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Arsenic (As) is highly toxic and over 100 million people living on the floodplains of Asia are exposed to excessive groundwater As. A very large spatial variability over small distances has been observed in the groundwater As concentrations. Advances in the prediction of the As distribution in aquifers would support drinking water management. The application of remote sensing of geomorphic paleo river features combined with geological, geophysical and archeological data and available groundwater As measurements may be used to predict groundwater As levels in rural areas, as shown by the example from the Red River delta, Vietnam. Groundwater in sediments deposited in the marine environment is low in As, probably due to the precipitation of As in sulfide minerals under anoxic conditions. Groundwater As levels in freshwater alluvial deposits in undisturbed floodplain areas are slightly increased and the highest As concentrations are associated with meander belts. The meander belts remain clearly visible in remote sensing and may well reflect the youngest preserved alluvial sediments. High As levels in the meander belt aquifers are probably related to the availability of highly reactive organic matter and consequent reduction of iron oxyhydroxides and As release. Furthermore, given similar hydrogeological conditions, the extent of flushing of As from the youngest alluvial sands is limited compared to the older Pleistocene sands. Even within abandoned meander belts a high spatial variability of As concentrations was observed. The younger channel belts (<1 ka BP) and old Holocene aquifers below undisturbed floodplain environments deposited during a period with high sea level host groundwater enriched in As. Low As groundwater is found in sandy channel belts deposited during the regression of the sea and in Pleistocene islands preserved within the floodplain. The decisive influence of the depositional environment of the aquifer sediments on groundwater As content is revealed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Hepatic arterial treatment (HAT) for liver metastases in patients with metastatic breast cancer (MBC) has only been investigated in few studies., Materials and Methods: Two phase II trials were initiated simultaneously to evaluate capecitabine in combination with oxaliplatin in patients with MBC and liver metastases. These two trials are reported together. Continuous capecitabine (1300 mg/m2) was combined with oxaliplatin (85 mg/m2) alternating between systemic treatment and HAT followed by degradable starch microspheres with EmboCept ® S every second week. Four patients participated in a pharmacokinetic analysis of oxaliplatin. Each patient had samples taken when receiving oxaliplatin systemically and as HAT with and without EmboCept ® S., Results: Totally, 52 patients received HAT: 14 with liver metastases only and 38 patients with additional limited metastatic disease. The patients had previously received a median of 2 (range 0-6) chemotherapeutic regimens for MBC. The response rate was 42.3% (95% confidence interval (CI) 28.7-56.8%) with 7.7% complete and 34.6% partial responses. Median progression free survival was 10.8 months (95% CI 6.9-14.7 months) and median overall survival 27.6 months (95% CI 20.4-34.8 months). The toxicity was moderate with hand-foot syndrome (15.4%), neuropathy (9.6%), fatigue (9.6%), and abdominal pain (9.6%) being the most common grade 3 adverse events. There was no clear difference between systemic blood concentrations of oxaliplatin when given systemic or as HAT., Conclusion: HAT oxaliplatin in combination with capecitabine is safe and efficient in patients with MBC. The results are promising with high response rates and a long median progression free and overall survival., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Cell free DNA (cfDNA) has shown promising utility as prognostic biomarker for patients with colorectal cancer (CRC), with an ongoing need to optimize and validate the laboratory methodology. Here, we report our optimization and validation of a direct fluorescent assay and display the potential utility in patients with colorectal cancer., Methods: Plasma cfDNA was analyzed by a direct fluorescent assay (DFA) and compared to quantification by droplet digital PCR (ddPCR). For clinical validation, baseline blood samples were available for a total of 273 patients from six different Nordic trials, covering patients with locally advanced rectal cancer (n = 176, cohorts A + B), liver limited metastatic CRC (n = 75C + D) and wide spread metastatic CRC (n = 22 E + F)., Results: Validating the DFA analysis with ddPCR revealed a strong correlation with an R2 of 0.81. For the clinical cohorts, the levels of cfDNA were: 0.8 ng/uL (95%CI 0.75-0.83) (A + B), 0.93 ng/uL (95%CI 0.86-1.02) (C + D) and 1.2 ng/uL (95%CI 0.85-1.47) (E + F), respectively (p < 0.01). All cohorts of colorectal cancer had higher levels of cell free DNA than healthy individuals (n = 94) (p < 0.01)., Conclusion: Analysis of cell free DNA by a direct fluorescent assay could be an attractive laboratory option for a rapid inexpensive quantification of cell free DNA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Treatment of patients with locally advanced rectal cancer (LARC) is based on a combination of chemo-radiotherapy (CRT) and surgery. The rate of distant recurrences remains over 25%. Circulating cell-free DNA (cfDNA) in plasma is a mixture of normal and cancer-specific DNA segments and is a promising biomarker in patients with colorectal cancer. The aim of our study was to investigate plasma cfDNA as a prognostic marker for outcome in patients with LARC treated with neoadjuvant CRT and surgery., Patients and Methods: In total, 123 patients with LARC were included in 2 biomarker studies. Patients were treated with neoadjuvant CRT before TME surgery. Fifty-two (42%) of the patients received induction chemotherapy with capecitabine + oxaliplatin. Total cfDNA was measured by direct fluorescent assay in EDTA plasma samples obtained at baseline, after induction chemotherapy, and after CRT. Serial samples 5 years after surgery were collected in 51 patients (41%)., Results: Median follow-up was 55 months. Distant or local recurrence was seen in 30.9% of the patients. Patients with baseline cfDNA levels above the 75th quartile had a higher risk of local or distant recurrence and shorter time to recurrence compared with patients with plasma cfDNA below the 75th percentile (HR = 2.48, 95% CI: 1.3-4.8, P = 0.007). The same applied to disease-free survival (DFS) (HR = 2.43, 95% CI: 1.27-4.7, P = 0.015). In multivariate analysis, a high cfDNA level was significantly associated with time to progression and DFS. During follow-up, the association remained significant regardless of time point for sample analysis., Conclusion: We have demonstrated an association between a high baseline plasma level of cfDNA and increased risk of recurrence, shorter time to recurrence, and shorter DFS in patients with LARC. Consequently, cfDNA could potentially improve pre- and post-treatment risk assessment and facilitate individualized therapy for patients with LARC.

