Detection of bladder dysplasia using 5-aminolaevulinic acid-induced porphyrin fluorescence

OBJECTIVE: To report results of a clinical investigation on the detection of bladder dysplasia and in situ carcinoma by using fluorescence induced by 5-aminolaevulinic acid (ALA). PATIENTS AND METHODS: The study included 50 patients with a primary bladder lesion, who had a bladder instillation of 50 mL of 3% ALA solution >or= 1 h before transurethral resection of the tumour. Random biopsies were taken using white-light cystoscopy, then using blue light to induce fluorescence; positive zones were noted and biopsied. The primary lesion was then resected. The frequency of dysplasia detected by ALA-induced fluorescence was evaluated, as was the risk of recurrence with a follow-up of >or= 2 years. RESULTS: In all patients the tumours were positive; in 21 fluorescence distant from the tumour was detected. The pathological report of the biopsies showed 11 cases of dysplasia, six of carcinoma in situ and four of inflammatory lesions. In 29 patients there was no fluorescence and quadrant biopsies were normal in all but three with moderate dysplasia. Within the minimum follow-up patients with bladder dysplasia detected by ALA-induced fluorescence had a higher risk of recurrence. CONCLUSION: ALA-induced fluorescence of the bladder significantly enhanced the detection of dysplasia and in situ carcinoma. However, this technique requires further investigation using well-characterized instrumentation and study protocols to determine any effect on treatment choice.     

Differential routing of coexisting neuropeptides in vasopressin neurons

The functional implications of intraneuronal coexistence of different neuropeptides depend on their respective targeting to release sites. In the rat hypothalamic magnocellular neurons, we investigated a possible differential routing of the coexpressed galanin and vasopressin. The respective location of proteins and messengers was assessed with double immunogold and in situ hybridization combining confocal and electron microscope analysis. The various populations of labelled granules were quantitatively compared in three subcellular compartments: perikarya, local processes and posthypophyseal nerve endings. Three subpopulations of granules were detected in all three compartments, but their respective amount showed significant differences. Galanin alone was immunolocalized in some secretory granules, vasopressin alone in others, and both peptides in a third subpopulation of granules. The major part of the granules containing vasopressin, either alone or in association with galanin, is found in neurohypophyseal nerve endings. In contrast, galanin single-labelled granules represent the most abundant population in dendritic processes, while double-labelled granules are more numerous in perikarya. This indicates a preferential distribution of the two peptides in the different compartments of magnocellular neurons. Furthermore, galanin and vasopressin messenger RNAs were detected at different domains of the endoplasmic reticulum, suggesting that translation might also occur at different locations, thus leading to partial segregation of galanin and vasopressin cargoes between two populations of secretory granules. The present study provides, for the first time in mammals, evidence suggesting that galanin and vasopressin are only partly copackaged and undergo a preferential targeting toward dendrites or neurohypophysis, suggesting different functions, autocrine/paracrine and endocrine, respectively.     

Science Review: Vasopressin and the cardiovascular system part 1 – receptor physiology

Vasopressin is emerging as a rational therapy for vasodilatory shock states. Unlike other vasoconstrictor agents, vasopressin also has vasodilatory properties. The goal of the present review is to explore the vascular actions of vasopressin. In part 1 of the review we discuss structure, signaling pathways, and tissue distributions of the classic vasopressin receptors, namely V₁ vascular, V₂ renal, V₃ pituitary and oxytocin receptors, and the P₂ class of purinoreceptors. Knowledge of the function and distribution of vasopressin receptors is key to understanding the seemingly contradictory actions of vasopressin on the vascular system. In part 2 of the review we discuss the effects of vasopressin on vascular smooth muscle and the heart, and we summarize clinical studies of vasopressin in shock states.     

