients in both groups. There was no significant difference in the [mean (SD)] leak pressure [i-gel: 23 (7) cm H₂O vs LMA-Supreme: 21 (8) cm H₂O; P = 0.14] or peak inspiratory pressure between both devices. Insertion time was shorter with the i-gel than with the LMA-Supreme [19 (7) sec vs 27 (17) sec, respectively; P = 0.003]. The vocal cords were completely visualized more often through the i-gel (70%) than through the LMA-Supreme (50%) (P = 0.007). Esophageal mucosa was easily visualized through the drain port in all but four patients, two patients in each group. There was no difference between groups regarding preoperative or postoperative complications. Postoperative patient discomfort was generally mild and comparable between both devices.

Conclusion

Both the LMA-Supreme and the i-gel offer similar performance for positive pressure ventilation in paralyzed patients during general anesthesia. The i-gel was associated with a slightly faster insertion time and better fibrescopic visualization of the glottis. This trial was registered at Clinicaltrials.gov: NCT01001078.     

In vivo anticancer activity of rhomboidal Pt(II) metallacycles

The development of novel antitumor agents that have high efficacy in suppressing tumor growth, have low toxicity to nontumor tissues, and exhibit rapid localization in the targeted tumor sites is an ongoing avenue of research at the interface of chemistry, cancer biology, and pharmacology. Supramolecular metal-based coordination complexes (SCCs) have well-defined shapes and geometries, and upon their internalization, SCCs could affect multiple oncogenic signaling pathways in cells and tissues. We investigated the uptake, intracellular localization, and antitumor activity of two rhomboidal Pt(II)-based SCCs. Laser-scanning confocal microscopy in A549 and HeLa cells was used to determine the uptake and localization of the assemblies within cells and their effect on tumor growth was investigated in mouse s.c. tumor xenograft models. The SCCs are soluble in cell culture media within the entire range of studied concentrations (1 nM–5 µM), are nontoxic, and showed efficacy in reducing the rate of tumor growth in s.c. mouse tumor xenografts. These properties reveal the potential of Pt(II)-based SCCs for future biomedical applications as therapeutic agents.Molecular assemblies of nanoscale-size and well-defined geometries have recently emerged as an interesting new paradigm in drug design and drug delivery. To date, liposomes, the self-assembled lipid nanoparticles held together by weak interactions, are among the most widely studied and clinically successful nanoparticle-based drug carriers. Their use allows the drug to achieve sustained plasma levels while encapsulated, with the size preventing the fast clearance by the kidneys that often occurs with the free drug. However, liposomes themselves do not produce a therapeutic effect and their application as drug carriers for medical purposes has often been hindered by poor loading capacity (<5 wt %) and the inability to pass through biological barriers (1, 2). Inorganic and hybrid porous materials, such as molecular organic frameworks (MOFs), have also shown promise due to their higher loading capacities (>25 wt %) (3–5), but MOFs have poor hydrolytic stability (6, 7). Recent studies on materials from Institut Lavoisier (MIL)-100(Cr) and MIL-100(Fe), however, suggest that MOFs can persist in biologically relevant environments and can act as vehicles for some anticancer and antiviral agents (8–10). These early findings have prompted further investigations into the biomedical applications of supramolecular coordination complexes (SCCs) (11–24). SCCs preserve the attractive properties of MOFs, such as building block modularity (22, 23, 25), yet afford an increased solubility in the biological milieu and lend themselves to small-molecule characterization techniques due to their well-defined structure.Although development of SCCs for biomedical applications is in its infancy, some SCCs, such as trigonal prisms self-assembled from p-cymene and ruthenium-based metal fragments with pyridyl donors, have shown the ability to act as effective carriers of some chemotherapeutic agents (26–28). Moreover, a library of cytotoxic to cancer cells p-cymene ruthenium-based polygons and cages has also been developed (11). For biomedical applications, the information about the cellular uptake, delivery of a guest, and metabolism of the drug delivery vehicle is critical, although currently the fate of SCCs in biological environments is not well understood. In a rare report, a systematic investigation of the structural stability of a water-soluble, hexacationic ruthenium-based trigonal prism was performed; however, it was determined that the ruthenium-based trigonal prisms decompose in the presence of amino acids histidine, lysine, and arginine (29).An intriguing approach is the design of tumor-targeted modalities that combine detection and treatment through the self-assembly of emissive, metal-based coordination complexes. Such modalities can be especially valuable as they often do not require photoexcitation to elicit cytotoxicity. Recently Gray, Gross, and Medina-Kauwe and coworkers reported HerGa, a self-assembled tumor-targeted particle that bears the Ga(III)-metalated derivative of the sulfonated corrole (30, 31). The particle, which contained Ga(III)-corrole noncovalently bound to the tumor-targeting cell penetration protein HerPBK10, provided both tumor detection and elimination. Systemic injection of this protein–corrole complex resulted in tumor accumulation, which can be visualized in vivo due to the red corrole fluorescence. Cytotoxic and cytostatic properties of these targeted Ga(III) corroles were found to be cell-line dependent, with the ability to induce late M-phase arrest in several cancer cell lines (32).Despite the well-known cytotoxic properties of mono- and multinuclear platinum complexes (33–35), studies of the antitumor properties of platinum-based SCCs are rare (17, 36). Moreover, recent reports have demonstrated that platinum-based SCCs can act as effective hosts for guests and have interesting photophysical properties (37–42). In particular, highly emissive rhomboids based on aniline-containing donors and Pt-based metal acceptors have been developed that display different photophysical properties from those of their constituent subunits (40). These assemblies are interesting targets to investigate the cytotoxicity of organoplatinum SCCs, whereas their emission spectra could be used for interrogating the structural integrity in vitro. Here, for the first time to our knowledge, we report the uptake of SCCs in vitro in cell-based assays, determined by using laser-scanning confocal microscopy, and an in vivo assessment of the anticancer activity of SCCs in mouse s.c. tumor xenograft models.     

Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK

Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32‐year‐old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became bow‐legged during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29‐111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical and radiographic findings, elevated serum markers, and disorganized bone morphology suggested amplified receptor activator of NF‐κB (RANK) signaling, even though his disorder differed from conditions with known constitutive activation of RANK signaling (eg, familial expansile osteolysis). We found a unique 12‐base pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the phenotypes and genetic basis of the mendelian disorders of RANK signaling activation. © 2014 American Society for Bone and Mineral Research.