Association of serum VEGF levels with prefrontal cortex volume in schizophrenia.

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples.

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Allopurinol enhanced thiopurine treatment for inflammatory bowel disease: safety considerations and guidelines for use.

WHAT IS KNOWN AND OBJECTIVE: The thiopurine medications are standard inflammatory bowel disease treatments. Therapeutic failure is observed, however, often because of variable drug metabolism. Allopurinol can enhance the potency of thiopurine treatment. Our objective is to review the relevant literature, and our own experience, to determine if allopurinol enhancement of thiopurine treatment is a reasonable therapeutic strategy. COMMENT: Published reports of, and our own experience using, allopurinol-thiopurine combination therapy indicate that the addition of allopurinol will enhance thiopurine treatment in up to 60% of patients. There are risks to this approach, but with appropriate monitoring, these risks should approximate those observed with thiopurine therapy alone. WHAT IS NEW AND CONCLUSION: Combination therapy with allopurinol and a thiopurine is a reasonable alternative for inflammatory bowel disease patients not responding to thiopurine monotherapy. Physicians experienced in thiopurine treatment, who have familiarity with thiopurine metabolism, and are willing to engage in appropriate therapeutic monitoring, should consider this strategy.

Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy.

Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.

Patterns of Aedes aegypti (Diptera: Culicidae) infestation and container productivity measured using pupal and Stegomyia indices in northern Argentina.

A citywide control program of Aedes aegypti (L.) (Diptera: Culicidae) mainly based on the use of larvicides reduced infestations but failed to achieve the desired target levels in Clorinda, northeastern Argentina, over 5 yr of interventions. To understand the underlying causes of persistent infestations and to develop new control tactics adapted to the local context, we conducted two pupal surveys in a large neighborhood with approximately 2,500 houses and recorded several variables for every container inspected in fall and spring 2007. In total, 4,076 lots and 4,267 containers were inspected over both surveys, and 8,391 Ae. aegypti pupae were collected. Large tanks used for potable water storage were the most abundant and the most productive type of container, accounting for 65-84% of all the pupae collected. Therefore, large tanks were key containers and candidates for improved targeted interventions. Multivariate analysis showed that containers located in the yard, at low sun exposure, unlidded, filled with rain water, and holding polluted water were all more likely to be infested by larvae or pupae. When only infested containers were considered, productivity of pupae was most closely associated with large tanks and rain water. A stochastic simulation model was developed to calculate the expected correlations between pupal and Stegomyia indices according to the characteristics of the distribution of larvae and pupae per container and the spatial scale at which the indices were computed. The correlation between pupal and Stegomyia indices is expected to increase as infestation levels decline.

Cholecystokinin A and B receptors are differentially expressed in normal pancreas and pancreatic adenocarcinoma.

Cholecystokinin (CCK) plays an important role in pancreatic carcinogenesis. While human CCK-A and -B receptors have been fully characterized, their relative roles in human pancreatic adenocarcinoma remain unclear. Thus, expression of CCK-A and -B receptors in normal human pancreas, pancreatic adenocarcinomas, and other human extrapancreatic tissues and malignancies was examined, using reverse transcription followed by the polymerase chain reaction (RT-PCR). mRNA isolated from 15 normal pancreas specimens, 22 pancreatic adenocarcinomas, and 58 extrapancreatic tissues and tumors was subjected to RT-PCR using primers specific for human CCK-A and -B receptors. Expression of CCK-B receptors was detected in all tissues arising from pancreas and in most extrapancreatic tissues and tumors. In contrast, CCK-A receptors exhibited a more selective pattern of expression in gall bladder, intestine, brain, ovary, spleen, and thymus. Of significance, CCK-A receptors were expressed selectively in all pancreatic adenocarcinomas, but not in any normal pancreas specimens. In situ hybridization, using receptor-specific riboprobes, localized CCK-A receptor expression to ductal cells, the presumed origin of most human pancreatic adenocarcinomas. Southern blot analysis revealed no evidence of CCK-A receptor gene amplification or rearrangement in pancreatic adenocarcinomas. Because of its selective expression, the CCK-A receptor may serve as selective biomarker for pancreatic adenocarcinoma.

Reversal of experimental diabetic neuropathy by VEGF gene transfer.

