Transoral parathyroid surgery—a new alternative or nonsense?

Purpose

In recent years, several endoscopic techniques have been explored in thyroid and parathyroid surgery, but only few gained acceptance among patients and surgeons. Based on extensive human cadaver and animal studies, we developed a technique for transoral partial parathyroidectomy (TOPP), which was performed for the first time in a patient with primary hyperparathyroidism (pHPT). We now report on results and the acceptance of this new technique 2 years after its implementation.

Methods

A pilot study was initiated to recruit a total of 10 patients with benign sporadic pHPT and a preoperatively localized parathyroid adenoma eligible for initial parathyroidectomy. The study protocol was approved by the ethics committee, and an insurance for unforeseen complications and risks was procured. Data of all patients evaluated and operated were prospectively collected, and follow-up examinations were carried out for 19 months on average, which included clinical examinations; ultrasonography; Ear, Nose, and Throat (ENT) investigations; and blood testing.

Results

Between January 2010 and May 2012, 75 patients with pHPT and a preoperative localized parathyroid adenoma were eligible for TOPP. After detailed information about the transoral procedure, only five (7 %) female patients consent to undergo TOPP. In three patients, a parathyroid adenoma could be removed via the transoral access, In two patients, the procedure had to be converted to the conventional technique. Median time until resection of a parathyroid adenoma was 122 min (range, 45–175). One patient had a transient recurrent laryngeal nerve palsy, while one patient suffered from a transient palsy of the right hypoglossal nerve and a slight but persisting dysgeusia. Three patients developed a hematoma of the mouth floor and swallowing problems. In four patients, the visual analog scale (VAS) pain score was high (>7) within the first 2 postoperative days.

Conclusions

Although TOPP is feasible, it is poorly accepted by patients and its complication rate is high. Thus, TOPP is nonsense with currently available devices.     

High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression

Rationale

Major depressive disorder has been associated with low serum levels of brain-derived neurotrophic factor (sBDNF), which is functionally involved in neuroplasticity. Although sBDNF levels tend to normalize following psychopathological improvement with antidepressant treatment, it is unclear how closely sBDNF changes are associated with treatment outcome.

Objectives

To examine whether baseline sBDNF or early changes in sBDNF are predictive of response to therapy.

Methods

Twenty-five patients with major depressive disorder underwent standardized treatment with duloxetine. Severity of depression, measured by the Hamilton Depression Rating Scale, and sBDNF were assessed at baseline, and after 1, 2, and 6 weeks of treatment. Therapy outcome after 6 weeks was defined as response (≥50 % reduction in baseline Hamilton Depression Rating score) and remission (Hamilton Depression Rating score <8). The predictive values for treatment outcome of baseline sBDNF, and early (i.e., ≤2 weeks) changes in sBDNF and Hamilton Depression Rating score were also assessed.

Results

At baseline, sBDNF correlated with Hamilton Depression Rating scores. Treatment response was associated with a higher baseline sBDNF concentration, and a greater Hamilton Depression Rating score reduction after 1 and 2 weeks. A greater early rise in sBDNF correlated with a decreased early Hamilton Depression Rating score reduction.

Conclusions

Even though higher baseline sBDNF levels are associated with more severe depression, they may reflect an increased capacity to respond to treatment. In contrast, changes in sBDNF over the full course of treatment are not associated with psychopathological improvement.     

Synthesis and biological study of acridine-based imidazolium salts

A new series of acridine based imidazolium salts was synthesized and evaluated for in vitro cytotoxicity against human cancer cell lines by an MTT assay. The synthesis applied a coupling of imidazoles with 9-chloroacridines, which originated from an Ullmann condensation of a 2-chloro-benzoic acid with an aniline. The target compounds were obtained in high yields. The DPPH assay indicated considerable antioxidant activity for target compounds with simple and short alkyl chains on the imidazole, while increasing chain length and the introduction of an additional π-electron system in most cases reduced the activity. All compounds exhibited low biotoxicity against non-cancerous cell lines, whereas a few compounds showed promising anticancer activity. Unlike for the reference drugs Tamoxifen and Paclitaxel, the anticancer activity of acridine imidazolium ions is specific for only selected cancer types. Reasonable fluorescent behaviour of the products provide potential for visualization of the distribution of active drugs in tissue.

A series of acridine-based imidazolium salts was synthesized and studied on cytotoxicity against human cancer cell lines.     

ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin

Vascular endothelial (VE)-cadherin is the major adhesion molecule of endothelial adherens junctions. It plays an essential role in controlling endothelial permeability, vascular integrity, leukocyte transmigration, and angiogenesis. Elevated levels of soluble VE-cadherin are associated with diseases like coronary atherosclerosis. Previous data showed that the extracellular domain of VE-cadherin is released by an unknown metalloprotease activity during apoptosis. In this study, we used gain-of-function analyses, inhibitor studies, and RNA interference experiments to analyze the proteolytic release of VE-cadherin in human umbilical vein endothelial cells (HUVECs). We found that VE-cadherin is specifically cleaved by the disintegrin and metalloprotease ADAM10 in its ectodomain, releasing a soluble fragment and generating a carboxyl-terminal membrane-bound stub, which is a substrate for a subsequent gamma-secretase cleavage. This ADAM10-mediated proteolysis could be induced by Ca(2+) influx and staurosporine treatment, indicating that ADAM10-mediated VE-cadherin cleavage contributes to the dissolution of adherens junctions during endothelial cell activation and apoptosis, respectively. In contrast, protein kinase C activation or inhibition did not modulate VE-cadherin processing. Increased ADAM10 expression was functionally associated with an increase in endothelial permeability. Remarkably, our data indicate that ADAM10 activity also contributes to the thrombin-induced decrease of endothelial cell-cell adhesion. Moreover, knockdown of ADAM10 in HUVECs as well as in T cells by small interfering RNA impaired T-cell transmigration. Taken together, our data identify ADAM10 as a novel regulator of vascular permeability and demonstrate a hitherto unknown function of ADAM10 in the regulation of VE-cadherin-dependent endothelial cell functions and leukocyte transendothelial migration.     