Whole-body fat oxidation rate and plasma triacylglycerol concentrations in men consuming an ad libitum high-carbohydrate or low-carbohydrate diet

BACKGROUND: High-carbohydrate diets may increase plasma triacylglycerol concentrations either by increasing production of triacylglycerols or by reducing their clearance. OBJECTIVE: We assessed whether the changes in plasma triacylglycerol concentrations induced by dietary interventions were associated with the changes in whole-body fat oxidation rates. DESIGN: In a parallel study, 37 healthy male subjects [body mass index (in kg/m(2)): 28 +/- 5, age: 34 +/- 11 y (x +/- SD)] consumed an ad libitum high-carbohydrate (60% of energy; n = 19) or low-carbohydrate (46% of energy), high-fat (41% of energy, 23% as monounsaturated fatty acids; n = 18) diet for 7 wk. The following variables were measured before and after the dietary interventions: 1) plasma triacylglycerols before and 2, 4, 6, and 8 h after a meal (containing 40% of daily energy needs and 41% fat); 2) indirect calorimetry throughout the 8-h test; and 3) postheparin plasma lipoprotein lipase (phLPL) activity at time 8 h of the test. RESULTS: The diets induced changes in 1) body weight: -2.5 +/- 2.8 kg (P < 0.01) and -1.7 +/- 3.1 kg (P < 0.05) and 2) fasting plasma triacylglycerols: 0.0 +/- 0.4 mmol/L (NS) and -0.3 +/- 0.3 mmol/L (P < 0.05) for the high-carbohydrate and the low-carbohydrate diets, respectively. In normoinsulinemic subjects (fasting insulin < 100 pmol/L), dietary changes in postprandial triacylglycerols were significantly predicted by changes in phLPL, body weight, respiratory quotient (or fat oxidation), and the type of diet (stepwise multiple linear regression). CONCLUSION: Postprandial plasma triacylglycerol concentrations may depend at least partly on fat oxidation, body weight, and LPL activity.     

Long-term functional outcome of neurogenic thoracic outlet syndrome in surgically and conservatively treated patients

PURPOSE: Neurogenic thoracic outlet syndrome (NTOS) in the absence of bony and electrodiagnostic abnormalities, often referred to as disputed NTOS, remains enigmatic. Optimal treatment, especially the role of surgery, is controversial. The long-term functional outcome of a cohort of patients undergoing independent medical examination for disputed NTOS with symptoms sufficiently severe to cause inability to work forms the basis for this report. METHODS: Patients with disputed NTOS and symptoms sufficiently severe to cause at least temporary inability to work seen for independent medical examinations from 1990-1998 formed the study group. None of the patients were treated by our group. Functional outcome was assessed with information from a standardized telephone interview or patient questionnaire. The patients' ability to return to work and an assessment of their current level of symptoms and symptom progression since the time of onset were determined. RESULTS: Seventy-nine patients were reevaluated at a mean follow-up of 4.2 years (range, 2-7.5 years) after our initial evaluation. Fifteen patients (19%) underwent first rib resection surgery performed by others, whereas 64 (81%) had no surgery. Patients undergoing surgery had missed more work time than those undergoing conservative management (27.6 +/- 6.0 months vs 14.9 +/- 2.6 months, P <.04). Return to work was achieved in nine patients who were operated on (60%) and in 50 patients who were not operated on (78%) (P = not significant [NS]). Among operated patients, current assessment of symptom severity was severe, moderate, mild, and asymptomatic in 7%, 47%, 40% and 7%, respectively. This distribution did not differ significantly from that observed in nonoperated patients (11%, 55%, 30%, 5%; P = NS). When asked about changes in symptomatic status since onset, 7% of the operated group had complete resolution, 27% had marked improvement, 40% had minimal improvement, 13% had no improvement, and 13% were worse. This did not differ significantly from the change in symptoms reported by the nonoperated group (2%, 30%, 22%, 31%, 16%; P = NS). CONCLUSION: Most patients with disputed NTOS in this nonrandomized series were able to return to work and demonstrated an improvement of symptoms with long-term follow-up. First rib resection did not improve functional outcome in this group.     

Developmental toxicity evaluation of inhaled toluene diisocyanate vapor in CD rats.

