Pentoxifylline and propentofylline prevent proliferation and activation of the mammalian target of rapamycin and mitogen activated protein kinase in cultured spinal astrocytes

Astrocyte activation is an important feature in many disorders of the central nervous system, including chronic pain conditions. Activation of astrocytes is characterized by a change in morphology, including hypertrophy and increased size of processes, proliferation, and an increased production of proinflammatory mediators. The xanthine derivatives pentoxifylline and propentofylline are commonly used experimentally as glial inhibitors. These compounds are generally believed to attenuate glial activity by raising cyclic AMP (cAMP) levels and inhibiting glial tumor necrosis factor (TNF) production. In the present study, we show that these substances inhibit TNF and serum‐induced astrocyte proliferation and signaling through the mammalian target of rapamycin (mTOR) pathway, demonstrated by decreased levels of phosphorylated S6 kinase (S6K), commonly used as a marker of mTOR complex (mTORC) activation. Furthermore, we show that pentoxifylline and propentofylline also inhibit JNK and p38, but not ERK, activation induced by TNF. In addition, the JNK antagonist SP600125, but not the p38 inhibitor SB203580, prevents TNF‐induced activation of S6 kinase, suggesting that pentoxifylline and propentofylline may regulate mTORC activity in spinal astrocytes partially through inhibition of the JNK pathway. Our results suggest that pentoxifylline and propentofylline inhibit astrocyte activity in a broad fashion by attenuating flux through specific pathways. © 2012 Wiley Periodicals, Inc.     

The effectiveness of medical and vocational interventions for reducing sick leave of self‐employed workers

We investigate whether interventions by (a) medical doctors and (b) occupational specialists are effective in reducing sick leave durations among self‐employed workers. Therefore, we exploit unique administrative data comprising all sick leave claims by self‐employed workers insured with a major Dutch private insurer between January 2009 and March 2014. We estimate a multivariate duration model dealing with nonrandom selection into the two intervention types by controlling for observable and unobservable claimant characteristics. We find adverse treatment effects for both interventions, irrespective of whether they are started early or (middle) late in the sickness spell.     

Implant survival in uncemented total hip arthroplasty for displaced intracapsular femoral neck fractures: outcomes of 115 patients in a single center

European Journal of Orthopaedic Surgery & Traumatology - There remains disagreement about the use of cemented or uncemented total hip arthroplasty (THA) for patients with a displaced...     

Adipokines correlate with pain in lower limb osteoarthritis: different associations in hip and knee

Purpose

Our aim was to investigate whether serum and synovial-fluid (SF) concentrations of interleukin-6 (IL-6), leptin, adiponectin, resistin or visfatin are associated with joint pain in hip and knee in end-stage osteoarthritis (OA).

Methods

A cross-sectional study assessing patients with hip and knee OA undergoing total joint arthroplasty between January and December 2010 was conducted at a large university hospital. Serum and SF cytokine and adipokine concentrations were determined in samples obtained on the day of surgery. The main outcome was pain severity measured pre-operatively using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and visual analogue scale (VAS) pain scores.

Results

A total of 206 patients were involved (112 with hip and 94 with knee OA). Median age was 72 years [interquartile range (IQR) 66–79], 59 % were women. All adipokine levels were significantly higher in the SF of hip joints than in that of knee joints, except for leptin, which tended to be higher in the knee. In both hip and knee OA, median serum concentrations of leptin, adiponectin, resistin and visfatin exceeded those in SF, whereas for IL-6, median concentrations were much higher in SF than in serum. In hip OA, worse pain was significantly associated with high SF concentrations of IL-6, visfatin and leptin; in knee OA, it was associated with high SF leptin and low SF adiponectin concentrations and a low adiponectin–leptin ratio.

Conclusion

Our findings support a connection between intra-articular concentrations of several adipokines and severity of preoperative OA pain. However, the specific adipokines differed by joints: in hip OA, pain was associated with IL-6 and visfatin and in knee OA with adiponectin; leptin played a role in both hip and knee OA.     

A Hybrid Radioactive and Fluorescent Tracer for Sentinel Node Biopsy in Penile Carcinoma as a Potential Replacement for Blue Dye

Background

Sentinel node (SN) biopsy in penile cancer is typically performed using a combination of radiocolloid and blue dye. Recently, the hybrid radioactive and fluorescent tracer indocyanine green (ICG)-^99mTc-nanocolloid was developed to combine the beneficial properties of both radio-guidance and fluorescence imaging.

Objective

To explore the added value of SN biopsy using ICG-^99mTc-nanocolloid in patients with penile carcinoma.

Design, setting, and participants

Sixty-five patients with penile squamous cell carcinoma were prospectively included (January 2011 to December 2012). Preoperative SN mapping was performed using lymphoscintigraphy and single-proton emission computed tomography supplemented with computed tomography (SPECT/CT) after peritumoural injection of ICG-^99mTc-nanocolloid. During surgery, SNs were initially approached using a gamma probe, followed by patent blue dye and/or fluorescence imaging. A portable gamma camera was used to confirm excision of all SNs.

