Transcranial Direct Current Stimulation of the Dorsolateral Prefrontal Cortex Alters Emotional Modulation of Spinal Nociception

Emotion has a strong modulatory effect on pain perception and spinal nociception. Pleasure inhibits pain and nociception, whereas displeasure facilitates pain and nociception. Dysregulation of this system has been implicated in development and maintenance of chronic pain. The current study sought to examine whether emotional modulation of pain could be altered through the use of transcranial direct current stimulation (tDCS) to enhance (via anodal stimulation) or depress (via cathodal stimulation) cortical excitability in the dorsolateral prefrontal cortex. Thirty-two participants (15 female, 17 male) received anodal, cathodal, and sham tDCS on three separate occasions, followed immediately by testing to examine the impact of pleasant and unpleasant images on pain and nociceptive flexion reflex (NFR) responses to electrocutaneous stimulation. Results indicated that tDCS modulated the effect of image content on NFR, F(2, 2175.06) = 3.20, P= .04, with the expected linear slope following anodal stimulation (ie, pleasant < neutral < unpleasant) but not cathodal stimulation. These findings provide novel evidence that the dorsolateral prefrontal cortex is critical to emotional modulation of spinal nociception. Moreover, the results suggest a physiological basis for a previously identified phenotype associated with risk for chronic pain and thus a potentially new target for chronic pain prevention efforts.PerspectiveThis study demonstrated that reduction of dorsolateral prefrontal cortical excitability by transcranial direct current stimulation attenuates the impact of emotional image viewing on nociceptive reflex activity during painful electrocutaneous stimulation. This result confirms there is cortical involvement in emotional modulation of spinal nociception and opens avenues for future clinical research.     

Value of biopsy of accessory salivary glands for the diagnosis of amyloidosis

There are few reports of amyloidosis diagnosed by deliberate biopsy of accessory salivary glands. Usually, a biopsy performed for dry mouth syndrome reveals an unsuspected amyloidosis. We report the case of 2 patients with lambda-type light chain monoclonal gammapathy complicated by generalized amyloidosis and in whom biopsy of the accessory salivary glands showed signs of amyloidosis. In the first patient accessory salivary gland biopsy was performed because these glands were enlarged, and the monoclonal dysglobulinaemia was subsequently diagnosed by serum immunoelectrophoresis. In the second patient with nephrotic syndrome, renal biopsy could not be carried out owing to the presence of a renal malformation; amyloidosis was confirmed by periumbilical fat aspiration, and a systematic biopsy of accessory salivary glands also showed evidence of amyloidosis. Biopsy of accessory salivary glands seems to be a particularly simple and safe method to detect generalized amyloidosis in patients with chronic inflammatory disease or monoclonal dysglobulinaemia.     

Phospholipase A2 regulates eicosanoid class switching during inflammasome activation

Initiation and resolution of inflammation are considered to be tightly connected processes. Lipoxins (LX) are proresolution lipid mediators that inhibit phlogistic neutrophil recruitment and promote wound-healing macrophage recruitment in humans via potent and specific signaling through the LXA₄ receptor (ALX). One model of lipoxin biosynthesis involves sequential metabolism of arachidonic acid by two cell types expressing a combined transcellular metabolon. It is currently unclear how lipoxins are efficiently formed from precursors or if they are directly generated after receptor-mediated inflammatory commitment. Here, we provide evidence for a pathway by which lipoxins are generated in macrophages as a consequence of sequential activation of toll-like receptor 4 (TLR4), a receptor for endotoxin, and P2X₇, a purinergic receptor for extracellular ATP. Initial activation of TLR4 results in accumulation of the cyclooxygenase-2–derived lipoxin precursor 15-hydroxyeicosatetraenoic acid (15-HETE) in esterified form within membrane phospholipids, which can be enhanced by aspirin (ASA) treatment. Subsequent activation of P2X₇ results in efficient hydrolysis of 15-HETE from membrane phospholipids by group IVA cytosolic phospholipase A₂, and its conversion to bioactive lipoxins by 5-lipoxygenase. Our results demonstrate how a single immune cell can store a proresolving lipid precursor and then release it for bioactive maturation and secretion, conceptually similar to the production and inflammasome-dependent maturation of the proinflammatory IL-1 family cytokines. These findings provide evidence for receptor-specific and combinatorial control of pro- and anti-inflammatory eicosanoid biosynthesis, and potential avenues to modulate inflammatory indices without inhibiting downstream eicosanoid pathways.A complex network of danger-sensing receptors and bioactive peptide and lipid signals, including cytokines and eicosanoids, regulates innate immunity. Toll-like receptor (TLR) priming is suggested as a precautionary step in building a significant inflammatory response by driving production of IL-1 family protokines, which remain inactive until a second stimulus drives them to bioactive maturation and secretion (1). The second step of this process has been most strongly linked to extracellular ATP and specifically to one of its purinergic receptors, P2X₇ (2, 3), particularly in macrophages (4).TLR stimulations also increase prostaglandin synthesis by activating cytosolic phospholipase A₂ (cPLA₂) through a Ca²⁺-independent mechanism to release arachidonic acid (AA) from phospholipids, and by increasing expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E₂ synthase-1. P2X₇ stimulation activates cPLA₂ through a Ca²⁺-dependent mechanism that couples AA metabolism with 5-lipoxygenase (5-LOX)-activating protein (FLAP), Ca²⁺-activated 5-LOX, and constitutive COX-1 to form leukotrienes (LTs) and prostaglandins (PGs). Short-term (∼1 h) TLR priming of Ca²⁺ ionophore/P2X₇-activated immune cells enhances LT synthesis (5, 6), but long-term TLR priming (16–18 h) significantly suppresses LT synthesis by different cell-type–specific mechanisms (7, 8).Whereas PGE₂, PGI₂, and LTC₄ promote local edema from postcapillary venules, and LTB₄ amplifies neutrophil recruitment to initiate pathogenic killing, subsequent “class switching” to lipoxin (LX) formation by “reprogrammed” neutrophils inhibits additional neutrophil recruitment during self-resolving inflammatory resolution (9). The direct link between inflammatory commitment and resolution mediated by eicosanoid signaling in macrophages remains unclear from short-term vs. long-term priming, but the complete temporal changes and important interconnections within the entire eicosadome are now demonstrated.     

