Hard domains, biased rationalizations, and unanswered empirical questions.

Cushman raises the intriguing possibility that rationalization accesses/constructs intuitions that are not otherwise cognitively available. However, he substantially over-reaches in arguing that rationalization is mostly right on average, based on claims that the process must have emerged adaptively. The adaptiveness of "bounded rationalization" is domain specific and is unlikely to be adaptive in a large number of important applications.

The effect of local anesthetic on pro-inflammatory macrophage modulation by mesenchymal stromal cells.

Administering local anesthetics (LAs) peri- and post-operatively aims to prevent or mitigate pain in surgical procedures and after tissue injury in cases of osteoarthritis (OA) and other degenerative diseases. Innovative tissue protective and reparative therapeutic interventions such as mesenchymal stromal cells (MSCs) are likely to be exposed to co-administered drugs such as LAs. Therefore, it is important to determine how this exposure affects the therapeutic functions of MSCs and other cells in their target microenvironment. In these studies, we measured the effect of LAs, lidocaine and bupivacaine, on macrophage viability and pro-inflammatory secretion. We also examined their effect on modulation of the macrophage pro-inflammatory phenotype in an in vitro co-culture system with MSCs, by quantifying macrophage tumor necrosis factor (TNF)-α secretion and MSC prostaglandin E2 (PGE2) production. Our studies indicate that both LAs directly attenuated macrophage TNF-α secretion, without significantly affecting viability, in a concentration- and potency-dependent manner. LA-mediated attenuation of macrophage TNF-α was sustained in co-culture with MSCs, but MSCs did not further enhance this anti-inflammatory effect. Concentration- and potency-dependent reductions in macrophage TNF-α were concurrent with decreased PGE2 levels in the co-cultures further indicating MSC-independent macrophage attenuation. MSC functional recovery from LA exposure was assessed by pre-treating MSCs with LAs prior to co-culture with macrophages. Both MSC attenuation of TNF-α and PGE2 secretion were impaired by pre-exposure to the more potent bupivacaine and high dose of lidocaine in a concentration-dependent manner. Therefore, LAs can affect anti-inflammatory function by both directly attenuating macrophage inflammation and MSC secretion and possibly by altering the local microenvironment which can secondarily reduce MSC function. Furthermore, the LA effect on MSC function may persist even after LA removal.

Effect of Local Anesthetics on Human Mesenchymal Stromal Cell Secretion.

Anti-fibrotic and tissue regenerative mesenchymal stromal cell (MSC) properties are largely mediated by secreted cytokines and growth factors. MSCs are implanted to augment joint cartilage replacement and to treat diabetic ulcers and burn injuries simultaneously with local anesthetics, which reduce pain. However, the effect of anesthetics on therapeutic human MSC secretory function has not been evaluated. In order to assess the effect of local anesthetics on the MSC secretome, a panel of four anesthetics with different potencies - lidocaine, procaine, ropivacaine and bupivacaine - was evaluated. Since injured tissues secrete inflammatory cytokines, the effects of anesthetics on MSCs stimulated with tumor necrosis factor (TNF)-α and interferon (IFN)-γ were also measured. Dose dependent and anesthesia specific effects on cell viability, post exposure proliferation and secretory function were quantified using alamar blue reduction and immunoassays, respectively. Computational pathway analysis was performed to identify upstream regulators and molecular pathways likely associated with the effects of these chemicals on the MSC secretome. Our results indicated while neither lidocaine nor procaine greatly reduced unstimulated cell viability, ropivacaine and bupivacaine induced dose dependent viability decreases. This pattern was exaggerated in the simulated inflammatory environment. The reversibility of these effects after withdrawal of the anesthetics was attenuated for TNF-α/IFN-γ-stimulated MSCs exposed to ropivacaine and bupivacaine. In addition, secretome analysis indicated that constitutive secretion changes were clearly affected by both anesthetic alone and anesthetic plus TNFα/IFNγ cell stimulation, but the secretory pattern was drug specific and did not necessarily coincide with viability changes. Pathway analysis identified different intracellular regulators for stimulated and unstimulated MSCs. Within these groups, ropivacaine and bupivacaine appeared to act on MSCs similarly via the same regulatory mechanisms. Given the variable effect of local anesthetics on MSC viability and function, these studies underscore the need to evaluate MSC in the presence of medications, such as anesthetics, that are likely to accompany cell implantation.

Efficacy of ginger on intraoperative and postoperative nausea and vomiting in elective cesarean section patients.

OBJECTIVE: To evaluate the efficacy of dry powdered ginger, given orally, on nausea and vomiting during and after an elective cesarean section performed under combined spinal epidural anesthesia. STUDY DESIGN: 239 women, ginger (n=116) and placebo (n=123), who underwent elective cesarean section at term under combined spinal-epidural anesthesia were provided with standard preoperative antiemetic treatment in addition to a randomized study drug. They were given two capsules (1g each) of either dry powdered ginger or placebo, one capsule a half-hour before induction of anesthesia and the second 2h after surgery. The study was double-blinded and the incidences of nausea and vomiting were assessed both intraoperatively and postoperatively. Levels of pain and pruritus were also assessed postoperatively. RESULTS: The intraoperative incidence of nausea was 52% and 61%, ginger versus placebo (p=0.149). The number of episodes of intraoperative nausea was less in the ginger group compared to placebo (mean difference was -0.396, 95% CI -0.738, -0.054) and the result was statistically significant (p=0.023). The incidence of intraoperative vomiting was 27.35% in the ginger group and 36.59% in the placebo group, and the difference was not statistically significant (p=0.126). The number of episodes of vomiting during surgery was less in the ginger group compared to placebo: (mean difference -0.158, 95% CI -0.626, 0.311) although statistically insignificant (p=0.505). Furthermore, postoperatively, there was no statistical difference in the incidence of nausea and vomiting assessed at 0, 2, 2 ½ and 24h after surgery. There were also no differences in postoperative pain or pruritus. CONCLUSION: Ginger given in dry powdered form reduced the number of episodes of intraoperative nausea compared to a placebo, but it had no effect on incidence of nausea, vomiting, or pain during and after an elective cesarean section performed under combined spinal epidural anesthesia.

