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Background and Objective: Under physiological conditions, cerebral oxygen delivery is kept constant by adaptation of the regional cerebral blood flow (CBF) in relation to the oxygen content. So far, decreases of the regional CBF induced by a higher arterial oxygen content have been produced under hyperbaric or hyperviscous conditions. We tested whether local CBF is also reduced by a high haemoglobin (Hb) concentration at a normal haematocrit (Hct).Methods: Compared with controls (n=8), Hb content was increased to 19 g dl(-1) in conscious rats by isovolaemic replacement of the plasma fraction with an artificially high Hb solution (Hb-based oxygen carriers; HH group, n=8). In another group (n=8), Hct was decreased by isovolaemic exchange with an Hb-based oxygen carrier resulting in a normal Hb content (NH group). Mean and regional CBF was measured by iodo-[(14)C]-antipyrine autoradiography. Oxygen delivery was calculated from arterial oxygen content and CBF.Results: Compared with the controls (Hb 15.3 g dl(-1), Hct 0.44), mean CBF was lower in the HH (Hb 20.3 g dl(-1), Hct 0.44) group by 23% (P < or = 0.05), but remained unchanged in the NH group (Hb 15.0 g dl(-1), Hct 0.29). On a local level, hyperoxygenation reduced CBF in 22 out of 39 brain regions. In the NH group mean CBF was unchanged, whereas local CBF was higher in 10 areas. In both groups, overall cerebral oxygen delivery was unchanged compared with the control group. Locally though, high arterial Hb content decreased oxygen delivery in one-third of the brain structures.Conclusion: Whereas the overall cerebral oxygen delivery in the brain is maintained during hyperoxygenation and haemodilution, local oxygen delivery is decreased by high arterial Hb content in some brain regions. [ABSTRACT FROM AUTHOR]

Background and objective: Acute isovolaemic haemodilution increases local and mean cerebral blood flow. It is nor known whether a single haemodilution has a short-term effect only or whether it affects cerebral perfusion over a longer time period. In the present study, local and mean cerebral blood flow were determined in conscious rats after a 4, 24 and 48 h period following one-time haemodilution. Methods: Thirty-six rats were randomized to three untreated sham groups and three groups of haemodilution (4, 24 or 48 h, n = 6 for each group). Isovolaemic haemodilution with albumin 5% aimed to a target haematocrit of 0.2. Local cerebral blood flow was measured in 38 brain regions by the iodo-[[sup 14]' Clantipyrine method in conscious normothermic rats. Results: Isovolaemic haemodilution reduced haematocrit from 0.44 to 0.20. During the following 24 and 48 h periods, haematocrit remained low (0.22 and 0.21). Mean cerebral blood flow was similar in untreated sham groups (88 ± 12 after 4 h, 92 ±11 alter 24 h, 96 ± 10 mL l00g [sup -1] min[sup -1] after 48 h). Haemodilution increased mean cerebral blood flow after 4 h (184 ±11 mL l00g [sup v-1] min [sup -1]), after 24h (153 ± 13 mL l00g [sup -1] min [sup -1]) and 48 h (149 ± 15 mL 100g[sup -1] min [sup -1])(P ≤ 0.05). Local cerebral blood flow increased in all 38 structures after 4 h haemodilution but decreased with time in six of 38 brain structures after 24 h and in 15 regions after 48 h (P ≤0.05). Conclusions : A single one-time haemodilution increased mean cerebral blood flow for 2 days. However, local adaptation of cerebral blood flow to a chronic low haematocrit occurred but was heterogeneous within the brain. [ABSTRACT FROM AUTHOR]

The clinical availability of artificial oxygen carriers (AOCs) would result in profound alterations in transfusion medical practice. Rapid progress in the scientific and technological development of AOCs has advanced to a critical stage at which safe and effective alternatives to the transfusion of red blood cells are emerging. Haemoglobin- and perfluorocarbon-based oxygen carriers are under current clinical investigation. Artificial oxygen-carrying solutions, by virtue of their acellular structure, can be used to transport oxygen to ischaemic tissues that cannot otherwise be reached by cellular blood components. Organs awaiting transplantation can be preserved for a long time after perfusion with AOCs and tumour susceptibility to chemo- and radiotherapy is increased. The use of AOCs is therefore not confined to their use as red blood cell substitutes, but may find a wide spectrum of interdisciplinary applications. [ABSTRACT FROM AUTHOR]