The pathogenetic basis for diabetic neuropathy has been enigmatic. Using two different animal models of diabetes, we have investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. Nerve blood flow, as measured by laser Doppler imaging or direct detection of a locally administered fluorescent lectin analogue, was markedly attenuated in rats with streptozotocin-induced diabetes, consistent with a profound reduction in the number of vessels observed. A severe peripheral neuropathy developed in parallel, characterized by significant slowing of motor and sensory nerve conduction velocities, compared with nondiabetic control animals. In contrast, 4 weeks after intramuscular gene transfer of plasmid DNA encoding VEGF-1 or VEGF-2, vascularity and blood flow in the nerves of treated animals were similar to those of nondiabetic control rats; constitutive overexpression of both transgenes resulted in restoration of large and small fiber peripheral nerve function. Similar experiments performed in a rabbit model of alloxan-induced diabetes produced comparable results. These findings support the notion that diabetic neuropathy results from microvascular ischemia involving the vasa nervorum and suggest the feasibility of a novel treatment strategy for patients in whom peripheral neuropathy constitutes a secondary complication of diabetes.

Hip-spine syndrome: A cadaveric analysis between osteoarthritis of the lumbar spine and hip joints.

BACKGROUND: Authors have recently proposed the concept of "hip-spine syndrome", however there exists limited evidence available to differentiate whether these concomitant arthritides are due to anatomic/structural causes, or systemic/metabolic effects. Exploring this relationship has important implications during the evaluation and treatment of both spine and hip disorders-a common clinical presentation of many patients. The purpose of this experiment was to investigate the individual contribution of hip arthritis towards the development of spine arthritis, with knee arthritis also being analyzed as a negative (systemic) control. HYPOTHESIS: Hip and spine arthritis are caused by both metabolic and anatomic causes. METHODS: A large, well-organized osteological database was queried, and osteoarthritis of the spine, hip, and knee joints was quantified using a validated scoring criteria. Six hundred and twenty-five specimens were chosen for analysis. Multivariate linear regression models were created to quantify the independent contributions of age, gender, race, height, and arthritis of the spine and hip joints. RESULTS: Age was the strongest predictor of arthritis at each site (standardized betas>0.281, P<0.001 for all). Hip arthritis was a stronger predictor of spine arthritis than was knee arthritis (standardized betas 0.215 and 0.155, respectively, P<0.001 for both). Spine arthritis was also a stronger predictor of hip arthritis than was knee arthritis (standardized betas 0.232 and 0.173, P<0.001 for both). CONCLUSIONS: Anatomic/structural influences about the lumbosacral-pelvic junction contribute towards the development of arthritis that is separate from any systemic/metabolic effects. Surgeons performing total hip arthroplasty should remain aware of these relationships, although future research is necessary regarding optimal surgical treatment of these patients. LEVEL OF EVIDENCE: N/A (cadaveric study).

Assessment of resuscitation as measured by markers of metabolic acidosis and features of injury.

AIMS: The best time for definitive orthopaedic care is often unclear in patients with multiple injuries. The objective of this study was make a prospective assessment of the safety of our early appropriate care (EAC) strategy and to evaluate the potential benefit of additional laboratory data to determine readiness for surgery. PATIENTS AND METHODS: A cohort of 335 patients with fractures of the pelvis, acetabulum, femur, or spine were included. Patients underwent definitive fixation within 36 hours if one of the following three parameters were met: lactate < 4.0 mmol/L; pH ≥ 7.25; or base excess (BE) ≥ -5.5 mmol/L. If all three parameters were met, resuscitation was designated full protocol resuscitation (FPR). If less than all three parameters were met, it was designated an incomplete protocol resuscitation (IPR). Complications were assessed by an independent adjudication committee and included infection; sepsis; PE/DVT; organ failure; pneumonia, and acute respiratory distress syndrome (ARDS). RESULTS: In total, 66 patients (19.7%) developed 90 complications. An historical cohort of 1441 patients had a complication rate of 22.1%. The complication rate for patients with only one EAC parameter at the point of protocol was 34.3%, which was higher than other groups (p = 0.041). Patients who had IPR did not have significantly more complications (31.8%) than those who had FPR (22.6%; p = 0.078). Regression analysis showed male gender and injury severity score to be independent predictors of complications. CONCLUSIONS: This study highlights important trends in the IPR and FPR groups, suggesting that differences in resuscitation parameters may guide care in certain patients; further study is, however, required. We advocate the use of the existing protocol, while research is continued for high-risk subgroups. Cite this article: Bone Joint J 2017;99-B:122-7.

Decreased and increased relative acetabular volume predict the development of osteoarthritis of the hip: an osteological review of 1090 hips.