The effects of diacylglycerols (DAG), pork back fat and sunflower oil on water and fat mobility in fermented sausages were studied with (1)H NMR relaxometry. The added fat affected the physicochemical parameters weight loss, water activity, moisture content and moisture content on a defatted-dry-matter basis of reduced-fat non-acid fermented sausages. The weight losses were the lowest in sausages prepared with DAG and sunflower oil, which resulted in higher water activity compared to sausages prepared with back fat. The relaxation times related to fat mobility differed between fat types and increased in the order: control

Background: Preoperative chemoradiation in patients with locally advanced rectal cancer has no impact on overall survival (OS) and distant recurrences. The aim of the study was to evaluate local downstaging, toxicity and long-term outcome in patients with locally advanced rectal cancer after induction therapy with capecitabine and oxaliplatin (CAPEOX) followed by radiotherapy concomitant with capecitabine [chemoradiotherapy (CRT)] before total mesorectal excision (TME)., Patients and Methods: Patients with T4 tumors, all T3N+ tumors or T3 tumors involving or with a distance ≤1 mm to the mesorectal fascia were included. Patients were planned for two cycles of CAPEOX followed by radiotherapy concomitant with capecitabine. TME was carried out 6 weeks after the completion of CRT., Results: Of 84 consecutively admitted patients starting induction CAPEOX, 77 patients underwent surgery. R0 resection was seen in 94% and T downstaging in 69%. In the intention-to-treat group, pathological complete response was seen in 23%. Five-year disease-free survival (DFS) and OS were 63% [95% confidence interval (CI), 52.2% to 73.7%] and 67% (95% CI, 56.1% to 77.3%), respectively. Grade 3/4 toxicity was seen in 18%, and four deaths occurred within 2 months of therapy., Conclusion: Induction chemotherapy before CRT and surgery showed a high local control rate and promising long-term outcome as OS and DFS.

Background: Chronotherapy is one of the several approaches to increase efficacy and reduce toxicity of chemotherapy. In a phase II study in the second-line in patients with metastatic colorectal cancer (mCRC), we found that chronomodulated XELOX (XELOX(30Chron)) was a well-tolerated regimen with potentially reduced toxicity., Patients and Methods: One hundred and forty-one patients with unresectable mCRC were enrolled in a randomized study comparing standard XELOX (XELOX(30)), arm A, and XELOX(30Chron), arm B-both with short-time infusion of oxaliplatin-with the primary aim of reducing overall toxicity., Results: Overall toxicity grade 2-4 was 90% versus 85%, P = 0.47 and grade 3-4 was 31% versus 37%, P = 0.6 in arm A and B, respectively. We found no significant differences in median overall survival (17.6 versus 15.5 months; P = 0.068) and median progression-free survival (8.9 versus 8.8 months; P = 0.7). The incidence of grade 3 neuropathy was 16% in arm A and 19% in arm B (P = 0.7) after a cumulative dose of oxaliplatin of 1000 mg/m(2)., Conclusion: XELOX(30Chron) does not reduce toxicity or improve efficacy. A 30-min infusion of oxaliplatin is safe and does not increase the severity of chronic neuropathy.

The number of applications of chemometrics to series of NMR spectra is rapidly increasing due to an emerging interest for quantitative NMR spectroscopy e.g. in the pharmaceutical and food industries. This paper gives an analysis of advantages and limitations of applying the two most common chemometric procedures, Principal Component Analysis (PCA) and Multivariate Curve Resolution (MCR), to a designed set of 231 simple alcohol mixture (propanol, butanol and pentanol) (1)H 400 MHz spectra. The study clearly demonstrates that the major advantage of chemometrics is the visualisation of larger data structures which adds a new exploratory dimension to NMR research. While robustness and powerful data visualisation and exploration are the main qualities of the PCA method, the study demonstrates that the bilinear MCR method is an even more powerful method for resolving pure component NMR spectra from mixtures when certain conditions are met.