Comparison between two thoracotomy closure techniques: postoperative pain and pulmonary function

OBJECTIVE:

To compare two thoracotomy closure techniques (pericostal and transcostal suture) in terms of postoperative pain and pulmonary function.

METHODS:

This was a prospective, randomized, double-blind study carried out in the Department of Thoracic Surgery of the Luzia de Pinho Melo Hospital das Clínicas and at the University of Mogi das Cruzes, both located in the city of Mogi das Cruzes, Brazil. We included 30 patients (18-75 years of age) undergoing posterolateral or anterolateral thoracotomy. The patients were randomized into two groups by the type of thoracotomy closure: pericostal suture (PS; n = 16) and transcostal suture (TS; n = 14). Pain intensity during the immediate and late postoperative periods was assessed by a visual analogic scale and the McGill Pain Questionnaire. Spirometry variables (FEV₁, FVC, FEV₁/FVC ratio, and PEF) were determined in the preoperative period and on postoperative days 21 and 60.

RESULTS:

Pain intensity was significantly greater in the PS group than in the TS group. Between the preoperative and postoperative periods, there were decreases in the spirometry variables studied. Those decreases were significant in the PS group but not in the TS group.

CONCLUSIONS:

The patients in the TS group experienced less immediate and late post-thoracotomy pain than did those in the PS group, as well as showing smaller reductions in the spirometry parameters. Therefore, transcostal suture is recommended over pericostal suture as the thoracotomy closure technique of choice.     

The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies

The endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine-to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta-analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37,415 cases and 84,406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P < .001) for every additional copy of the G allele. No evidence for association with MI was observed.     

Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly

It has been suggested that treatment with adequate dose titration of pegvisomant, a GH antagonist, up to a maximum of 40 mg daily, can achieve IGF-1 normalisation in virtually all patients with acromegaly. On the other hand, temozolomide (TMZ), an alkylating cytostatic agent, has been reported to reduce pituitary tumour size and hormone hypersecretion in a small number of aggressive pituitary macroadenomas. In this paper we report the case of a patient resistant to very high doses of pegvisomant used in combination with somatostatin analogs (SSA) and to TMZ therapy. The patient, initially a 22 year-old man with an invasive GH-secreting pituitary macroadenoma (IGF-1, 371% upper limit of normal), had active acromegaly despite a repeat transsphenoidal surgery followed by radiotherapy and SSA (octreotide 800 μg sc daily) (IGF-1, 262% ULN). In combination with SSA, pegvisomant was started at 20 mg daily and doses were titrated up to 60 mg daily. IGF-1 was moderately reduced and stabilized at 200% ULN after 1 year of treatment. Serum pegvisomant level was 30,500 ng/l, the denaturalized GHBP concentration 1,120 pM and the endogenous GH level was 220 μg/l. Pegvisomant was stopped and TMZ therapy was given for 5 cycles. However, the patient reported an increase of acromegaly symptoms and the serum IGF-1 was raised to the same level prior to pegvisomant therapy. Consequently, pegvisomant was tried again with doses up to 100 mg daily finally resulting in normalisation of serum IGF-1 level and improvement of acromegaly symptoms and patient well-being. We conclude that in some patients with severe acromegaly refractory to multimodal therapy, biochemical control may be difficult to attain with conventional doses of pegvisomant or TMZ therapy.     

Sirolimus therapy may cause cardiac tamponade

The side‐effects associated with the immunosuppressive drug sirolimus are numerous and constitute a major limitation for its use in renal transplantation. In this study, we describe two cases of renal transplant recipients treated with sirolimus who developed pericardial tamponade associated with interstitial pneumonia, proteinuria, microcytic anemia and, in one case, lymphocytic meningitidis. An extensive search for infectious agents was negative, and all symptoms disappeared after sirolimus interruption. Therefore, this case demonstrates for the first time that sirolimus can cause pericardial tamponade as well as lymphocytic meningitidis.