Mechanisms of vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34 in rat bone resistance arteries.

UNLABELLED: Parathyroid hormone (PTH) augments bone metabolism and bone mass when given intermittently. Enhanced blood flow is requisite to support high tissue metabolism. The bone arteries are responsive to all three PTH analogs, which may serve to augment skeletal blood flow during intermittent PTH administration. INTRODUCTION: PTH augments bone metabolism. Yet, mechanisms by which PTH regulates bone blood vessels are unknown. We deciphered (1) endothelium-dependent and endothelium-independent vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34, (2) the signaling pathways (i.e., endothelial nitric oxide synthase [eNOS], cyclooxygenase [COX], protein kinase C [PKC], and protein kinase A [PKA]), and (3) receptor activation. METHODS: Femoral principal nutrient arteries (PNAs) were given cumulative doses (10(-13)-10(-8) M) of PTH 1-84, PTH 1-34, and PTHrP 1-34 with and without signaling pathway blockade. Vasodilation was also determined following endothelial cell removal (i.e., denudation), PTH 1 receptor (PTH1R) inhibition and to sodium nitroprusside (SNP; a nitric oxide [NO] donor). RESULTS: Vasodilation was lowest to PTH 1-34, and maximal dilation was highest to PTHrP 1-34. Inhibition of eNOS reduced vasodilation to PTH 1-84 (-80 %), PTH 1-34 (-66 %), and PTHrP 1-34 (-48 %), evidencing the contribution of NO. Vasodilation following denudation was eliminated (PTH 1-84 and PTHrP 1-34) and impaired (PTH 1-34, 17 % of maximum), highlighting the importance of endothelial cells for PTH signaling. Denuded and intact PNAs responded similarly to SNP. Both PKA and PKC inhibition diminished vasodilation in all three analogs to varying degrees. PTH1R blockade reduced vasodilation to 1, 12, and 12 % to PTH 1-84, PTH 1-34, and PTHrP 1-34, respectively. CONCLUSIONS: Vasodilation of femoral PNAs to the PTH analogs occurred via activation of the endothelial cell PTH1R for NO-mediated events. PTH 1-84 and PTHrP 1-34 primarily stimulated PKA signaling, and PTH 1-34 equally stimulated PKA and PKC signaling.

Identification of candidate circulating cisplatin-resistant biomarkers from epithelial ovarian carcinoma cell secretomes.

BACKGROUND: The majority of patients diagnosed with advanced epithelial ovarian carcinoma (EOC) relapse with resistant disease, and there are no biomarkers that possess clinical utility to identify or monitor these patients. This study aimed to identify secreted proteins ('secretome') collected from human EOC cell lines that differ in their inherent platinum sensitivity. METHODS: Secreted proteins collected from conditioned medium from ovarian cancer cell lines that vary in their sensitivity to cisplatin were digested with trypsin and analysed by liquid chromatography-tandem mass spectrometry for peptide identification. RESULTS: Of the 1688 proteins identified, 16 possessed significant differential abundances (P<0.05) between the platinum-resistant and -sensitive cell lines. A number of these were verified by immunoblot, including COL11A1, which was also found to be associated with worse progression-free survival (PFS; N=723) and overall survival (OS; N=1183) as assessed from publicly available transcript expression data from ovarian cancer tumour specimens. CONCLUSION: Secretome proteomics of EOC cells resulted in the identification of a novel candidate biomarker, COL11A1. The expression level of COL11A1 correlates to worse PFS and OS, and is predicted to reside in peripheral circulation making this an attractive candidate for validation in sera as a biomarker of cisplatin resistance and poor outcome.

Illusory Essences: A Bias Holding Back Theorizing in Psychological Science.