Surgical procedure

Patients underwent SN biopsy of the cN0 groin and treatment of the primary tumour.

Outcome measurements and statistical analysis

The number and location of preoperatively identified SNs were documented. Intraoperative SN identification rates using radio- and/or fluorescence guidance were assessed and compared with blue dye. Statistical evaluation was performed using a two-sample test for equality of proportions with continuity correction.

Results and limitations

Preoperative imaging after injection of ICG-^99mTc-nanocolloid enabled SN identification in all patients (a total of 183 SNs dispersed over 119 groins). Intraoperatively, all SNs identified by preoperative SN mapping were localised using combined radio-, fluorescence-, and blue dye guidance. Fluorescence imaging enabled visualisation of 96.8% of SNs, while only 55.7% was stained by blue dye (p < 0.0001). The tissue penetration of the fluorescent signal, and the rapid flow of blue dye limited the detection sensitivity. A tumour-positive SN was found in seven patients.

Conclusions

ICG-^99mTc-nanocolloid allows for both preoperative SN mapping and combined radio- and fluorescence-guided SN biopsy in penile carcinoma patients and significantly improves optical SN detection compared with blue dye.     

Location of Lymph Node Involvement in Patients with Esophageal Adenocarcinoma Predicts Survival

Background

The location of positive lymph nodes has been abandoned in the seventh classification of the TNM staging system for esophageal adenocarcinoma. The present study evaluates whether distribution of involved nodes relative to the diaphragm in addition to TNM 7 further refines prediction.

Methods

Pathology reports of patients who underwent esophagectomy between 2000 and 2008 for adenocarcinoma of the esophagus were reviewed and staging was performed according to the seventh UICC-AJCC staging system. In addition, lymph node involvement of nodal stations above and below the diaphragm was investigated by endoscopic ultrasonography (EUS) in a separate cohort of patients who were scheduled for esophagectomy between 2008 and 2009 at two institutions. Survival was calculated by the Kaplan–Meier method, and multivariate analysis was performed with a Cox regression model.

Results

Some 327 patients who had undergone esophagectomy for cancer were included. Multivariate analysis revealed that patients with from three to six involved lymph nodes in the resection specimen on both sides of the diaphragm had a twofold higher chance of dying compared to patients with the same number of involved lymph nodes on one side of the diaphragm. EUS assessment of lymph node metastases relative to the diaphragm in 102 patients showed that nodal involvement on both sides of the diaphragm was associated with worse survival than when nodes on one side or no nodes are involved [HR (95 % CI) 2.38 (1.15–4.90)].

Conclusions

A combined staging system that incorporates distribution of lymph nodes relative to the diaphragm refines prognostication after esophagectomy as assessed in the resected specimen and pretreatment as assessed by EUS. This improved staging has the potential to have a great impact on clinical decision making as to whether to embark upon potentially curative or palliative treatments.     

Comparison of the flap survival with ischemic preconditioning on different pedicles under varied ischemic intervals in a rat bilateral pedicled flap model

The study was undertaken to search whether pedicle selection for ischemic preconditioning (IP) and duration of global ischemia applied after IP influenced efficacy of IP on flap viability in epigastric adipocutaneous island flap with bilateral pedicles in rat model. In total, 159 rats were divided into one control and three (primary, secondary, or bilateral pedicle) IP treatment groups. IP was performed on different pedicles by three cycles of 10 minutes of pedicle clamping and 10 minutes of release. After IP procedure secondary pedicle was ligated in all groups, and flaps were exposed to 0, 1, 2, 4, or 6 hours of global ischemia by clamping primary pedicle. In control groups, after the perfusion of bipedicled flaps for 1 hour, left pedicle was ligated and flaps were exposed to global ischemia as in IP groups. On day 5 post‐surgery, tissue samples and topographic measurements were taken. No significant differences in semi‐quantitative scorings of polymorphonuclear leukocytes infiltration, chronic inflammation, interstitial edema, neovascularization, VEGF, and CD105 expression levels among groups were found (P > 0.05). Percentages of necrosis were consistently smaller in IP groups compared to controls for the same duration of global ischemia, with exception of the no‐ischemia. Area of necrosis was significantly smaller in primary IP group versus secondary IP group in the absence of global ischemia (P < 0.01). In the presence of global ischemia, both primary and secondary pedicle IP groups had significantly smaller percentage of necrosis than controls (P < 0.05) and there was no significant difference between primary and secondary IP groups (P > 0.05). Thus, IP performed on different pedicles may ameliorate flap survival in a comparable fashion, depending on the duration of global ischemia. Secondary pedicle IP was as effective as primary pedicle IP and may be feasible in free flap transfers. © 2013 Wiley Periodicals, Inc. Microsurgery 34:129–135, 2014.