C1-inhibitor reduces hepatic leukocyte-endothelial interaction and the expression of VCAM-1 in LPS-induced sepsis in the rat

INTRODUCTION: Increased leukocyte-endothelial interaction (LEI) leading to hepatic microperfusion disorders is proposed as major contributor for hepatic failure during sepsis. Recently it has been demonstrated that complement inhibition by C1-inhibitor (C1-INH) is an effective treatment against microcirculatory disturbances in various diseases. The purpose of this study was to investigate the influence of C1-INH on microcirculation and LEI in the liver in a rat model of sepsis. MATERIALS AND METHODS: Rats received lipopolysaccharides (LPS) from Escherichia coli intravenously. Controls received Ringer solution only. Ninety minutes after LPS infusion some animals were treated with C1-INH intravenously (LPS + C1-INH). Others (LPS + SC) and controls (Ringer + SC) received sodium chloride (SC). Hepatic LEI and mean erythrocyte velocity (MEV) were quantified by intravital microscopy (IVM) 90 min after LPS or Ringer infusion (0) and 30, 60, 90 and 120 min following treatment. VCAM-1 m-RNA in hepatic tissue, C3a, TNF-alpha and hepatic enzyme liberation in blood was analysed. RESULTS: Leukocyte sticking to the endothelial wall in postsinusoidal venules was significantly reduced in the LPS + C1-INH vs. the LPS + SC group 30, 60, 90 and 120 min after treatment. VCAM-1 m-RNA expression in the hepatic tissue was markedly and C3a levels in plasma were significantly reduced in the LPS + C1-INH vs. the LPS + SC group. No differences in TNF-alpha levels were detected between these two groups. MEV was improved in the LPS + C1-INH vs. the LPS + SC group. CONCLUSIONS: Our results indicate that even upon delayed treatment hepatic adhesion molecule expression and LEI can be reduced by C1-INH. The multifunctional regulator may reduce hepatic microcirculatory disturbances during sepsis under clinical conditions.     

A hemocyanin from the Onychophora and the emergence of respiratory proteins

The velvet worms (Onychophora) are considered living fossils and are closely related to the Euarthropoda. Onychophora possess a tracheal system for respiratory function, but oxygen-transport proteins have been considered unnecessary. Here, we show that the hemolymph of the Epiperipatus sp. (Onychophora: Peripatidae) contains an arthropod-type hemocyanin, demonstrating that such protein exists outside the Euarthropoda. Thus, the evolution of oxygen carriers preceded the divergence of the Onychophora and Euarthropoda and was most likely linked to the evolution of an efficient circulatory system in a low-oxygen environment. The cDNA of the Epiperipatus hemocyanin subunit comprises 2,287 bp and encodes for a protein of 641 aa (73.6 kDa). Phylogenetic analyses of the arthropod hemocyanin sequences show that the Onychophora form a robust sister-group of the Euarthropoda, whereas the monophyly of the Tracheata is not supported.     

Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with newly diagnosed/untreated multiple myeloma

Introduction

Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination in patients with multiple myeloma (MM). In the present protocol, bortezomib was combined with bendamustine and prednisone, in order to assess the efficacy and safety of this combination therapy in patients with newly diagnosed/untreated MM.

Methods

Between June 2006 and October 2013, 49 patients with newly diagnosed/untreated MM were treated with bendamustine 60 mg/m² on days 1 and 2, bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 bendamustine, prednisone and bortezomib (BPV) once every 21 days. Patients were divided into three groups: group A (n = 19) consisted of patients with normal renal function or mild dysfunction (eGFR ≥60 ml/min), group B (n = 15) patients with moderate or severe renal dysfunction (eGFR 15–59 ml/min) and group C (n = 15) patients with renal failure/dialysis (eGFR <15 ml/min).

Results

A median number of two (range 1–5) BPV treatment cycles were given to the patients. The majority of the patients (n = 40, 82 %) responded after at least one cycle of BPV therapy with five stringent complete responses (CRs), nine near complete responses, 12 very good partial responses and 14 partial responses. Five patients had MR, three stable and one progressive disease. After a median observation time of 13 months, progression-free survival (PFS) and overall survival (OS) at 12 months were 92 and 94 %, respectively, for patients with normal renal function or mild renal dysfunction (group A) and 83 and 93 %, respectively, for patients with moderate or severe renal dysfunction (group B). Outcome for these patients was slightly better but not statistically significantly better than that for patients with renal failure/dialysis (group C), who had a PFS, and OS of 66 % (p = 0.08) and 73 % (p = 0.05), respectively.

Summary

These results indicate that this BPV combination is feasible, effective and well tolerated in patients with newly diagnosed MM and normal or impaired renal function.