The reliance in psychology on verbal definitions means that psychological research is unusually moored to how humans think and communicate about categories. Psychological concepts (e.g., intelligence, attention) are easily assumed to represent objective, definable categories with an underlying essence. Like the "vital forces" previously thought to animate life, these assumed essences can create an illusion of understanding. By synthesizing a wide range of research lines from cognitive, clinical, and biological psychology and neuroscience, we describe a pervasive tendency across psychological science to assume that essences explain phenomena. Labeling a complex phenomenon can appear as theoretical progress before there is sufficient evidence that the described category has a definable essence or known boundary conditions. Category labels can further undermine progress by masking contingent and contextual relationships and obscuring the need to specify mechanisms. Finally, we highlight examples of promising methods that circumvent the lure of essences and suggest four concrete strategies for identifying and avoiding essentialist intuitions in theory development.

An overview of the Central Queensland University self-contained evapotranspiration beds.

The Central Queensland University (CQU) has championed a self-contained concrete lined evapotranspiration channel. Any non-transpired effluent returns to a holding tank and is recirculated through the evapotranspiration channel until it is used. This paper examines the results from the Rockhampton trial site. Nutrient ions in the effluent were quantified over time and found not to accumulate in solution. Microbial analysis of the treated effluent was performed and was found to be within the ranges required by the relevant legislative codes. Citrus fruit grown in the evapotranspiration channel were sampled and no elevated levels of faecal coliforms were recorded. Macronutrients and micronutrients of the soil in the channels were measured over a 5-year period. No toxic accumulations or nutrient deficiencies in the soil occurred. Levels of salinity and sodicity in the evapotranspiration channel soil were quantified. Salinity rose slightly, as did sodium. Concentrations of salts and sodium did not reach unsustainable levels. The aim of the trial was to develop an on-site treatment and reuse system that is sustainable and protects public and environmental health.

Premature death and associated risk factors in urban middle-aged men.

The full range of premature mortality and associated risk factors was analyzed for a follow-up period of three and a half to eight years in a uniform group of 7,935 middle-aged males (46 to 48 years old at screening) participating between the years 1975 and 1979 in the preventive population program in Malmö (participation rate 76.7 percent). Of the 218 deaths that occurred, necropsy was performed in 181 (83.0 percent). Three major causes of death were established: cancer (61/218), alcohol-related deaths (55/218), and coronary heart disease (50/218). In these three main categories of male premature mortality, significant and distinctly differential risk factor patterns were found. In coronary heart disease, smoking (p = 0.0062), serum cholesterol level (p = 0.00014), serum triglyceride level (p = 0.00013), systolic blood pressure (p = 0.000012), and diastolic blood pressure (p = 0.0021) were the strongest single determinants, but the independent role of the diastolic blood pressure disappeared in a multivariate analysis whereas all the others could be combined in a highly predictive logistic model. In the alcohol-related group, equal or stronger risk factor associations were present for serum gamma-glutamyltransferase level (p less than 0.0001), questionnaire alcoholism screening response (p less than 0.0001) and, inversely, serum cholesterol level (p = 0.0046) and serum creatinine level (p less than 0.0001), all of which were independent and could be combined in an even more predictive logistic model than in the coronary heart disease group. In the cancer deaths, significant associations were found for serum urate level (p = 0.023) and, inversely, serum cholesterol level (p = 0.056 - 0.031). Malignant and alcohol-related diseases constituted at least equally prominent groups as the cardiovascular disorders of the total premature deaths that occurred during middle age in these cohorts of Malmö males. All of these conditions are potentially avoidable and seem to be associated with significant and distinctive risk factor patterns. It seems possible that these factors may be applied, in current alcohol-related disorders and in future malignant diseases, both as indicators of the respective risks and as signals and instruments for directed preventive measures like the previously well established and tested methods for the regulation of blood pressure, serum lipids levels, and so on.

Aryl hydrocarbon hydroxylase induction levels in patients with malignant tumors associated with smoking.

