IL17A and IL23R gene polymorphisms affect the clinical features and prognosis of patients with multiple myeloma.

Single nucleotide polymorphisms (SNPs) in interleukin 17 (IL17A) and IL-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. We investigated the influence of IL17A and IL23R SNPs on the risk of developing multiple myeloma (MM) and its clinical features. We obtained genomic DNA from 120 patients with MM and 201 healthy controls and detected IL17A -197 G/A (rs2275913) and IL23R H3Q (rs1884444) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method. There were no significant differences in the genotype and allele frequencies of IL17A -197 G/A and IL23R H3Q between the controls and patients with MM. Compared with the GG and GA genotypes, the IL17A AA genotype was significantly associated with lower hemoglobin levels. The IL23R HH genotype was significantly associated with higher frequency of bone lesions and plasmacytoma than the HQ and QQ genotypes. We observed significant differences in overall survival (OS) between patients treated with thalidomide and/or bortezomib and those treated conventionally. Therefore, we also examined the effect of IL17A and IL23R polymorphisms on the clinical variables and OS in patients treated with thalidomide and/or bortezomib. We observed that the IL23R HH genotype was significantly associated with poor survival compared with the QH and HH genotypes in these patients. Our findings indicate that IL17A -197 G/A and IL23R H3Q are not associated with susceptibility to MM. However, IL-17 and IL-23R polymorphisms may affect severity, bone lesions, and extra-medullary disease in patients with MM. Moreover, IL23R polymorphisms may contribute to poor prognosis in patients with MM treated with thalidomide and/or bortezomib.

Stress-induced modulation of nociceptive responses in the rat anterior cingulate cortex.

In the limbic system, the anterior cingulate cortex (ACCX) is one of the key areas involved in the close association between pain and emotion. However, neuronal changes in ACCX nociceptive responses after stress conditioning have not yet been quantitatively investigated. We investigated the modulation of nociceptive responses in the ACCX neurons following restraint stress in rats. The present study demonstrated that stress-conditioning enhanced excitatory nociceptive responses in the ACCX following tail stimuli in the mid-term (7 days). Short-term (3 days) and long-term (21 days) of stress conditioning did not affect these responses significantly. Nociceptive responses evoked by other sites of the body (nose, back and four paws) stimulation were not changed by stress-conditioning, indicating that neural information from the tail is important for emotional system modulation. It is suggested that the emotional/affective part of the pain sensation is strongly modified by stress through neuroplasticity in the ACCX.

Hypergravity conditioning on ileal movements in rats.

INTRODUCTION: Stress is a common trigger for various physiological disturbances, including feeding disorders. One of the possible mechanisms for feeding disorders may be linked to changes in intestinal movement caused by stress. Therefore, here we investigated in vitro stress-induced changes in ileal movement. METHODS: Rats (female Wistar, SPF) were divided into Control (1 G) and hypergravity (hyperG) groups. HyperG stress was applied daily for 10 min by a centrifugal apparatus for 1 to 30 d. Under barbiturate anesthesia, a 1-cm long section of the ileum was isolated and fixed in a Magnus-type chamber filled with tyrode solution. Intestinal movement was evoked by applying acetylcholine (Ach, 10(-7)-10(-5) g x ml(-1)). Antagonistic effects of adrenalin (Adr, 10(-4) g x ml(-1)) on the Ach-evoked movements were also observed. RESULTS: Clear ileum movements were observed after Ach application. The movement pattern was phasic (early) and tonic (late). Peak amplitude of the phasic wave was dose-dependent on the Ach concentration. No significant differences in the averaged peak amplitude between control and hyperG groups were observed. The peak amplitude was decreased by Adr application in both the control and hyperG groups; however, the degree of the decrement was higher in hyperG than in control at 1 d after stress loading. DISCUSSION: The present study indicates that gravity stress modified ileal movement. Although basic ileum movements evoked by Ach were not influenced by stress, they were modified by Adr at a quite early stage after stress loading, suggesting an increase in the sensitivity of Adr receptors, but not of Ach receptors in the ileum.

