Activation of peripheral 5-HT4 receptors attenuates colonic sensitivity to intraluminal distension

Tegaserod is a 5-HT(4) receptor partial agonist approved for the treatment of irritable bowel syndrome in women with constipation and in both men and women with chronic constipation. The efficacy of tegaserod is based on the importance of 5-HT(4) receptors regulating intestinal peristalsis and secretion, and possibly visceral sensory pathways. Our aim was to investigate the effect of tegaserod on colorectal sensitivity using models of normal and exaggerated responsiveness to colorectal distension (CRD). The visceromotor responses (VMR) to CRD at graded pressures (0-60 mmHg) were measured by the number of reflex abdominal contractions. Acute colorectal hypersensitivity was induced by intracolonic infusion of dilute acetic acid. Chronic hypersensitivity was observed in rats following spontaneous resolution of trinitrobenzenesulfonic acid-induced colitis. Rats with normosensitive colons served as controls. Tegaserod (0.1-10 mg kg(-1)) caused dose-dependent reduction of the VMR to CRD in control rats and in those with colonic hypersensitivity. 5-HT(4) antagonists reversed the effects of tegaserod in rats with normosensitive colons, and partially inhibited effects in rats with colonic hypersensitivity. Central administration of tegaserod had no inhibitory effect. These results support the assumption that colonic hypersensitivity could be normalized by tegaserod acting, at least in part, through peripheral 5-HT(4) receptors.     

Digit cooling influences grasp efficiency during manipulative tasks

A commonly experienced effect of cold is a sensation of numbness and loss of sensibility in the fingers. Intact tactile sensibility of the grasping digits is essential for the efficient scaling of grip force level during the manipulation of hand-held objects. We investigated whether or not cooling of the grasping digits affects scaling of the grip force magnitude in relation to the loads resulting from continuous vertical arm movements performed with a grasped instrumented object. Maxima and minima of load force occurred at the lower and upper turning point of the movement cycle, respectively, and were accompanied by maximum and minimum peaks in grip force occurring close in time prior to and following digit cooling, respectively. Thus, digit cooling did not influence the ability to adjust the grip force profile in anticipation of movement-induced fluctuations in load force. However, subjects established significantly higher grip forces against the hand-held object following digit cooling and generated a 10–70% higher ratio between grip and load forces at the upper and lower turning points of the movement cycle. It is thought that the impaired economical scaling of grip force level is the result of reduced sensory feedback from the grasping fingers during digit cooling. The results provide further evidence to support the suggestion that cutaneous afferent input plays a subordinate role in the predictive temporal regulation of the grip force profile, but is used to adapt economically the force level to the actual loading requirements during dynamic object manipulation. Electronic Publication     

Improved prognostic stratification power of CIBMTR risk score with the addition of absolute lymphocyte and eosinophil counts at the onset of chronic GVHD

The CIBMTR chronic graft-versus-host disease (cGVHD) risk score can be refined and improved for better prognostic stratification. Three hundred and seven consecutive patients diagnosed with cGVHD by the NIH consensus criteria were retrospectively reviewed and had the CIBMTR risk score applied and analyzed. The CIBMTR risk score was successfully validated in our cohort (n = 307). The 3-year overall survival (OS) rates in each risk group (RG) were 82.5 ± 11.3% (RG1), 79.4 ± 3.0% (RG2), 71.8 ± 6.3% (RG3), and 27.3 ± 13.4% (RG4). A significantly lower OS rate and higher non-relapse mortality (NRM) were noted in RG4 compared to the other RGs. However, there were no differences in OS or NRM among RG1 to 3. To improve prognostic stratification power of the CIBMTR risk score, we incorporated the absolute lymphocyte (ALC) and eosinophil count (EC) at time of cGVHD into the CIBMTR risk score. Lower ALC (<1.0 × 10⁹/L, HR 1.94, p = 0.014) and lower EC (<0.5 × 10⁹/L, HR 3.27, p = 0.014) were confirmed as adverse risk factors for OS. Patients were stratified into four revised risk groups (rRG). The 3-year OS rates were 93.3 ± 6.4% (rRG1, score 0–3), 84.9 ± 3.4% (rRG2, score 4–6), 70.9 ± 4.4% (rRG3, score 7–9), and 32.0 ± 1.1% (rRG4, score ≥ 10) (p < 0.001). The 3-year NRM rates were 0.0% (rRG1), 6.7 ± 0.4% (rRG2), 18.4 ± 0.7% (rRG3), and 57.7 ± 5.1% (rRG4) (p < 0.001). The revised CIBMTR risk score was superior to the original CIBMTR risk score for OS (p < 0.001). The revised CIBMTR risk score including ALC and EC at the onset of cGVHD improved the prognostic stratification power of the CIBMTR risk score for long-term outcomes.     

Encephalitogenic T lymphocytes develop from SJL/J hematopoietic cells transplanted into severe combined immimodeficient ( SCID) mice

Previously, we constructed chimeras by injecting hematopoietic cells from experimental autoimmune encephalomyelitis (EAE)-susceptible SJL (H-2^S) strain mice into severe combined immunodeficient (SCID) C.B-17scid /scid (H-2^d) mice. These SCID mouse-SJL mouse hematopoietic cell chimeras developed passive EAE following adoptive transfer of PLP S139–151-specific SJL T lymphocyte line cells, but were resistant to active EAE induced by primary immunization with PLP S139–151. In order to gain an understanding of the encephalitogenic potential of transplanted hematopoietic progenitors in SCID mouse-SJL mouse chimeras, we attempted to induce EAE in hematopoietic chimeras constructed with or without an additional SJL fetal thymus implant. Chimeras with the thymus implant were susceptible to passive and active EAE while chimeras without the thymus implant were susceptible to passive but not active EAE. Encephalitogenic, CD4⁺, TCR⁺ T lymphocytes were selected in vitro from PLP S139-151-immunized, thymus-implanted chimeras. These results showed that hematopoietic SJL progenitors developed into antigen-presenting accessory cells and immunocompetent encephalitogenic T lymphocytes following transplantation into SCID mice. The development of primary immune reactivity depended on a fetal thymus implant for expression in SCID mouse-SJL mouse chimeras.