Mated female CD (Sprague-Dawley) rats, 25/group, were exposed to toluene diisocyanate (TDI) vapor, for six h/day on gestational days (gd) 6 through 15, at 0.00, 0.02, 0.10, or 0.50 p.p.m.. Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gd 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified: resorptions and dead and live fetuses. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre- and postimplantation loss, sex ratio/litter, or fetal body weights/litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapor by inhalation, during major organogenesis in CD rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm no observed adverse effect level (NOAEL) for maternal and developmental toxicity was 0.10 ppm. No treatment-related embryotoxicity or teratogenicity was observed.     

Two-generation reproductive toxicity study of inhaled toluene diisocyanate vapor in CD rats.

Twenty-eight 42-day-old pups/sex/group (F0) were exposed to toluene diisocyanate vapor (TDI; 80% 2,4-TDI, 20% 2,6-TDI) by inhalation at 0.0, 0.02, 0.08, or 0.3 ppm, 6 h/day, 5 days/week, for 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapor, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.     

Inflammatory hyperalgesia induced by zymosan in the plantar tissue of the rat: effect of kinin receptor antagonists

The Randall-Selitto paradigm (maximal tolerated pressure externally applied by a mechanical device) was used to develop a rat model of localized inflammatory hyperalgesia in order to compare the analgesic effects of bradykinin (BK) B1 and B2 receptor antagonists and of a non-steroidal anti-inflammatory drug (NSAID). Intra-plantar injection of zymosan (12.5 mg per paw) induced a considerable inflammation as evidenced from gross and histological evaluation and a mechanical hyperalgesia at 6 h. The contra-lateral paw of zymosan-treated animals or saline vehicle-injected paws did not exhibit a decreased pressure tolerance, relative to pre-injection measurements. Since the B1 receptor may be induced under inflammatory situations, we examined the amount of corresponding mRNA using quantitative RT-PCR. We found a significant increase of B1 receptor mRNA in the zymosan--but not the saline-injected paw at 6 h. Drugs were given subcutaneously 2 h before the 6 h readings to test their analgesic potential. The kinin B1 receptor antagonists [Leu8]des-Arg9-BK (3-30 nmol/kg) and R-715 (100 nmol/kg), the B2 receptor antagonists Hoe 140 (15 nmol/kg) and LF 16.0687 (3 and 10 mg/kg), as well as the NSAID diclofenac sodium (1 and 3 mg/kg) significantly reversed zymosan-induced hyperalgesia. We conclude that zymosan-induced hyperalgesia is a model suitable for the rapid evaluation of analgesic drugs with a peripheral site of action interfering either with kinin receptors or with prostanoid formation. In this regard, results of the present study confirm that blocking kinin B1 receptors is a novel approach for treatment of inflammatory pain.     

Advance directives: implementation into clinical practice

Legislation recently passed by Congress will require health care organizations to maintain specific procedures regarding the right of patients to prepare advance directives. Previous studies have shown that patients may wish to discuss issues regarding future terminal care, but few patients complete living wills or durable powers of attorney. Although physicians often have positive attitudes regarding advance directives, the majority do not initiate discussions regarding these issues. The new regulations may increase the awareness of directives and increase the documentation of patients' desires into the medical record. However, the widespread acceptance of the advance directive and its impact on health care decisions remain to be seen.     

Further evidence for the presence of "small eaters" and "large eaters" among women

One hundred thirty-four women, aged 36 +/- 4 (mean +/- SD) y, BMI 20 +/- 3 kg/m2, perceiving themselves as having either a low or high energy intake (EI), participated in a study to determine variations in EI. Information on EI and activity level was obtained from repeated 7-d records. The 40 subjects with the lowest EI (in kcal/kg body wt) were categorized as small eaters (SEs); the 40 subjects with the highest EI were considered to be large eaters (LEs). The absolute (in kcal) and relative (in kcal/kg body wt) EIs of the SE and LE groups were 1488 +/- 312 and 27 +/- 4 for the SE group, respectively and 2393 +/- 509 and 47 +/- 6 for the LE group, respectively. There was no significant difference in activity level or fat-free mass (FFM) between the groups. However, LEs weighed significantly less (51 vs 55 kg) and were leaner (22% body fat vs 33%) than were SEs. Individuals with similar FFM and activity level can vary significantly in EI needs.