The worldwide used herbicide dichlobenil (2,6-dichlorobenzonitrile) has resulted in widespread presence of its metabolite 2,6-dichlorobenzamide (BAM) in surface water and groundwater. To evaluate the potential for natural attenuation of this BAM pollution in groundwater, we studied the degradation of BAM and dichlobenil in 16 samples of clayey till, unconsolidated sand and limestone, including sediments from both oxidized and reduced conditions. The degradation of dichlobenil occurred primarily in the upper few meters below surface, although dichlobenil was strongly sorbed to these sediments. However, the degradation of dichlobenil to BAM could not be correlated to either sorption, water chemistry, composition of soils or sediments. Degradation of dichlobenil to BAM was limited (<2% degraded) in the deeper unsaturated zones, and no degradation was observed in aquifer sediments. This illustrates, that dichlobenil transported to aquifers does not contribute to the BAM-contamination in aquifers. A small, but significant degradation of BAM was observed in the upper part of the unsaturated zones in sandy sediments, but no degradation was observed in the clayey till sediment or in the deeper unsaturated zones. The insignificant degradation of BAM in aquifer systems shows that BAM pollution detected in aquifers will appear for a long time; and consequently the potential for natural attenuation of BAM in aquifer systems is limited.

The present study investigated the circulating levels and cerebral fluxes of calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY) and their relation to cerebral blood flow (CBF) during normoventilation and hyperventilation in patients with fulminant hepatic failure (FHF). Sixteen patients with FHF were studied and compared to six patients with cirrhosis of the liver. CBF was measured by the (133)Xe wash-out technique. Blood samples were obtained simultaneously from the artery and internal jugular bulb. Concentrations of CGRP and VIP were higher in FHF than in cirrhosis, 87 (55-218) vs. 29 (21-42) pmol/L, and 11 (6-29) vs. 5 (3-9)pmol/L, respectively. NPY was normal, none of the measures were related to CBF, and there was no detectable net brain fluxes. Hyperventilation did not alter any of the measures. CGRP and VIP in FHF seem to reflect hemodynamic changes in the systemic rather than in the cerebral circulation., (Copyright 2001 Harcourt Publishers Ltd.)

Background/aim: Brain edema is a common fatal complication in acute liver failure. It is related to an acute change in brain osmolarity secondary to the glial accumulation of glutamine. Since high cerebral blood flow (CBF) precedes cerebral herniation in fulminant hepatic failure we first determined if an increase in brain water and glutamine are prerequisite to a rise in CBF in a model of ammonia-induced brain edema. Secondly, we determined if such a cerebral hyperperfusion is mediated by nitric oxide synthase (NOS)., Methods: Male rats received an end-to-side portacaval anastomosis (PCA). At 24 h, they were anesthetized with ketamine and infused with ammonium acetate (55 microM/kg per min). Studies were performed at 60, 90, 120, 150 and 180 min after starting the ammonia infusion and once the intracranial pressure had risen three-fold (mean 210'). Brain water (BW) was measured using the gravimetry method and CBF with the radioactive microsphere technique. Glutamine (GLN) in the CSF was sampled via a cisterna magna catheter. The neuronal NOS was specifically inhibited by 1-2-trifluoromethylphenyl imidazole (TRIM, 50 mg/kg intraperitoneally) and in separate studies nonspecifically by N-omega-nitro-L-arginine (L-NNA, 2 microg/kg per min intravenously), Results: At 90', brain water was significantly increased (P < 0.015) as compared to the 60' group while CBF was significantly different at 150'. A significant correlation was observed between values of CBF and brain water (r = 0.88, n = 36, P < 0.001). Administration of either TRIM or L-NNA did not prevent the development of cerebral hyperperfu. sion and edema., Conclusion: We observed that cerebral hyperemia follows an initial rise in brain water content, rather than in the cerebrospinal fluid concentration of glutamine. The rise in CBF further correlated with brain water accumulation and was of critical importance for the development of intracranial hypertension. The unique mechanism for the rise in CBF in hyperammonemia was not prevented by NOS inhibition indicating that NO is not the mediator of high CBF and intracranial hypertension.

Pleurodesis of malignant pleural effusion provides for a substantially better quality of life compared to onging exudation with the need for repeated evacuation of fluid. Successful pleurodesis leads to permanent cessation of fluid production as a result of the formation of fibrous adhesion between the lung and costal pleura which in theory, however, might restrict lung mobility. In patients with poor lung function, or with need for bilateral pleurodesis, the apprehension of further impairment of lung function often arises. The aim of this study was to evaluate the effects of pleurodesis on lung function. Therefore 10 patients with malignant pleurisy with very limited tumour were investigated. They were without radiological signs of tumour infiltration in the lung parenchyma, without visible tumour growth in the pleural space during thoracoscopy and had undergone a successful one-sided pleurodesis. Respiratory function tests were performed at different times, 1-102 months after pleurodesis. The assessment consisted of: static and dynamic spirometry, exercise testing with blood gas determination and radiospirometry. Spirometric values were slightly low, but in general within the reference limits. Blood gas determination showed no signs of alveolar hypoventilation. Radiospirometry showed a slight attenuation of activity in the treated lung but similar turnover of gas of the treated vs. the untreated side. The study showed that pleurodesis in malignant pleurisy has only minor impact on respiratory function.

