CD8+ T cell-derived IL-13 increases macrophage IL-10 to resolve neuropathic pain.

Understanding the endogenous mechanisms regulating resolution of pain may identify novel targets for treatment of chronic pain. Resolution of chemotherapy-induced peripheral neuropathy (CIPN) after treatment completion depends on CD8+ T cells and on IL-10 produced by other cells. Using Rag2-/- mice lacking T and B cells and adoptive transfer of Il13-/- CD8+ T cells, we showed that CD8+ T cells producing IL-13 were required for resolution of CIPN. Intrathecal administration of anti-IL-13 delayed resolution of CIPN and reduced IL-10 production by dorsal root ganglion macrophages. Depleting local CD206+ macrophages also delayed resolution of CIPN. In vitro, TIM3+CD8+ T cells cultured with cisplatin, apoptotic cells, or phosphatidylserine liposomes produced IL-13, which induced IL-10 in macrophages. In vivo, resolution of CIPN was delayed by intrathecal administration of anti-TIM3. Resolution was also delayed in Rag2-/- mice reconstituted with Havcr2 (TIM3)-/- CD8+ T cells. Our data indicated that cell damage induced by cisplatin activated TIM3 on CD8+ T cells, leading to increased IL-13 production, which in turn induced macrophage IL-10 production and resolution of CIPN. Development of exogenous activators of the IL-13/IL-10 pain resolution pathway may provide a way to treat the underlying cause of chronic pain.

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin-dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.

p53/p21(WAF1/CIP1) expression and its possible role in G1 arrest and apoptosis in ellagic acid treated cancer cells.

Ellagic acid is a phenolic compound present in fruits and nuts including raspberries, strawberries and walnuts. It is known to inhibit certain carcinogen-induced cancers and may have other chemopreventive properties. The effects of ellagic acid on cell cycle events and apoptosis were studied in cervical carcinoma (CaSki) cells. We found that ellagic acid at a concentration of 10(-5) M induced G arrest within 48 h, inhibited overall cell growth and induced apoptosis in CaSki cells after 72 h of treatment. Activation of the cdk inhibitory protein p21 by ellagic acid suggests a role for ellagic acid in cell cycle regulation of cancer cells.

Imaging appearances of metastases from neuroendocrine tumours of the pancreas.

Endocrine tumours of the pancreas (ETPs) are rare neoplasms that are frequently malignant. Despite their usual slow growth, metastases do occur and have a major impact on prognosis. Metastases may be the first manifestation of disease, and recognition of particular radiological features of these hypervascular metastases should suggest their possible neuroendocrine origin. Although somatostatin receptor scintigraphy has changed the imaging strategy for these tumours and has become their principal imaging modality, radiological techniques are still required for precise localization of scintigraphic hot spots and monitoring of response to therapy. This pictorial review shows the typical radiological features of ETP metastases and emphasizes the role of different imaging modalities.

[Thrombosis from mechanical valve prostheses in the Reunion island]. / Thrombose de prothèses valvulaires mécaniques à l'île de la Réunion.

Between October 1991 and January 1995, 10 patients presented 14 episodes of thrombosis of mechanical valve prosthesis, 11 obstructive, 3 nonobstructive. In two cases, the thrombosis was recurrent (one after thrombolysis, one after surgical thrombectomy). In another two cases, the thrombosis was a recurrence (on a valve already surgically replaced because of thrombosis). Anticoagulant therapy had been ineffective in 9 cases; protein S deficiency was diagnosed in one case. Transoesophageal echography allowed diagnoses in all cases. Thrombolysis was the treatment of first intention in 9 cases (completed by a second course of thrombolysis in one case and by valvular replacement in two cases. The other patients were managed by immediate valve replacement in two cases, thrombectomy in one case, long-term parenteral anticoagulation in two cases (one of which was followed by valve replacement). Transoesophageal echography showed improved valve motion. Incomplete thrombus dissolution was observed in 50% of cases. Thrombolytic therapy was complicated by cerebrovascular accidents in two patients, one of which was fatal. One patient had regressive hemiplegia, one patient had a local hematoma. The authors conclude that thrombosis is a serious complication of valve replacement and usually occurs in patients inadequately anticoagulated. Thrombolysis may enable some patients to avoid reoperation but its risks limits its use to those patients thought to be unacceptable surgical risks. An apparently high frequency of this complication durind this period has led to the initiation of a study to determine the predisposing factors and to put preventive measures into action.

[Interest of coronary flow reserve of the LAD during dobutamine stress echocardiography]. / Faisabilité et intérêt de la mesure de la réserve coronaire de l'IVA lors de l'échographie dobutamine.

AIM OF THE STUDY: To assess the value of the coronary flow reserve (CFR) in the left anterior descending artery (LAD) during dobutamine stress echocardiography in the diagnosis of significant LAD stenosis (more than 70%). METHOD: Retrospective study of 81 patients with a positive stress echocardiography who underwent a coronarography. RESULTS: Measurement of coronary flow reserve was able in half echocardiographic exams. Medium Pic diastolic velocity was 0.33 m/s (SD 0.20), medium maximal diastolic velocity during stress was 0.62 m/s (SD 0.20), medium CFR was 2.25 (SD 0.65). In 50 patients LAD was not seen; in five of them LAD was occluded. The predictive positive value (PPV) of a low coronary flow reserve to detect LAD stenosis is 66.7% and the negative predictive value (NPV) is 65.4%. An abnormal anterior contraction during stress echo with a low reserve has a PPV of 75% for the diagnosis of significant IVA stenosis and a normal contraction during stress with normal coronary flow reserve means a NPV of 65%. We did not show a significant correlation between low coronary flow and abnormal contraction during stress echocardiography (kappa 0.51). CONCLUSION: Coronary flow reserve of LAD during stress echo is feasible but does not really improve exam performance to detect significant IVA stenosis. This measurement remains to be clear in coronary patients management.

