Effects of 5-HT(3) antagonism on postprandial gastric volume and symptoms in humans

BACKGROUND: Alosetron reduces symptoms of dyspepsia, but the physiological basis for the symptomatic benefit is unclear. AIM: To assess 5-HT3 antagonism on postprandial gastric volume and symptoms after ingestion of maximum tolerable volume of a liquid meal. METHODS: In 36 healthy volunteers, we assessed effects of placebo, 0.5 and 1 mg b.d. alosetron on fasting and postprandial gastric volumes (using single photon emission computed tomography) and symptoms based on 100 mm VAS, 30 min after maximum volume ingested. RESULTS: The 5-HT3 antagonist reduced postprandial symptoms (aggregate score: P < 0.05), nausea (P < 0.001), and tended to reduce bloating (P=0.08). Both 0.5 and 1 mg alosetron reduced nausea (P < 0.025); 1 mg alosetron reduced aggregate symptoms (P < 0.05) and bloating (P < 0.05). Effects on pain (P=0.19) and fullness (P=0.14) were not statistically significant. There were no significant effects of the 5-HT3 antagonist on volume of meal tolerated or on SPECT-measured fasting or postprandial gastric volumes. CONCLUSION: 5-HT3 antagonism reduces aggregate symptoms, nausea and bloating after a liquid meal without increase in gastric volumes, suggesting a role for 5-HT3 in afferent functions in healthy humans during the postprandial period.     

Frameless stereotactic radiosurgery for recurrent head and neck carcinoma

The aim of this study was to assess the feasibility and toxicity of stereotactic radiosurgery (CK-SRS) using the CyberKnife Frameless Radiosurgery System (Accuray Inc., Sunnyvale, CA) in the management of recurrent squamous cell carcinoma of the head and neck region (SCCHN). Between November 2001 and February 2004, 22 patients with recurrent, previously irradiated SCCHN were treated with CK-SRS. The following endpoints were assessed post-CK-SRS: local control (LC), cause-specific survival (CSS), overall survival (OS), symptom relief, and acute and late toxicity. Kaplan-Meier survival analyses were used to estimate the LC, CSS, and OS rates. Clinical symptoms were graded as "improved," "stable," or "progressed" after CK-SRS. Acute and late toxicity were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) scale, version 2.0. Seventeen patients were followed until their death. The median follow-up in the remaining five patients was 19 months (range 11-40 months). The median survival time for the entire cohort was 12 months from the time of CK-SRS. The 2-year LC, CSS, and OS rates were 26%, 26%, and 22%, respectively. After CK-SRS, symptoms were improved or stable in all but one patient who reported increasing pain. The treatment was well tolerated, with one case each of Grade 2 and 3 mucositis. There were no acute Grade 4 or 5 CTC toxicities. There were no late toxicities in this cohort. Frameless stereotactic radiosurgery for recurrent SCCHN is feasible and safe in the setting of high doses of prior irradiation. The majority of patients experienced palliation of disease without excess toxicity.     

Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins

Preeclampsia is a potentially fatal complication of human pregnancy characterized by hypertension, proteinuria, and edema. Placental oxidative stress is a key element in the pathogenesis of the syndrome and results in the release of a cocktail of factors, including proinflammatory cytokines and apoptotic debris, that in turn cause activation of the maternal endothelium. The intermediary molecular mechanisms underlying this release are unknown, but they represent a potential target for therapeutic interventions. We examined activation of signaling pathways during hypoxia-reoxygenation of villous explants in vitro. Hypoxia-reoxygenation activated the p38 and stress-activated protein kinase mitogen-activated protein kinase (MAPK) and the nuclear factor-kappaB pathways. Downstream consequences included increased tissue concentrations and secretion of tumor necrosis factor-alpha and interleukin-1 beta, increased expression of cyclooxygenase-2, and increased apoptosis. Administration of vitamins C and E to explants blocked activation of the p38 and stress-activated protein kinase MAPK and nuclear factor-kappaB pathways. Vitamin administration or p38 pathway inhibition also reduced cyclooxygenase-2 expression, tumor necrosis factor-alpha and interleukin-1 beta secretion, and the levels of apoptosis. We conclude that oxidative stress is a potent inducer of placental synthesis and release of proinflammatory factors. Most of these effects are mediated through the p38 MAPK and nuclear factor-kappaB pathways and can be effectively blocked by vitamins C and E in vitro.     

Are clinicians failing to supply adequate information when requesting a histopathological investigation?