Aims: Acute phase reactants (APRs) are believed to play an important biological role in trauma, sepsis and malignant disease. We have investigated the induction of the APR, C-reactive protein (CRP), by the biological response modifier, polyadenylic-polyuridylic acid (PAPU) during the peri-operative period., Methods: Twenty post-menopausal women with breast cancer undergoing mastectomy were randomized into a double blind, placebo-controlled, parallel group pilot study. PAPU (150 mg) or placebo was given intravenously the day prior to surgery (D -1), the day of surgery (D 0) and post-operatively on days (D 1, 3, 5, 7 and 14). Blood samples were collected on eight different days (D -2, -1, 0, 1, 2, 4, 6 and 18). CRP was significantly elevated in the PAPU group (P<0.05) on days 2 and 4, when compared with patients receiving placebo. The serum levels of cytokines believed to induce hepatic APRs, were also measured., Results: The serum concentration of IL-6 was elevated on days 1, 2, 4 and 6 (P<0.05), TNF- alpha and IL-1 beta levels were increased on days 1 and 2 (P<0.05), respectively, while the serum level of soluble interleukin-2 receptor (sIL-2R) was elevated above the baseline on days 0, 2, 4, 6 and 18 in the PAPU group, when compared with the baseline., Conclusions: This modulation of acute phase response may have important implications for patients with cancer undergoing surgery., (Copyright 1999 Harcourt Publishers Ltd.)

Lung volume reduction surgery for severe emphysema with removal of 20-30% of the most destroyed parts of the lung parenchyma has been reported to improve lung function substantially. Increased elastic recoil has been suggested as one underlying mechanism for the improvement. Fourteen patients, seven men and seven women with a mean age of 62 years, who underwent bilateral lung volume reduction surgery have been followed up for 3 months. We here report the data on quality of life, lung function and elastic recoil. FEV1.0 increased by a mean of 26% from 0.581 to 0.731 (P < 0.01). The mean TLC was reduced by 16% from 8.91 to 7.51 (P < 0.001). The level of hyperinflation decreased as implied by a reduction in the ratio of RV to TLC from 0.70 to 0.60 (P < 0.001). The pulmonary elastic recoil improved, with an increase in the transpulmonary pressure at maximal inspiration (PelTLC) from 0.95 kPa to 1.35 kPa (P < 0.05) and an average increase in the coefficient of retraction PelTLC/TLC) from 0.12 kPa l-1 to 0.19 kPa l-1 (P < 0.01). The resting PaO2 increased from a mean of 8.7 kPa to 9.8 kPa (P < 0.01). The patients reported a high degree of subjective improvement according to the St. George's Respiratory Questionnaire and the working capacity on a bicycle increased by 26% from a mean of 38 W to 48 W (P < 0.01). The promising short-term results of lung volume reduction surgery for severe emphysema appear to be related to improved pulmonary elastic recoil.

By combination of fast magic-angle spinning (MAS) and detection of the free-induction decay during a rotor-synchronized quadrupolar Carr-Purcell-Meiboom-Gill (QCPMG) train of refocusing pulses, the sensitivity of quadrupolar-echo MAS NMR spectra for the central transition of half-integer quadrupolar nuclei exhibiting large quadrupolar couplings may be significantly enhanced. Enhancements by an order of magnitude may easily be realized while maintaining information about the anisotropic interactions. In the present study the so-called QCPMG-MAS experiment is demonstrated experimentally and by numerical simulations for the two 87Rb sites in Rb2SO4., (Copyright 1998 Academic Press.)

Background/aims: In patients with acute liver failure loss of cerebral blood flow autoregulation may result from cerebral vasodilatation. Since arterial hypocapnia induces cerebral vasoconstriction, we investigated whether cerebral blood flow autoregulation could be reestablished by mechanical hyperventilation., Methods: Seven consecutive patients (median age 45, range 30-50 years) with acute liver failure and hepatic encephalopathy stage IV entered the study. They were all maintained on mechanical ventilation. Cerebral blood flow autoregulation was evaluated by using transcranial Doppler sonography to assess mean flow velocity (Vmean) in the middle cerebral artery, during a rise in mean arterial pressure by norepinephrine infusion (0.5-10 microg/h). The patients were subsequently hyperventilated for 15 min before cerebral blood flow autoregulation was re-evaluated in the same mean arterial pressure range., Results: At baseline PaCO2 (4.0 (3.5-4.9)kPa), all patients had impaired cerebral blood flow autoregulation as Vmean increased from 47 (30-78) to 68 (49-107) cm x s(-1) (p<0.05), as MAP was raised from 82 (60-88) to 106 (89-123) mmHg. During hyperventilation, five of seven patients restored cerebral autoregulation as Vmean remained unchanged at 51 (45-70) cm x s(-1) during a rise in MAP from 84 (65-94) to 110 (89-130) mmHg. Cerebral blood flow autoregulation was not restored in two patients, but hyperventilation reduced the slope of the mean arterial pressure-Vmean correlation. These two patients had renal failure and were treated with intermittent hemodialysis., Conclusions: Cerebral blood flow autoregulation was restored by hyperventilation in five of seven patients with acute liver failure, indicating that cerebral vasodilatation is of pathophysiological importance in dysregulation of cerebral circulation in acute liver failure.