Transmission clustering drives the onward spread of the HIV epidemic among men who have sex with men in Quebec.

Phylodynamic analysis and epidemiologic data identified 3 patterns of spread of primary human immunodeficiency virus type 1 infection (PHI) among men who have sex with men (2001-2009): 420 unique PHIs, 102 small clusters (2-4 PHIs per cluster, n = 280), and 46 large clusters (5-31 PHIs per cluster, n = 450). Large clusters disproportionately increased from 25.2% of PHIs in 2005 to 39.1% in 2009 (χ(2) = 33.9, P < .001). Scalar expansion of large clusters over 11 months (interquartile range, 3.5-25.5 months) correlated with cluster membership size (r(2) = 0.174, F = 4.424, P = .047). PHI cohort data revealed variations in social networks and risk behaviors among the 3 groups, suggesting the need for tailored prevention measures.

Two uneliminated uses for "concepts": hybrids and guides for inquiry.

Machery's case against hybrids rests on a principle that is too strong, even by his own lights. And there are likely important generalizations to be made about hybrids, if they do exist. Moreover, even if there were no important generalizations about concepts themselves, the term picks out an important class of entities and should be retained to help guide inquiry.

Bicarbonate plus epinephrine shortens the onset and prolongs the duration of sciatic block using chloroprocaine followed by bupivacaine in sprague-dawley rats.

BACKGROUND: Chloroprocaine is a fast-acting local anesthetic, whereas bupivacaine is a long-acting one. They have been coadministered with limited success. The objective of this study was to determine the effect of additives on the efficacy of regional blockade using chloroprocaine followed by bupivacaine. METHODS: Four groups of Sprague-Dawley rats, 20 each, were administered chloroprocaine followed by bupivacaine to induce sciatic nerve blockade. Group 1 received chloroprocaine with isotonic sodium chloride solution followed by bupivacaine and was used as a control. Group 2 received chloroprocaine with isotonic sodium chloride solution and epinephrine followed by bupivacaine with epinephrine. Group 3 received chloroprocaine with sodium bicarbonate followed by bupivacaine, and group 4 received chloroprocaine with sodium bicarbonate and epinephrine followed by bupivacaine with epinephrine. The time to onset and duration of anesthesia were measured for all 4 groups. RESULTS: The block using chloroprocaine followed by bupivacaine in group 1 had an onset of 2.5 mins (SD, 0.4 mins) and duration of 104 mins (SD, 16 mins). Adding epinephrine to both chloroprocaine and bupivacaine (group 2) did not significantly change the onset (2.8 mins [SD, 1.3 mins]; P = 0.35) or duration (110 mins [SD, 25 mins]; P = 0.23). With group 3, adding bicarbonate to chloroprocaine hastened the onset (1.2 mins [SD, 0.4 mins]; P < 0.0001) and shortened the duration (87 mins [SD, 13 mins]; P = 0.008). In group 4, adding bicarbonate and epinephrine to chloroprocaine and epinephrine to bupivacaine hastened the onset (1.4 mins [SD, 0.4 mins]; P < 0.0001) and increased the duration (130 mins [SD, 23 mins]; P < 0.0001). CONCLUSIONS: Sodium bicarbonate plus epinephrine shortens the onset and prolongs the duration of a chloroprocaine-bupivacaine sciatic block in Sprague-Dawley rats.

Comparison of the potency of lidocaine and chloroprocaine in sciatic nerve block in Sprague-Dawley rats.

AIM: This study investigates the relative potencies and ED(50) of the local anesthetics lidocaine and chloroprocaine in a sciatic block in Sprague-Dawley rats. METHODS: The study involved 80 rats (chloroprocaine n = 40, lidocaine n = 40). Each rat was injected close to the sciatic nerve with 0.1 ml of the concentration of local anesthetic being tested. Using the up-and-down allocation technique, the next concentration was determined by the response of the previous subject to a higher or lower concentration. A successful block was assessed by pinching the fifth metatarsal. Absent vocalization and a very weak withdrawal response were defined as the onset of block. RESULTS: Using the up-and-down methodology, the estimates of ED(50) for chloroprocaine was 0.1 ml of 1.2% (with 95% CI of 1.1-1.6), and that for lidocaine was 0.1 ml of 0.65% (with 95% CI of 0.65-0.88), giving a lidocaine/chloroprocaine potency ratio of 1.85 (with 95% CI of 1.66-2.61). DISCUSSION: Using the results of this study, the effects of the two drugs can be compared using the commercially available concentrations of chloroprocaine and lidocaine in a peripheral nerve block.