The levels of aryl hydrocarbon hydroxylase (AHH) inducibility were assessed in 173 patients with cancers statistically associated with smoking, i.e., squamous cell and transitional cell carcinomas, at various sites. In 34 patients with carcinomas of the oral cavity, 41 patients with laryngeal carcinomas, and 22 patients with pulmonary carcinomas there was a highly significant overrepresentation of high inducers, whereas 30 patients with carcinomas of the renal pelvis and ureter and 46 patients with urinary bladder carcinomas did not differ significantly in this respect from a control population comprising 92 subjects with no history of neoplastic disease. The results add further support to the concept of AHH as a major activator of carcinogens belonging to the group of polycyclic aromatic hydrocarbons (PAH) when these affect the oral cavity and/or the respiratory tract. The role of AHH in urothelial carcinogenesis seems to be less explicit.

The intention to act improves unilateral left neglect: two demonstrations.

Unilateral neglect involves a spatial bias to one side of space, usually to the right. Perceptual and motor systems interact in the manifestation of this disorder, and there is also evidence that motor manipulative responses may have access to unique streams of information not available for non-motoric judgements. It is therefore predicted that the manifestation of neglect may be alterable by changing the purpose of otherwise very similar responses to spatially extended objects. In Experiment 1, neglect-based deviation to the right of centre was significantly less when subjects reached towards metal rods as if to pick them up in the centre, compared to when they pointed to their centres. In Experiment 2, subjects pointed to the centre of a rectangular box with a swivelled lid. They were then asked to place a coin at the centre of this lid, in a position sufficiently central to prevent the lid tilting and the coin falling into the box; in fact, the lid was fixed and subjects never received feedback. Responses were significantly more central with the balancing response than with the pointing one. These results suggest that prehensive movements towards objects allow 'leakage' of information about their spatial extent, via an unaffected stream of information available for motor-manipulative responses.

Effects of thrombin, acetyl salicylic acid and prostaglandins on spontaneous efflux of norepinephrine and beta-thromboglobulin from platelets in calcium/magnesium deficient environment.

The effect of different substances on the spontaneous efflux of 14C-norepinephrine (14C-NE) and beta-thromboglobulin (beta TG) from platelets in Ca2+ - and Mg2+ - free buffer was tested. Addition of increasing concentrations of thrombin (0.015-0.625 U/ml) resulted in an immediate increase of 14C-NE detectable in the supernatants, but the slopes of the efflux curves from 10 min after thrombin addition were almost identical and parallel with the slope before thrombin addition. Also beta-thromboglobulin was steadily released after thrombin addition. Prostaglandin E1 and prostacyclin in concentrations that gave a 30-fold increase in cAMP accumulation resulted in a moderate decrease in efflux of 14C-NE from 10 to 30 min but did not influence the efflux thereafter up to 80 min. Acetyl salicylic acid in vivo and in vitro (200-500 mumol/l) did not influence the efflux of 14C-NE or beta TG. The conclusions are that factors known to exert considerable effects on aggregation, desaggregation and acute release produce only transitory effects in a Ca2+ - and Mg2+ - free environment and that the basal efflux of alpha-granule components seems to be a stable process.

Believing what you feel: using proprioceptive feedback to reduce unilateral neglect.

Unilateral spatial neglect declines when participants reach to grip the center of long metal rods compared with when they point to the perceived center, suggesting that visuomotor control systems are less affected by neglect than other representational systems (I. H. Robertson, D. Nico, & B. Hood, 1995). In this study, 16 participants with unilateral left neglect actually picked up rods, and we predicted short-term improvements in neglect because of induced conflict between a phenomenally symmetrical visual world on the one hand and a proprioceptively conveyed rightward-biased world on the other. With participants serving as their own controls, significant short-term improvements in neglect were found on 2 out of 4 neglect tasks after participants experienced proprioceptive feedback discrepant from the judgments they made on the basis of visual information alone.

Hospitalization and alcohol-related morbidity within three years after screening in middle-aged men.