Background/aims: Normally, cerebral blood flow responds to changes in the arterial carbon dioxide tension (PaCO2) but not to changes in mean arterial pressure, commonly referred to as the cerebral CO2-reactivity and autoregulation. In patients with fulminant hepatic failure and in the rat with thioacetamide-induced liver failure, autoregulation is absent, presumably due to cerebral vasoparalysis. Since also CO2-reactivity may then be compromised, it was studied in patients with fulminant hepatic failure and rats with thioacetamide-induced liver failure., Methods: In ten patients (median age 32 (range 20-48) years)) and in ten age-matched volunteers, cerebral perfusion was elevated by transcranial Doppler assessed mean flow velocity (V(mean)) in the middle cerebral artery during hypo- and hyper-capnia. In six rats with liver failure and in six control rats, cerebral blood flow was measured repeatedly by the intracarotid 133 Xenon injection technique., Results: In the patients and volunteers, PaCO2 was lowered from 33 (23-44) to 28 (23-39) mmHg by hypocapnia and raised to 40 (34-48) mmHg by hypercapnia or 5% CO2 inhalation. During hypocapnia, the CO2-reactivity did not differ significantly between patients and volunteers, 4.0 (1.1-7.4) vs. 3.0 (1.7-5.0)% mmHg(-1), while it was reduced during hypercapnia in the patients, 2.2 (1.8-5.2) vs. 4.6 (3.0-8.0)% mmHg(-1) (p < 0.05). In the rats, PaCO2 was reduced from 39 (37-40) to 30 (29-31) mmHg and then raised to 51 (41-55) mmHg. During hypocapnia, CO2-reactivity was similar in rats with liver failure and in control rats, 2.3 vs 2.7% mmhg(21), respectively. In all rats with liver failure CO2-reactivity was abolished during hypercapnia, while it was 1.5% mmHg(-1) in the control rats (p < 0.01)., Conclusions: The finding that cerebral CO2 reactivity is reduced in hypercapnia, while it is preserved in hypocapnia, suggests that gradual dilation of the cerebral resistance vessels develops in fulminant hepatic failure and connects previous morphological studies with changes in the regulation of cerebral blood flow, i.e. impaired cerebral autoregulation and blunted CO2-reactivity.

A patient underwent pulmonary thromboendoarterectomy for chronic, major-vessel thromboembolic pulmonary hypertension. After operation the patient developed reperfusion oedema and hypoxaemia which was treated successfully with inhalation of nitric oxide. Before operation, the response to inhaled nitric oxide was characterized by a slight reduction in pulmonary vascular resistance but without improvement in gas exchange. The postoperative improvement in oxygenation after inhalation of nitric oxide contrasted sharply with the preoperative reaction.

In management of patients with fulminant hepatic failure, it is recommended that mean arterial pressure should be raised if cerebral perfusion pressure is lower than 50 mmHg, but the influence of such therapy on cerebral blood flow is unknown. We examined cerebral blood flow autoregulation in seven consecutive patients with fulminant hepatic failure during treatment of imminent insufficient cerebral perfusion pressure. Cerebral perfusion was evaluated by transcranial Doppler assessed mean flow velocity in the middle cerebral artery and by the arterio-venous difference for oxygen. Intracranial pressure was recorded by a subdural transducer and cerebral perfusion pressure calculated as the difference between mean arterial pressure and intracranial pressure. After 20 (range 10 to 43) min, mean arterial pressure was raised from 74 (43-80) to 94 (76-114) mmHg by i.v. noradrenaline, cerebral perfusion pressure increased from 49 (26-75) to 82 (50-108) mmHg (p < 0.01) as the intracranial pressure remained unchanged at 26 (3-35) mmHg. The mean flow veolocity increased from 68 (30-134) to 108 (48-168) cm s-1 and the arterio-venous difference for oxygen by 46 (10-82)% (p < 0.05). Both mean flow velocity (r = 0.63) and arterio-venous difference for oxygen (r = 0.71) were correlated to mean arterial pressure (p < 0.001), and a lower blood pressure limit of autoregulation could not be identified in any of the patients. These data suggest that the cerebral blood flow is not autoregulated in patients with fulminant hepatic failure and therefore cerebral blood flow should be "clamped" within the normal physiologic range by manipulation of arterial blood pressure in order to avoid cerebral hypoxia and/or hypertensive induced cerebral oedema.

We have studied the effects of labetalol on cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2) in eight healthy volunteers. CBF was measured by single photon emission computerized tomography before and during infusion of labetalol. CMRO2 was calculated as CBF x cerebral arteriovenous oxygen content difference (CaO2-CvO2). CBF autoregulation was tested during infusion of labetalol by changing arterial pressure and estimating relative changes in global CBF from changes in (CaO2-CvO2). CBF before and during infusion of labetalol was 67 and 65 ml/100 g min-1, respectively (P > 0.05). CMRO2 was 2.9 and 2.8 ml/100 g min-1, respectively (P > 0.05). CBF autoregulation was preserved in all subjects. The lower limit of CBF autoregulation was 88 mm Hg (94% of baseline mean arterial pressure). We conclude that labetalol did not influence global or regional CBF, or CMRO2, and CBF autoregulation was preserved.