AIMS: There is a perception among histopathologists that specimens are often received without adequate clinical details. This is the first study to determine the adequacy of information provided when histopathological investigations are requested. METHODS: Two thousand sequential requests for histological examination were assessed for adequacy and completeness. RESULTS: There was no significant difference in the demographic details supplied by physicians and surgeons. Clinical details were inadequate in 6.1% of cases: those from physicians were significantly more often adequate (98.7% v 90.6%) and more often included a diagnosis (74.4% v 38.8%) than those from surgeons. Physicians were more likely to supply their name and contact number but requests frequently lacked details of the sender. CONCLUSIONS: Specimens are infrequently received with inadequate demographic details, but clinical details and details of the sender are more often lacking. Education of clinical colleagues is required if pathologists are to manage the demand for the service.     

Characterization of large deletions in the DHCR7 gene

Pathogenic variants in the DHCR7 gene cause Smith–Lemli–Opitz syndrome (SLOS), a defect of cholesterol biosynthesis resulting in an autosomal recessive congenital metabolic malformation disorder. In approximately 4% of patients, the second mutation remains unidentified. In this study, 12 SLOS patients diagnosed clinically and/or by elevated 7‐dehydrocholesterol (7‐DHC) have been investigated by customized multiplex ligation‐dependent probe amplification (MLPA) analysis, because only one DHCR7 sequence variant has been detected. Two unrelated patients of this cohort carry different large deletions in the DHCR7 gene. One patient showed a deletion of exons 3–6. The second patient has a deletion of exons 1 and 2 (non‐coding) and lacks the major part of the promoter. These two patients show typical clinical and biochemical phenotypes of SLOS. Second disease‐causing mutations are p.(Arg352Trp) and p.(Thr93Met), respectively. Deletion breakpoints were characterized successfully in both cases. Such large deletions are rare in the DHCR7 gene but will resolve some of the patients in whom a second mutation has not been detected.     

A comparison of proliferating cell nuclear antigen (PCNA) immunostaining, nucleolar organizer region (AgNOR) staining, and histological grading in gastrointestinal stromal tumours.

Gastrointestinal stromal tumours are lesions in which it is difficult to predict clinical outcome from the histological appearances. Sixty cases were studied using three different methods of assessing aspects of cellular proliferation; these were (i) immunostaining for proliferating cell nuclear antigen (PCNA), (ii) interphase nucleolar organizer region staining (AgNORs), and (iii) a histological grading system based on mitotic counts. Both PCNA immunostaining and AgNOR counts were found to correlate well with histological grading and all three methods independently showed good correlations with survival. This suggests that these proliferation-associated markers may be used as additional features to support histological grading in this relatively uncommon group of tumours.     

The use of successive blood-pressure measurements to estimate blood-pressure variability

Multiple daily, self-determined blood-pressure measurements were obtained from 254 hypertensive patients for 1 month. In an effort to establish a practical and reliable technique for estimating blood-pressure variability, standard deviations from three (at one time of day) or nine (throughout the day) successive self-determinations were compared with a reference value, taken to be the standard deviation for the entire month (252 determinations per subject). Neither the standard deviation of three measures taken on one occasion nor that of nine measures taken throughout the day correlated well with the reference value (average R₃=.21 for SBP, .20 for DBP; average R₉=.39 for SBP, .38 for DBP). However, when a sample consisting of 12 measures (taken three at a time, at the same time of day, weekly for 4 weeks) was used, the average correlation rose to .60 for SBP and .54 for DBP. Thus, it appears that 12 samples taken in this way provide a reliable estimate of the standard deviation for an entire month, and it is suggested that this sampling technique also would enhance the reliability of conclusions drawn from assessments of the prognostic value of blood-pressure variability.     

Generation of chimeric C5a/formyl peptide receptors: towards the identification of the human C5a receptor binding site

We employed the polymerase chain reaction to produce a series of chimeric C5a/formyl peptide receptors. Chinese hamster ovary cells transfected with these constructs were tested for their ability to bind C5a. Substitution of three of the extracellular domains of the C5a receptor with the corresponding domains of the formyl peptide receptor abolished C5a binding, whilst replacement of the first extracellular loop of the C5a receptor with that of the formyl peptide receptor had little effect on the affinity of the receptor for C5a. We therefore conclude that this first outer loop of the C5a receptor does not participate in ligand binding, whilst involvement of the other extracellular domains of the receptor cannot be ruled out.