AIMS: Recently, there has been considerable interest in quantifying the associations between bony abnormalities around and in the hip joint and osteoarthritis (OA). Our aim was to investigate the relationships between acetabular undercoverage, acetabular overcoverage, and femoroacetabular impingement (FAI) with OA of the hip, which currently remain controversial. MATERIALS AND METHODS: A total of 545 cadaveric skeletons (1090 hips) from the Hamann-Todd osteological collection were obtained. Femoral head volume (FHV), acetabular volume (AV), the FHV/AV ratio, acetabular version, alpha angle and anterior femoral neck offset (AFNO) were measured. A validated grading system was used to quantify OA of the hip as minimal, moderate, or severe. Multiple linear and multinomial logistic regression were used to determine the factors that correlated independently with the FHV, AV, and the FHV/AV ratio. RESULTS: Female cadavers had smaller FHVs (standardised beta -0.382, p < 0.001), and AVs (standardised beta -0.351, p < 0.001), compared with male patients, although the FHV/AV ratio was unchanged. Every 1° increase in alpha angle increased the probability of having moderate OA of the hip compared with minimal OA by 7.1%. Every 1 mm decrease in AFNO increased the probability of having severe or moderate OA of the hip, compared with minimal OA, by 11% and 9%, respectively. The relative risk ratios of having severe OA of the hip compared with minimal OA were 7.2 and 3.3 times greater for acetabular undercoverage and overcoverage, respectively, relative to normal acetabular cover. CONCLUSION: Acetabular undercoverage and overcoverage were independent predictors of increased OA of the hip. The alpha angle and AFNO had modest effects, supporting the hypothesis that bony abnormalities both in acetabular dysplasia and FAI are associated with severe OA. Cite this article: Bone Joint J 2017;99-B:432-9.

Relationship between pelvic incidence and osteoarthritis of the hip.

OBJECTIVES: Sagittal alignment of the lumbosacral spine, and specifically pelvic incidence (PI), has been implicated in the development of spine pathology, but generally ignored with regards to diseases of the hip. We aimed to determine if increased PI is correlated with higher rates of hip osteoarthritis (HOA). The effect of PI on the development of knee osteoarthritis (KOA) was used as a negative control. METHODS: We studied 400 well-preserved cadaveric skeletons ranging from 50 to 79 years of age at death. Each specimen's OA of the hip and knee were graded using a previously described method. PI was measured from standardised lateral photographs of reconstructed pelvises. Multiple regression analysis was performed to determine the relationship between age and PI with HOA and KOA. RESULTS: The mean age was 60.2 years (standard deviation (sd) 8.1), and the mean PI was 46.7° (sd 10.7°). Multiple regression analysis demonstrated a significant correlation between increased PI and HOA (standardised beta = 0.103, p = 0.017). There was no correlation between PI and KOA (standardised beta = 0.003, p = 0.912). CONCLUSION: Higher PI in the younger individual may contribute to the development of HOA in later life.Cite this article: Dr J. J. Gebhart. Relationship between pelvic incidence and osteoarthritis of the hip. Bone Joint Res 2016;5:66-72. DOI: 10.1302/2046-3758.52.2000552.

Ectopic expression of guanylyl cyclase C in CD34+ progenitor cells in peripheral blood.

PURPOSE: To examine the utility of guanylyl cyclase C (GC-C)-specific nested reverse transcriptase polymerase chain reaction (RT-PCR) to detect circulating tumor cells in patients with colorectal cancer. PATIENTS AND METHODS: Peripheral-blood mononuclear cells from 24 patients with Dukes' stage D colorectal cancer were analyzed by GC-C-specific nested RT-PCR using 1 microg of total RNA. Peripheral-blood mononuclear cells from 20 healthy volunteers served as controls. Additionally, peripheral-blood CD34+ progenitor cells were assayed for the expression of both GC-C and other epithelial cell-specific markers. RESULTS: GC-C mRNA was detected in blood mononuclear cells from all 24 patients with colorectal cancer and all healthy volunteers. These unexpected positive results reflected low-level ectopic transcription of GC-C in CD34+ progenitor cells. Moreover, CD34+ progenitor cells expressed other epithelial cell-specific markers, including prostate-specific antigen, prostate-specific membrane antigen, carcinoembryonic antigen, CK-19, CK-20, mucin 1, and GA733.2. Limiting the quantity of mononuclear cell total RNA analyzed to < or = 0.8 microg eliminated detection of GC-C and other tissue-specific transcripts in blood of healthy volunteers. However, under the same conditions, GC-C mRNA was detected in mononuclear cells from all 24 patients with metastatic colorectal cancer. Using 0.5 microg of total RNA and GC-C-specific primers, nested RT-PCR detected a single human colon carcinoma cell (approximately 20 to 200 GC-C transcripts/cell) in 10(6) to 10(7) mononuclear blood cells. CONCLUSION: These data suggest that GC-C may be useful for detecting circulating colorectal cancer cells. They also demonstrate that CD34+ cells are a source of ectopically expressed epithelial cell-specific markers and that CD34+ cells may contribute to the high false-positive rate generally observed when those markers are used to detect rare circulating metastatic cancer cells by RT-PCR.