Cerebral blood flow normally remains constant within a wide range of mean arterial blood pressure values. In fulminant hepatic failure, however, it is not known whether autoregulation of cerebral blood flow is maintained. In the present study, cerebral blood flow autoregulation was investigated in rats 3 days after induction of fulminant hepatic failure. Wistar rats were given intraperitoneal thioacetamide or saline injections. The mean arterial blood pressure was varied by means of norepinephrine infusion or venesection, respectively. As mean arterial blood pressure declined, repeated cerebral blood flow measurements were performed by the intracarotid 113Xenon injection method. The relation between mean arterial blood pressure and cerebral blood flow was examined by statistical regression analysis, and the lower limit of autoregulation was determined in each rat. Cerebral blood flow baseline values were unaltered in liver failure compared to the control group (73 (36-92) vs. 79 (57-87) ml.100 g-1.min-1, median and range). Baseline mean arterial blood pressure was also similar in the two groups (90 (75-113) vs. 95 (70-112)). Mean arterial blood pressure varied between 40 (35-50) and 110 (90-135) mmHg in the control rats and between 50 (45-68) and 110 (95-126) mmHg in the rats with liver failure. A lower limit of autoregulation was identified in all control rats at a mean arterial blood pressure of 67 (55-78) mmHg. Below this limit, cerebral blood flow declined in parallel with mean arterial blood pressure. None of the rats with liver failure exhibited autoregulation, and cerebral blood flow changed in parallel with mean arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

In Sweden, acute myocardial infarction (AMI) incidence has been found to differ considerably between the neighboring counties of Stockholm and Gävleborg, with an increase in Stockholm during the 1970s. We estimated the AMI incidence in Stockholm in 1973 and in both areas in 1981. To determine if there were differences in the validity of hospital discharge diagnoses, random samples of AMI patients were examined for diagnostic criteria for AMI. In both genders, AMI incidence was higher in Gävleborg than in Stockholm (relative risk (RR) 1.34 for men and 1.21 for women) and increased in Stockholm from 1973 to 1981 (RR 1.21 for men and 1.29 for women). The proportion of patients fulfilling the diagnostic criteria for AMI was similar in both areas in 1981 but 10% less in Stockholm in 1981 than in 1973. These results suggest that differences in the validity of hospital discharge diagnoses cannot explain the geographical differences in AMI incidence, but that this may have contributed to the increasing incidence seen in Stockholm county.

The effect of dietary fiber viscosity on apparent ileal nitrogen and amino acid digestibility, proteolytic enzyme activity and digestive organ weights was investigated. Eighteen growing rats were fed for 21 d purified casein-based diets containing carboxymethylcellulose (50 g/kg) of low (20 cP), medium (800 cP) and high (2000 cP) viscosity (LV, MV and HV treatment groups, respectively). Dietary fiber viscosity did not significantly affect apparent ileal (terminal 15 cm of the ileum) nitrogen or amino acid digestibility, trypsin or chymotrypsin activity in the small intestinal contents and pancreatic tissue, aminopeptidase-N activity in the small intestinal contents and tissue, or the weights of the stomach, pancreas, small or large intestines. Intragastric pepsin activity in LV rats was significantly higher than in MV or HV rats (P < 0.01), but fiber viscosity did not affect pepsin activity in the stomach tissue. The intragastric pH of the HV and MV rats was significantly higher than that for the LV rats (P < 0.01). The stomach contents (dry matter) of MV and HV rats were greater than in LV rats (P < 0.05). Delayed passage rate of the more viscous digesta may have resulted in greater absorption of amino acids, because the HV rats had a higher estimated true ileal digestibility than the LV animals for threonine, serine, aspartic acid, glutamic acid, histidine, tyrosine and phenylalanine.

The early growth response gene, Egr-1 (NGFI-A, krox 24, zif 268, TIS 8), is a member of a family of genes with suggested importance in the regulation of cell growth and differentiation. Retinoic acid has been shown to markedly induce Egr-1 gene expression in mouse embryonal carcinoma cells and rat preosteoblastic cells. In this study we demonstrate that treatment of cultured human skin fibroblasts with retinoic acid results in a rapid transient four-fold induction of Egr-1 transcripts, being maximum at 60 min and returning to a basal level by 120 min. However, treatment of cultured human keratinocytes with retinoic acid did not significantly induce Egr-1 transcripts. Expression of Egr-1 message in keratinocytes was observed to be induced by fetal bovine serum and tetra-decanoyl phorbol acetate, whereas calcium, 1,25-dihydroxyvitamin D3, and cyclic adenosine monophosphate caused little or no induction. Topical application of 0.1% retinoic acid cream in vivo resulted in a two- to threefold induction of Egr-1 transcripts following treatment for 24 and 48 h, returning to nearly basal levels by 96 h. Taken together, these data are consistent with the possibility that Egr-1 is a proximal component of an intracellular molecular cascade that may give rise to alterations in cell phenotype in response to retinoic acid.

Immunological assays for fragments of the cartilage large aggregating proteoglycan, aggrecan, have been widely used to monitor cartilage turnover. These assays have commonly employed the monoclonal keratan sulphate antibody, 5D4. Keratan sulphate, however, is present in many tissues and 5D4 affinity is critically dependent on antigen structure. We have therefore raised and characterized a monoclonal antibody (1-F21) that reacts with the core protein of aggrecan without interference from the glycosaminoglycan side chains and, using this antibody, we have optimized a sensitive, competitive ELISA. The within-assay and between-assay coefficients of variation were 4.9-8.9% and 11.1-13.0%, respectively. The mean concentrations of core protein in synovial fluid, serum and urine were 76.4 micrograms/ml, 104.0 ng/ml and 81.0 ng/ml, respectively. In synovial fluids the concentrations were closely correlated with the concentrations of keratan sulphate as determined by 5D4 (r = 0.94), whereas in serum and urine there was no obvious correlation between the determinations. These findings show that measurement of both core protein and keratan sulphate results in a more precise description of aggrecan turnover.