All men living in Malmö who were born in 1926-1929 were invited for a health screening examination which included, among many other things, measurement of gamma-glutamyltransferase (GGT). They were followed up and within three years after the screening 963 of 4571 men had been hospitalized. They had 17158 hospital days or almost 6 days per individual each year. The impact of alcohol on the admissions was analysed both according to the International Classifications of Diseases and a new design where all the diagnoses were grouped and coded in conditions which were judged to be alcohol-related, potentially alcohol-influenced and non-alcohol-related. Of the total days in hospital, alcohol psychosis and alcoholism accounted for 13.6 per cent. Altogether 29.2% of the days were caused by alcohol-related and potentially alcohol-influenced conditions. GGT values at the screening investigation were significantly increased in 25% of the hospitalized men. Alcohol-related admissions were seven times as many in men with GGT values in the highest quintile compared with those who had values in the lowest quintile.

Spontaneous efflux of platelet alpha-granule components in relation to 14C-norepinephrine in buffers.

In an investigation of the spontaneous efflux of beta-thromboglobulin (beta-TG), 14C-norepinephrine (14C-NE) and growth stimulating activity (GSA), measured as incorporation of 3H-thymidine in rabbit aortic smooth cells, from platelets resuspended in Ca++- and Mg++-free buffer a continuous increase in 3H-thymidine incorporation was seen during 120 min. There was good stoichiometric parallelism between beta-TG and 14C-NE during the 80 minutes the experiment lasted, indicating that norepinephrine is incorporated in alpha-granules and release by exocytosis.

Two intact executive capacities in children with autism: implications for the core executive dysfunctions in the disorder.

Many studies have shown that children with autism perform at a much lower level than control subjects on tests of executive functioning, defined as tasks requiring subjects to hold information in mind while suppressing a prepotent response. These tasks have invariably required subjects to (a) follow arbitrary and novel rules and (b) make a nonverbal response. We report that when one of these features is absent, children with autism are not impaired relative to controls. They perform at a similar level to normally developing children on the "tubes" task (containing no arbitrary and novel rules) and on the day/night task (in which the output is verbal). Results are consistent, at least, with the hypothesis that children with autism are challenged by executive tasks because they are unlikely to encode rules in a verbal form.

Serum gamma-glutamyl transferase and a somatic health score in middle-aged men.

In an ongoing population investigation of middle-aged men in Malmö, Sweden, several health screening variables showed strong but crude individual covariations with the level of the hepatic enzyme, serum gamma-glutamyl transferase (GGT). These variables were combined, according to an analysis of their normal distributions, into a score index which exhibited a much smoother correlation with low, normal, and elevated levels of GGT when tested in a random population subsample. It is concluded that this scoring system may find further utilisation as a general descriptive method of recording statistical covariations between health screening tests and sum them up.

Prevention of alcohol-related problems in urban middle-aged males.

More than 30,000 individuals have been investigated in the continuous screening and intervention study in Malmö. Large subsamples of individuals with different levels of GGT (gamma-glutamyltransferase) have been characterized. GGT has proven to be a useful and simple tool in tracing, identifying, treating and controlling heavy drinkers. Furthermore, GGT seems to be a new and strong indicator of alcohol-related disabilities and short term mortality in the male population. Individuals with GGT in the tenth deecentile of the GGT distribution have been randomly selected for treatment or control. Results and follow-up for 60 months in the intervention study with randomized controls in middle-aged heavy drinkers indicate a significant reduction in alcohol consumption, sick absence, hospitalization and mortality. Thus, the intervention program seems to be effective in preventing complications of alcoholism on an individual basis.

Arylhydrocarbonhydroxylase inducibility and smoking habits in patients with laryngeal carcinomas.

There is considerable evidence that the inducible enzyme aryl hydrocarbon hydroxylase (AHH) plays an important role in the activation of polycyclic aromatic hydrocarbons (PAH) to ultimate carcinogens. In man, a genetic heterogeneity of AHH inducibility has been demonstrated, and correlated to susceptibility to bronchogenic carcinomas following exposure to PAH. We assessed AHH inducibility in a control group of 102 healthy Swedish citizens and in 41 patients with laryngeal carcinomas. Frequencies of the three phenotypes of high, intermediate and low AHH inducibility in our control group; 8.8%, 42.2% and 49%, respectively, did not differ significantly from frequencies found in a white US population. In the laryngeal carcinoma group, there was a statistically highly significant overrepresentation of patients with high AHH inducibility, 36.6%, whereas 43.9% had an intermediate and 19.5% a low level. Most of the patients were heavy smokers. These findings add further support to the concept that susceptibility to PAH-induced carcinomas is associated with high levels of inducible AHH activity.