Prognostic factors in medulloblastoma, including DNA ploidy.

PURPOSE: DNA ploidy status, completeness of surgical resection, use of chemotherapy, adequacy of radiation therapy, metastatic stage, sex, and age at diagnosis were evaluated as predictors of relapse in 58 patients with cerebellar medulloblastoma. METHODS: Flow cytometry (FCM) and/or image analysis (IA) were used to characterize tumor DNA ploidy. Twelve tumors (21%) were found to be aneuploid, 11 (19%) tetraploid, and 35 (60%) diploid. RESULTS: The most significant predictors of relapse in univariate analyses were the adequacy of radiation (> or = 50 Gy) (P = .02), metastatic staging (P = .05), completeness of resection (P = .085), and DNA ploidy status (diploid/tetraploid v aneuploid; P = .11). When the 52 patients who received > or = 50 Gy were included in a multivariate Cox model analysis, those with diploid/tetraploid tumors had fewer recurrences than those with aneuploid tumors (relative risk, 0.33; 95% confidence interval, 0.12 to 0.89; P = .03). Patients with complete resections (P = .07), or with stage M0 disease (P = .06) had fewer recurrences than other patients, but these factors were not independent predictors of outcome. DNA ploidy status was correlated with age; 10 of the 12 aneuploid tumors were found in children ages 3 to 10 years. Age, sex, and the use of chemotherapy were not prognostically significant in these analyses. CONCLUSION: The adequacy of radiation dose and DNA ploidy were the most important prognostic factors in this series. Contrary to previous reports, when corrected for adequacy of treatment, DNA aneuploidy was associated with a poor outcome. By multivariate analyses, DNA ploidy was an independent variable, even when controlling for extent of surgical resection and metastatic stage.

Influence of prostaglandin I2 on fibronectin-mediated phagocytosis in vivo and in vitro.

This study evaluated the effect of prostaglandin I2 (PGI2) on fibronectin-mediated macrophage phagocytosis in vivo and in vitro. Phagocytosis measured in vivo in rats by the vascular clearance rate and hepatic localization gelatinized sheep erythrocytes was inhibited in a dose-dependent manner after intravenous administration of PGI2. Phagocytosis was assessed in vitro in terms of uptake of fibronectin-dependent gelatinized sheep erythrocytes by monolayers of casein-elicited rat peritoneal macrophages. Concentrations of 1 ng/ml PGI2 or greater resulted in inhibition of particle internalization but not attachment to macrophages. This inhibitory effect was enhanced by aminophylline, a phosphodiesterase inhibitor. PGI2 increased cAMP levels and these were further increased in the presence of aminophylline. These data indicate that PGI2 inhibits macrophage uptake of gelatinized particles and support the idea that this is mediated by increased intracellular levels of cyclic AMP. PGI2 should thus be considered a potential etiologic factor in the phagocytic depression observed in association with thrombosis.

Analysis of colorectal cancer stage among HMO members targeted for screening.

BACKGROUND: This study is a retrospective analysis of data collected from patient medical records, a fecal occult blood test (FOBT) screening program, and computerized health maintenance organization (HMO) claims and encounters records. OBJECTIVE: To identify factors associated with a diagnosis of early (Dukes A and B) colorectal cancer among older adults targeted for annual FOBT screening. METHODS: Study subjects were insured by the former US Healthcare Inc (Blue Bell, Pa), an independent practice association-type HMO. The HMO was recently integrated into Aetna-US Healthcare. Before diagnosis, subjects were eligible for free annual FOBT screening through the HMO's colorectal cancer screening program. The study subjects included men and women (N = 222) who were aged 50 years or older and had a diagnosis of colorectal cancer between 1987 and 1990. Variables considered were patient age, gender, socioeconomic status, medical history, screening history, length of enrollment in the HMO, and stage of disease at diagnosis. RESULTS: Univariate analyses indicate that colorectal cancer diagnosis due to FOBT screening (P = .03), frequency of FOBT screening (P = .09), and length of HMO membership (P = .10) were positively related to being diagnosed as having early stage colorectal cancer. Multivariable analysis shows that having a screen-detected colorectal cancer was significantly and positively related (P = .03) to being diagnosed as having early stage disease. CONCLUSIONS: Findings support annual FOBT screening among older adults. Results illustrate the value of applying standard methods to the collection and analysis of patient data in a managed care context. The study also highlights a need for research on patient adherence to screening and physician follow-up of abnormal screening test results.

