Neurokinin NK1 and NK3 receptors as targets for drugs to treat gastrointestinal motility disorders and pain

NK1 and NK3 receptors do not appear to play significant roles in normal GI functions, but both may be involved in defensive or pathological processes. NK1 receptor antagonists are antiemetic, operating via vagal sensory and motor systems, so there is a need to study their effects on other gastro-vagal functions thought to play roles in functional bowel disorders. Interactions between NK1 receptors and enteric nonadrenergic, noncholinergic motorneurones suggest a need to explore the role of this receptor in disrupted colonic motility. NK1 receptor antagonism does not exert consistent analgesic activity in humans, but similar studies have not been carried out against pain of GI origin, where NK1 receptors may have additional influences on mucosal inflammatory or "irritant" processes. NK3 receptors mediate certain disruptions of intestinal motility. The activity may be driven by tachykinins released from intrinsic primary afferent neurones (IPANs), which induce slow EPSP activity in connecting IPANs and hence, a degree of hypersensitivity within the enteric nervous system. The same process is also proposed to increase C-fibre sensitivity, either indirectly or directly. Thus, NK3 receptor antagonists inhibit intestinal nociception via a "peripheral" mechanism that may be intestine-specific. Studies with talnetant and other selective NK3 receptor antagonists are, therefore, revealing an exciting and novel pathway by which pathological changes in intestinal motility and nociception can be induced, suggesting a role for NK3 receptor antagonism in irritable bowel syndrome.     

Hereditary chronic lymphocytic leukemia: an extended family study and literature review

Leukemia is manifested in about 1-2% of people in Western industrialized nations. The most common form of leukemia is B-cell chronic lymphocytic leukemia (B-CLL), which accounts for approximately 30% of all cases. While CLL's etiology remains elusive, there is increasing evidence that substantially supports the role of hereditary factors in a subset of cases of this disease. Our purpose is to describe an extremely well documented CLL family wherein the disease has been verified in a father and his four sons; two of the sons are identical twins. The family history, including available medical records and pathology reports, was gathered and reviewed. Peripheral blood lymphocytes were used for cytogenetic and fluorescence in situ hybridization analyses. The family reported herein shows classic findings in support of an autosomal dominant mode of genetic transmission of CLL. Given the explosive developments in molecular genetics during the past decade, it is certain that families of this type will provide important clues to the etiology, pathogenesis, and ultimate prevention of CLL.     

Return to work outcomes after work-related hand trauma: the role of causal attributions

PURPOSE: This study examined the relationship between workers' judgments of responsibility for their accidents (causal attributions) and work-site avoidance after work-related injuries. METHODS: Ninety-two hand-injured workers referred for psychologic treatment of posttraumatic stress and depressive symptoms were assessed for their beliefs about the cause(s) of their accidents. Causal attributions were obtained before and after psychologic intervention. RESULTS: Workers who blamed coworkers or equipment for their injuries were more likely to resist returning to former work activities than workers who judged themselves responsible for their accidents. In addition those with relatively minor injuries were as much at risk for work-site avoidance as those with more severe injuries. Age, gender, and length of employment with current employer were unrelated to avoidance. CONCLUSIONS: These results suggest the importance of causal attributions as potential predictors of work-site avoidance after traumatic work-related hand injuries, and support the risk for psychologic symptom development after less-severe injuries.     

Evidence for the involvement of central 5-HT7 receptors in the micturition reflex in anaesthetized female rats

(1) The effects of the selective 5-HT7 receptor antagonists SB-269970 (3-300 microg kg-1; n=5-6) and SB-656104 (30 microg kg-1; n=5) administered centrally (i.c.v.) were investigated on the 'micturition reflex' in the urethane anaesthetized female rat. (2) In cystometric recordings, SB-269970 caused significant increases in volume of 58+/-15 and 138+/-33% and pressure of 140+/-46 and 149+/-60% thresholds at 10 and 30 microg kg-1. These changes were associated with significant decreases in distension-induced bladder contraction of 62+/-14 and 60+/-11%, respectively. However, there was no change in residual volume. At the higher doses, SB-269970 blocked the micturition reflex. SB-656104 had similar effects to SB-269970 but in addition significantly increased the residual volume. (3) SB-269970 (10 microg kg-1; n=5) given i.v. had no effect on the micturition reflex. (4) SB-269970 (30 microg kg-1; n=4) given intrathecally (i.t.) had no effect on micturition reflex, although the selective 5-HT1A receptor antagonist WAY-100635 given i.t. after SB-269970 caused a significant increase in the volume threshold. (5) Using an isovolumetric method in which urethral changes were measured, SB-269970 (30 microg kg-1; n=4; i.c.v.) failed to have any effect on these urethral-evoked changes although they significantly reduced the amplitude of the bladder contraction. (6) These data demonstrate that 5-HT7 receptors located supraspinally in the rat are involved in the control of micturition.     