The effect of dietary fiber viscosity on the excretion of endogenous nitrogen and amino acids from the small intestinal lumen of growing rats was investigated. Rats were fed for 12 d protein-free diets containing 5% cellulose (negligible viscosity) or 5% carboxymethylcellulose of low (20 cP), medium (800 cP) or high (2000 cP) viscosity, as the sole dietary fiber source. As dietary fiber viscosity increased from 0 to 2000 cP, there was a significant (P < 0.05) linear increase in the flow of endogenous nitrogen, aspartic acid, serine, glutamic acid, proline, threonine, glycine, alanine, isoleucine, histidine, valine, methionine, leucine and lysine at the terminal ileum. The amino acid composition of the ileal digesta was unaffected by changes in fiber viscosity. It seems that either endogenous protein of a similar origin was secreted in larger amounts or that the digestion and absorption of endogenous amino acids was inhibited as dietary fiber viscosity increased. There was a significant (P < 0.05) linear increase in the concentration of sialic acids relative to chromic oxide in the small intestinal contents with increasing fiber viscosity, indicating an increase in mucoproteins.

Acitretin has recently been introduced to replace etretinate in the treatment of severe psoriasis due to a considerable shorter terminal half-life. The previously recommended 2-month anticonceptive period after acitretin treatment has been extended to 2 years after the detection of etretinate in certain acitretin recipients. In the present study, 10 patients with severe psoriasis were treated with 30 mg acitretin daily for 3 months. Seven patients had detectable mean steady-state plasma etretinate concentrations in the range of 2.5 to 56.7 ng/ml. Four of the patients showed teratogenic levels of plasma etretinate. Consumption of alcohol appeared to be an important contributing factor for the formation of etretinate. As judged from the dose- and body-weight-normalized AUC values (AUCcor) there was a great inter-individual variation (sixfold) in the systemic availability of acitretin. After discontinuation of therapy, the rate of elimination of both acitretin (t1/2 range 1.0 to 25.4 d) and 13-cis-acitretin (t1/2 range 1.5 to 25.7 d) was found to be related to the observed mean steady-state level of etretinate as evidenced by a longer terminal t1/2 of patients with high levels of etretinate in plasma. A mean terminal elimination half-life of etretinate was found to be 45.7 d +/- 10.6 (mean +/- SD; range 27.0 to 59.3 d). The risk of metabolic formation of etretinate in acitretin recipients makes it impossible to draw any definite conclusion with regard to recommendation of length of anticonceptive period following acitretin therapy in psoriatics. Monitoring of plasma etretinate levels in acitretin-treated fertile women is advisable.

The frequencies of sites for rare-cutting restriction enzymes in 2.9 million bp of human genomic DNA sequence in the EMBL database have been determined and compared with the expected frequencies. Rare cutters can be divided into four groups based on certain features of their recognition sites. Mlu, I, Nru I, Spl I, and Pvu I are predicted to cleave genomic DNA most infrequently, which is borne out by the fragment lengths observed for Mlu I and Nru I. Thus, these four enzymes are ideal for making long-range maps based on pulsed-field electrophoresis. Other enzymes like Not I are useful for making more detailed maps. Finer maps for identification of CpG islands and associated genes should involve several rare cutters including Eag I, Sac II and Bss HII. A cluster of sites for at least two such enzymes is a good indicator of a CpG island, and 78% of the island-associated genes can be located in this way.

Obese subjects are at increased risk for cardiovascular disease manifestations. The CK value is an important aid in the diagnosis of myocardial infarction, but may also be increased by factors such as muscle mass or breakdown of muscle tissue. We analysed CK values in 120 obese patients in our Obesity Unit and also monitored CK values during a weight reduction programme in 26 of these patients. CK values did not increase with body weight, and during weight loss in a diet programme no systematic CK changes were observed. We conclude that in the evaluation of an elevated CK value in a coronary care unit, such an increased value cannot be accounted for by the overweight per se.

Following myocardial damage as in acute myocardial infarction (AMI) or open heart surgery, the tissue damage might result in a release of mitochondrial CK (CK-MIT). The presence of this CK isoenzyme in serum may be detected after chromatographic separation of CK-activity on Sephacryl S-200. By combining chromatographic separation of CK-MB with immunologic inhibition of CK-M, both CK-MB and CK-MIT can be estimated in serum. Using this procedure changes in enzyme activities were studied in ten patients with AMI and twelve patients subjected to open heart surgery using cardioplegia. Following AMI CK-MB peaked about 24 h after onset of ischaemic symptoms. CK-MIT increased similarly and reached a plateau after 24 h where it remained during an additional 24-36 h. At peak CK-MB concentration, the corresponding CK-MIT activity was about 22% of the CK-MB activity. Following cardiac surgery there was a rapid release of CK-MB with a peak about 5 h after release of aortic cross-clamping, and with a simultaneous CK-MIT activity amounting to 19% of the CK-MB activity. In conclusion, CK-MIT is released into serum following myocardial ischaemia. Its appearance has time characteristics similar to that of other mitochondrial enzymes. The CK-B method does not specifically determine CK-B, but non-CK-M, which in cardiac ischaemia at peak serum CK-MB concentrations includes about 20% CK-MIT.