Videoconference pediatric and congenital cardiology consultations: a new application in telemedicine.

BACKGROUND: The relative rarity of congenital heart disease gives it an orphean disease status, requiring specialised centres. The present maturity of information technology allows telemedicine to be integrated into current medical practice. We report our experience of telemedicine between the cardiology department at St Pierre Hospital on the island of Réunion and the pediatric cardiology department at the teaching hospital in Toulouse. AIMS: The aims of this work were to 1. verify the technical feasibility of transmitting echocardiographic images, 2. determine an optimal therapeutic strategy for each patient, and 3. deliver precise information live to patients and their families. METHODS: Five pediatric cardiology videoconference consultation sessions were transmitted between April 2006 and May 2007. The videoconference equipment, POLYCOM VSX 7000 (R), was used to relay information between the two centres, using six high-debit digital telephone lines, allowing a transfer rate of 384 kbits/s and an image frequency of 25 frames per second. The echocardiographic equipment at St Pierre Hospital was connected to the videoconference equipment by an S-VHS video output. The transmitted sources alternated between the echographic video output and the signal from a video camera, with continuous audio transmission. RESULTS: The telemedicine meeting was made up of three main elements: 1. a consultation with real-time echocardiographic acquisition and transmission, 2. a discussion between medical colleagues, and 3. a discussion with the family. Five videoconference consultation sessions were organised between April 2006 and May 2007. 22 patients were involved (median age 3 years, age range 7 days to 48 years). Heart disease was congenital in 20 patients, and acquired in 2 patients. The aim of the telemedicine consultation was to specify: 1. medical treatment in 7 patients, and 2. an indication for surgery or interventional catheterisation in 15 patients. There was no significant change in diagnosis, but in 2 patients with complex heart disease some anatomical clarifications were made. For 3 patients, the videoconference discussion was essential to get the extremely reticent families to accept the indication for surgery. CONCLUSION: This is the first experience in France of telemedicine consultation for pediatric and congenital cardiology. These videoconferences allowed patients in the south of Réunion to benefit from a specialist opinion on optimal therapeutic strategy, with no delay or need to travel a long distance.

Characterization of the cloned HEL cell thromboxane A2 receptor: evidence that the affinity state can be altered by G alpha 13 and G alpha q.

Thromboxane A2 (TXA2) induces activation of platelets and vascular smooth muscle contraction via cell surface receptors. A platelet type TXA2 receptor from the megakaryocyte-like HEL cell was cloned with a deduced amino acid sequenced identical to that previously reported for the human placental TXA2 receptor. Transient expression of the HEL cell TXA2 receptor cDNA and radioligand binding studies with the agonist 125I-BOP showed a single class of binding sites with an affinity comparable to a low affinity platelet TXA2 receptor. Using a series of 13-azapinane TXA2 analogs, which discriminate between TXA2 receptor subtypes in platelets and vascular smooth muscle, we found that the cloned HEL cell TXA2 receptor is characteristic of a platelet type TXA2 receptor and that its binding characteristics are different from those of vascular smooth muscle cells. The affinity of the HEL cell TXA2 receptor for 125I-BOP was significantly (P < .05) increased upon co-transfection with G alpha 13 alone, or with G alpha q alone and with G alpha 13 and G alpha 12 together (n = 4-6). GTP gamma S significantly (P < .05) decreased the affinity of the receptor for 125I-BOP in COS-7 cell membranes coexpressing HEL-TXR and G alpha 13 to a value comparable to HEL-TXA2 receptor alone. We conclude that 1) the cloned HEL cell TXA2 receptor has pharmacological characteristics of a low affinity platelet type receptor and 2) that the affinity state of this receptor may be influenced by interaction with G alpha 13 and G alpha q.

Upper extremity digital subtraction venography with gadoterate meglumine before fistula creation for hemodialysis.

BACKGROUND: The purpose of this study was to evaluate the feasibility, safety, and potential role of gadoterate meglumine (Gd-DOTA) as a contrast agent for upper extremity venography before the creation of an arteriovenous fistula (AVF) for nondialyzed renal insufficiency patients. METHODS: Over a 16-month period, 50 venographies were performed on end-stage renal insufficiency patients, using Gd-DOTA as a contrast agent on a high-resolution digital subtraction angiography system. Three sequences were performed on forearm, arm, and chest at 3 mL/sec for a total of 35 mL of Gd-DOTA. Examinations were reviewed by two radiologists for diagnostic and opacification quality. Tolerance was evaluated on the evolution of serum creatinine levels and occurrence of pain during injection. RESULTS: Good interobserver correlation was obtained in evaluating the feasibility of AVF creation by vein segment (0.64 < kappa < 0.88) and in relationship to opacification quality (0.62 to 0.87). No deterioration in renal function (creatinine level before and after) or pain was observed. Twenty-six patients underwent surgical creation of brachiobasilic (N = 8), brachiocephalic (N = 8), radiocephalic (N = 8), and cubitocephalic (N = 1) fistulas or insertion of a polytetrafluoroethylene (PTFE) graft (N = 1). Seventeen were awaiting AVF or were on peritoneal dialysis. Two died before surgery for reasons unconnected with the venography. CONCLUSIONS: Venography with Gd-DOTA is an effective and safe technique in planning AVFs for renal insufficiency patients.