LTP but not seizure is associated with up-regulation of AKAP-150

We have used differential display to profile and compare the mRNAs expressed in the hippocampus of freely moving animals after the induction of long-term potentiation (LTP) at the perforant path-dentate gyrus synapse with control rats receiving low-frequency stimulation. We have combined this with in situ hybridization and have identified A-kinase anchoring protein of 150 kDa (AKAP-150) as a gene selectively up-regulated during the maintenance phase of LTP. AKAP-150 mRNA has a biphasic modulation in the dentate gyrus following the induction of LTP. The expression of AKAP-150 was 29% lower than stimulated controls 1 h after the induction of LTP. Its expression was enhanced 3 (50%), 6 (239%) and 12 h (210%) after induction, returning to control levels by 24 h postinduction. The NMDA receptor antagonist CPP blocked the tetanus-induced modulation of AKAP-150 expression. Interestingly, strong generalized stimulation produced by electroconvulsive shock did not increase the expression of AKAP-150. This implies that the AKAP-150 harbours a novel property of selective responsiveness to the stimulation patterns that trigger NMDA-dependent LTP in vivo. Its selective up-regulation during LTP and its identified functions as a scaffold for protein kinase A, protein kinase C, calmodulin, calcineurin and ionotropic glutamate receptors suggest that AKAP-150 encodes is an important effector protein in the expression of late LTP.     

Magnifying prismatic lenses for vitrectomy

PURPOSE: Viewing the fundus at higher magnification during vitrectomy makes surgical procedures much safer; however, the scope of magnification of the peripheral fundus has been limited. For better visualization of the periphery of the fundus, we have developed two new contact lenses called magnifying prismatic lenses. METHODS: The magnifying 15 degrees and 30 degrees prismatic lenses are made of a glass with a high index of refraction (n = 1.883). The lenses have a convex upper surface to provide a magnified view of the peripheral fundus. RESULTS: These magnifying 15 degrees and 30 degrees prismatic lenses provide an approximately 2x magnified view of the peripheral fundus. They also provide a more extensive view of the peripheral fundus than a regular (plano-concave) prismatic lens when the eye is tilted. CONCLUSION: The magnifying prismatic lenses are useful for viewing into the peripheral fundus with higher magnification.     

Congenitally anomalous tented eyebrows

PURPOSE: An uncommon congenital anomaly of the eyebrows is described. METHODS: Case report and review of the literature. RESULTS: Two articles in the English literature were found describing patients similar to ours. CONCLUSIONS: Congenital upward tenting of the midportion of the eyebrows, resembling the eyebrow line of an owl, is uncommon. This anomaly is thought to be transmitted in an autosomal dominant fashion and may be accompanied by myopia and strabismus, but has not been associated with systemic disease.     

Cultural analysis of communication behaviors among juveniles in a correctional facility

This study addressed communication behaviors of female juvenile delinquents in a correctional facility. Qualitative methodology was used to study 78 participants ranging in age from 13.1 to 18.9 (years; months), over a five-month period. Data collection consisted of observations, participant observation, interviews, and a review of documents. Additionally, participants were tested on the Clinical Evaluation of Language Fundamentals-3. Listening and following rules, utterance types, topics of conversion, politeness, and conversational management emerged as themes. Findings indicated that as many as 22% of participants were potential candidates for language services. Implications for speech-language pathologists (SLPs) providing communication services will be provided.     

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone (HDMP) to prevent 'trafficking' of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the 'blood brain barrier (BBB)'. Three men with newly diagnosed PCNSL, ages 62, 76 and 78y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin's lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+ months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.