Disinhibitory involvement of the anterior cingulate cortex in the descending antinociceptive effect induced by electroacupuncture stimulation in rats.

The present study was conducted to clarify the role of the anterior cingulate cortex (ACCX) in acupuncture analgesia. Experiments were performed on 35 female Wistar albino rats weighing about 300 g. Single unit recordings were made from ACCX neurons with a tungsten microelectrode. Descending ACCX neurons were identified by antidromic activation from electrical shocks applied to the ventral part of the ipsilateral PAG through a concentric needle electrode. Cathodal electroacupuncture stimulation of Ho-Ku (0.1 ms in duration, 45 Hz) for 15 min was done by inserting stainless steel needles bilaterally. An anodal silver-plate electrode (30 mm x 30 mm) was placed on the center of the abdomen. Naloxone (1.0 mg/kg, i.v.) was used to test whether changes of ACCX activities were induced by the endogenous opioid system. Data were collected from a total of 73 ACCX neurons. Forty-seven neurons had descending projection to the PAG, and the other 26 had no projections to the PAG. A majority of descending ACCX neurons were inhibited by electroacupuncture stimulation. By contrast, non-projection ACCX neurons were mainly unaffected by electroacupuncture. Naloxone did not reverse acupuncture effects on the changes of ACCX neuronal activities. Acupuncture stimulation had predominantly inhibitory effects on the activities of descending ACCX neurons. Since the functional connection between ACCX and PAG is inhibitory, electroacupuncture caused disinhibition of PAG neurons, whose activity is closely related to descending antinociception to the spinal cord. This disinhibitory effect elicited by acupuncture stimulation is thought to play a significant role in acupuncture analgesia.

Comparison of stress-induced modulation of smooth-muscle activity between ileum and colon in male rats.

Stress is a well-known cause of numerous digestive conditions, including gastrointestinal-function disorders. The autonomic nervous system regulates intestinal movements via cholinergic and adrenergic efferent fibers; however it is not clear how stress could affect these control mechanisms and in particular whether in a site-dependent manner. In this study we tested in vitro the effects of topical application of acetylcholine (Ach) and adrenalin (Adr) on smooth-muscle contractions of intestinal segments isolated from stress-conditioned rats. Stress was loaded by hypergravity stimulation (10min/day) for periods of 1, 6 or 30days. As a result, stress-conditioning affected intestinal sensitivity to Ach and Adr differently at sections of the ileum and colon. In the ileum no significant differences were found between control and stress-conditioned rats, whereas in the colon, samples from 6- and 30-day stress-conditioned rats showed larger amplitudes of Ach-induced contraction, as well as greater antagonization by Adr application. These results suggest that stress conditioning can modify autonomic control of intestinal movements by altering smooth-muscle sensitivity to Ach and Adr.

Response properties of nucleus reticularis lateralis neurons after electroacupuncture stimulation in rats.

A descending inhibitory mechanism from the periaqueductal gray (PAG) to the spinal cord through the nucleus raphe magnus (NRM) is strongly involved in endogenous analgesic system produced by acupuncture stimulation. In addition to the PAG to NRM system which descends in the medial pathway of the brain stem, the nucleus reticularis lateralis (NRL) situated in the lateral part of the brain stem is reported to play an important role in modulating centrifugal antinociceptive action. In the present study, to clarify the role of NRL in acupuncture analgesia, we investigated the response properties of NRL neurons to acupuncture stimulation. The majority of NRM-projecting NRL neurons were inhibited by electroacupuncture stimulation. This effect was antagonized by ionophoretic application of naloxone, indicating that endogenous opioids act directly onto these NRL neurons. By contrast, about half of spinal projecting NRL neurons were excited by electroacupuncture stimulation, suggesting that part of the NRL neurons may modulate pain transmission directly at the spinal level.