delta9-Tetrahydrocannabinol (THC; 2.5, 5.0, 10.0 mg/kg, PO) impaired avoidance and rotarod performance, and caused bradycardia and hypothermia. Phencyclidine (PCP; 1.25, 2.5, 5.0 mg/kg, IP) impaired avoidance and rotarod performance and caused a marked increase in photocell activity. When combined, the depressant properties of each drug were enhanced and the stimulation of photocell activity cg/kg THC and its interactions with PCP followed subacute treatment for six days, whereas many of the effects of PCP were enhanced after subacute treatment with a dose of 2.5 mg/kg. Open-field behavior was affected by each drug alone and in combination in a similar way as photocell activity, but the depression caused by their interaction was greater; both drugs caused an increase in urination. Response rates on an FR-10 schedule of food reinforcement were decreased by 2.5 mg/kg PCP, but not by 5.0 mg/kg THC; the combination caused greater response suppression than either drug alone. The functional interactions between THC and PCP were not related to changes in the concentrations of 14C or 3H in plasma or brain derived from 14C-delta9-THC and 3H-PCP, respectively.

Male, Fischer strain rats were resistant to the impairing effects of delta9--THC (15-60 mg/kg, IG) on performance of a conditioned pole-climb avoidance response (CAR) after daily subacute pretreatment for 4 or 6 days. A single administration of 20 mg/kg delta9--THC independent of the performance test did not attenuate the subsequent impairment caused by delta9--THC when tested 1-6 days later; however, administration 2 hr before each test attenuated the effect on subsequent tests given at intervals of 1-5 weeks. Similarly, subacute treatment with 20 mg/kg delta9--THC for 4 days independent of the performance test attenuated the impairment caused by delta9--THC during tests given to separate groups of rats 1 or 6, but not 14 days later. However, when the tests for tolerance were conducted repeatedly in the same rats, the attenuation appeared to persist for intervals up to 5 weeks. The results are discussed in terms of metabolic, functional and compensatory (behavioral) tolerance.

It has been found that binding of low molecular weight ligands to human serum albumin is generally nonsaturating. Equations commonly used for describing the binding equilibria, i.e., the Scatchard and Klotz (Adair) equations, are saturation functions. We have accordingly tried to establish an equation which would fit the observed data, i.e., not reach a saturation plateau. An empirical equation, in which the bound ligand is expressed as a function of the free ligand [R(C) = b1 in (b2C + 1)], is shown to give reasonably good fits to observed binding equilibrium data for the binding of several organic ligands to human serum albumin, when the two parameters, b1 and b2, are given suitable values. The curve of bound versus free ligand, as plotted from this equation, has the same slope and curvature as that obtained from the Klotz stepwise binding equation at C = 0, if b1 = K1/[2(K1 - 2K2)] and b2 = 2(K1 - 2K2), where K1 and K2 are the first and second stoichiometric binding constants.

The acute, reciprocal dose-response interactions between delta9-tetrahydrocannabinol (delta9-THC; 2.5, 5.0 and 10.0 mg/kg; IG) and each of three stimulants - d-amphetamine (dA; 1, 2 and 4 mg/kg; IP), cocaine (COC; 10, 20 and 30 mg/kg; IP), and nicotine (NIC; 0.25, 0.5 and 1.0 mg/kg; IP) were studied for their effects on performance of a conditioned avoidance response (CAR), photocell activity, heart rate, body temperature, and rotarod performance. delta9-THC impaired CAR and rotarod performance, depressed photocell activity, and decreased heart rate and body temperature. None of the three stimulants influenced CAR performance, but dA and COC increased the number of intertrial responses, and this latter effect was partially antagonized by delta9-THC. dA and COC, but not NIC, stimulated photocell activity. delta9-THC completely blocked this effect of dA, whereas there was mutual antagonism between delta9-THC and COC on this measure and NIC markedly potentiated the depression caused by delta9-THC. dA and COC tended to offset the impairment of rotarod performance caused by delta9-THC, whereas NIC augmented it. The bradycardia and hypothermia caused by delta9-THC tended to be augmented by these stimulants, especially NIC. The interactions were also studied after subacute treatment for six days with delta9-THC and/or each of the three stimulants. There was evidence for tolerance to the effects of delta9-THC on all measures and this tolerance generally resulted in less interactive effects between delta9-THC and the stimulants. Little or no tolerance was seen for the effects of the three stimulants or their interaction with delta9-THC. The time course of radioactivity derived from 14C-delta9-THC and each of the radiolabelled stimulants was determined in plasma and brain. Only minor interactive effects were found and, in general, they could not account for the functional interactions.

Transthoracic electrical impedance (TEI) is related to thoracic fluid content. In order to analyze this relation, we studied the acute effects of changes in body posture and of intravenous administration of furosemide on TEI in patients with different diuretic regimens. The TEI was measured using a tetrapolar electrode system, and a 100 microA constant current at 100 kHz. The measurements were performed repeatedly during the first two days in 15 consecutive patients with acute myocardial infarction (AMI) and without overt left heart failure, as evaluated from clinical data and bedside catheterization. It was concluded that TEI appears to be a sensitive, noninvasive means of evaluating changes in thoracic fluid content in AMI.