The stress of the transition to university: a longitudinal study of psychological disturbance, absent-mindedness and vulnerability to homesickness.

A longitudinal study was conducted to examine the effects of the transition to university in residential and home-based students. All students showed evidence of raised psychological disturbance and absent-mindedness following the transition. Although there were no differences between resident and home-based students in this respect, those who reported homesickness were distinguished from the remainder in terms of higher levels of psychological disturbance and cognitive failure following the transition to university. Covariate analysis established that the gain in psychological disturbance following the transition was greater for the homesick group. The results are discussed in terms of the effects of stressful transitions on psychological state and the concept of personal vulnerability.

Vulnerability factors in the transition to university: self-reported mobility history and sex differences as factors in psychological disturbance.

A study was conducted on the psychological reaction to the transition to university in 198 first year residential students. Female subjects had higher levels of psychological disturbance and cognitive failure. Thirty-one per cent of the subjects reported experiencing homesickness. These subjects had higher levels of psychological disturbance and cognitive failure than non-homesick subjects. There were no sex differences in homesickness reporting. The non-homesick group were found to be more likely to have been away from home before either to attend boarding school or to take holidays. This suggests either that selective aspects of previous mobility experience are beneficial or that self-selection factors operate in that those who do not feel distress at leaving home are more likely to acquire mobility experience.

Fascioloidiasis in game-ranched elk from Montana.

The distribution of Fascioloides magna in game-ranched elk and the potential for spread of the parasite through movement of infected animals was examined in Montana (USA). Fecal samples (n = 448) collected from captive elk on 29 game ranches were examined for eggs of F. magna by fecal sedimentation. Eggs were detected in elk on 5 ranches. This suggests that F. magna has been translocated by infected game-ranched elk. The wide distribution of snail intermediate hosts for F. magna in Montana indicates a potential to spread the parasite to other captive cervids domestic livestock or free-ranging wildlife.

Bovine tuberculosis in a free-ranging mule deer (Odocoileus hemionus) from Montana.

A survey of 41 mule deer (Odocoileus hemionus) and three white-tailed deer (O. virginianus) for bovine tuberculosis was conducted on a Montana (USA) cattle ranch from 2 November 1993 through January 1994. Gross and microscopic lesions typical of tuberculosis were present in tonsil and lymph nodes of the head, thorax, and abdomen of one adult female mule deer. Additionally, a single microgranuloma considered morphologically suggestive of tuberculosis was present in one lymph node of the head of a second mule deer. Mycobacterial isolates from lymph nodes of the head and thorax of the first deer were identified as Mycobacterium bovis.

An incremental approach to a Web-based computerized medical record.

Acceptance of an electronic medical record within physician practices is a challenge that the Everett Clinic and the Wenatchee Valley Clinic in Washington State have chosen to approach incrementally. These two independent clinics, with 180 physicians each, joined forces in 1995 to form an information service organization, CliniTech Information Resources, to consolidate operation of their practice management and lab systems. With that done, in 1997 they asked CliniTech to come up with a solution to give physicians online access to clinical data in a way that didn't interrupt their work-flow or decrease their productivity--not a small order. The first HTML application was On Line Transcription, for viewing chart notes and radiology reports. Next, the On Line Patient Profile was developed to replace the face sheet. On Line Lab Results followed as a way to view results from the clinics' internal and reference lab systems. A single user interface was created in 2000 to link these components to the physician's schedule and clinical references. The new computerized medical record (CMR) has been embraced by the clinics' physicians (currently at 70 percent usage) and will continue to grow with additional results and images. Electronic signature capabilities for transcription and results are also slated for 2001 and will be the first change to how the physician practices.