Variable effect of recombinant human granulocyte-macrophage colony-stimulating factor on bone marrow fibrosis in patients with myelodysplasia.

Eleven patients with myelodysplastic syndrome (MDS) and bone marrow fibrosis were identified out of a group of 15 patients with MDS who received recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) as part of a phase I/II trial. Bone marrow biopsies were obtained before and after one or more courses of GM-CSF at 250 micrograms/m2 administered as a 12-h infusion each day for 14 days. The biopsies were blindly evaluated and reticulin formation and collagen deposition were graded on a scale of 0-4. Fibrosis unequivocally increased in three patients and decreased in three patients. There were equivocal increases in an additional two patients and decreases in one subject. It was unchanged in one subject and unevaluable in one patient. Although patients in whom fibrosis increased tended to have smaller increases in neutrophil and reticulocyte counts on therapy, the difference was not statistically significant. In this small group of patients, it was not possible to determine clinical features that predicted response. Although GM-CSF can lead to partial resolution of marrow fibrosis in some individuals, it can also accelerate its deposition; improvement in granulocyte or reticulocyte count does not preclude increasing marrow fibrosis. Thus, the use of GM-CSF in patients with myelodysplasia with marrow fibrosis must be undertaken with caution.

Synthetic atrial natriuretic factor does not dilate resistance-sized arteries.

The effects of synthetic atrial natriuretic factor and atriopeptin III on induced tone in resistance-sized arteries from the rat were examined in vitro. Cylindrical segments of small mesenteric or cerebral arteries were mounted on a microcannula and pressurized to a transmural pressure of 75 mm Hg. After equilibration, the level of tone in cerebral arteries was on the order of - 35 change in diameter; addition of atrial natriuretic factor or atriopeptin III in cumulative doses from 10(-10) to 10(-7) M did not produce any transient or sustained changes in diameter. Similarly, atrial natriuretic factor or atriopeptin III did not alter the contractile responses of cerebral vessels to serotonin or prostaglandin F2 alpha. Mesenteric arteries, which do not possess an intrinsic myogenic tone, were precontracted with potassium (30 mM), norepinephrine (10(-6) M), or prostaglandin F2 alpha (1.1 X 10(-5) M) and exposed to the synthetic natriuretic peptides, also without effect. Transmural electrical stimulation (0.3-msec pulses; 180 mA; 4/second) relaxed cerebral and contracted mesenteric arteries; preincubation in 10(-7) M atrial natriuretic factor or atriopeptin III did not alter subsequent responses. These observations suggest that the hypotensive action of atrial natriuretic factor cannot be attributed to direct vasodilation of splanchnic or cerebral resistance-sized arteries.

Effect of limb restraints on serum creatine phosphokinase activity in normal volunteers.

Increased serum creatine phosphokinase (CPK) activity is sometimes found in acutely psychotic patients. In order to study factors affecting CPK activity, we investigated in normal subjects the effect on serum CPK activity of resistance to being restrained and to struggle against leather limb restraints (LLR) sometimes used for control of assaultive of self-destructive behavior of psychiatric patients. Blood samples were obtained 24 hr and immediately before restraint; and immediately, 6, 24, 48, and 72 hr after restraint. Serum CPK activity increases ranged from 3 to 16 times base line levels for all subjects. These increases exceeded the 95% upper limit of normal. Serum pyruvate kinase (PK) activity also increased significantly. In a second study, five male subjects were passively placed in LLR and then struggled against LLR for 1 hr. Serum CPK activity also increased significantly under these conditions, but less than after being forcibly restrained. Serum PK activity and lactic dehydrogenase activity also increased significantly, but serum aspartate aminotransferase (SGOT) activity did not. Since serum CPK activity is increased well above the normal limits in normal subjects after struggle against LLR, studies of serum CPK activity in psychotic patients must avoid the use of restraints as well as other types of trauma, which may produce serum CPK increases persisting as long as 72 hr.