Background: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies but can result in heart failure if left untreated. Here, we hypothesized that the membrane fusion and repair protein dysferlin is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy., Methods: Stimulated emission depletion and electron microscopy were used to localize dysferlin in mouse and human cardiomyocytes. Data-independent acquisition mass spectrometry revealed the cardiac dysferlin interactome and proteomic changes of the heart in dysferlin-knockout mice. After transverse aortic constriction, we compared the hypertrophic response of wild-type versus dysferlin-knockout hearts and studied TAT network remodeling mechanisms inside cardiomyocytes by live-cell membrane imaging., Results: We localized dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum, a.k.a. junctional complexes for Ca 2+ -induced Ca 2+ release. Interactome analyses demonstrated a novel protein interaction of dysferlin with the membrane-tethering sarcoplasmic reticulum protein juncophilin-2, a putative interactor of L-type Ca 2+ channels and ryanodine receptor Ca 2+ release channels in junctional complexes. Although the dysferlin-knockout caused a mild progressive phenotype of dilated cardiomyopathy, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction, dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while dysferlin-knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging showed a profound reorganization of the TAT network in wild-type left-ventricular myocytes after transverse aortic constriction with robust proliferation of axial tubules, which critically depended on the increased expression of dysferlin within newly emerging tubule components., Conclusions: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-sarcoplasmic reticulum junctional complexes for regulated excitation-contraction coupling and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure overload., Competing Interests: None.

The use of genome-wide genotyping arrays in pharmacogenomics (PGx) research and clinical implementation applications is increasing but it is unclear which arrays are best suited for these applications. Here, we conduct a comparative coverage analysis of PGx alleles included on genome-wide genotyping arrays, with an emphasis on alleles in genes with PGx-based prescribing guidelines. Genomic manifest files for seven arrays including the Axiom Precision Medicine Diversity Array (PMDA), Axiom PMDA Plus, Axiom PangenomiX, Axiom PangenomiX Plus, Infinium Global Screening Array, Infinium Global Diversity Array (GDA) and Infinium GDA with enhanced PGx (GDA-PGx) Array, were evaluated for coverage of 523 star alleles across 19 pharmacogenes included in prescribing guidelines developed by the Clinical Pharmacogenetic Implementation Consortium and Dutch Pharmacogenomics Working Group. Specific attention was given to coverage of the Association of Molecular Pathology's Tier 1 and Tier 2 allele sets for CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, NUDT15, TPMT and VKORC1 . Coverage of the examined PGx alleles was highest for the Infinium GDA-PGx (88%), Axiom PangenomiX Plus (77%), Axiom PangenomiX (72%) and Axiom PMDA Plus (70%). Three arrays (Infinium GDA-PGx, Axiom PangenomiX Plus and Axiom PMDA Plus) fully covered the Tier 1 alleles and the Axiom PangenomiX array provided full coverage of Tier 2 alleles. In conclusion, PGx allele coverage varied by gene and array. A superior array for all PGx applications was not identified. Future comparative analyses of genotype data produced by these arrays are needed to determine the robustness of the reported coverage estimates., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood. The main intracellular route for iron uptake in cardiomyocytes is clathrin-mediated endocytosis., Methods: We investigated subcellular iron uptake mechanisms in patient-derived and CRISPR/Cas-edited induced pluripotent stem cell-derived cardiomyocytes as well as patient-derived heart tissue. We used an integrated platform of DIA-MA (mass spectrometry data-independent acquisition)-based proteomics and signaling pathway interrogation. We employed a genetic induced pluripotent stem cell model of 2 inherited mutations ( TnT [ troponin T ]-R141W and TPM1 [ tropomyosin 1 ]-L185F) that lead to dilated cardiomyopathy (DCM), a frequent cause of heart failure, to study the underlying molecular dysfunctions of DCM mutations., Results: We identified a druggable molecular pathomechanism of impaired subcellular iron deficiency that is independent of systemic iron metabolism. Clathrin-mediated endocytosis defects as well as impaired endosome distribution and cargo transfer were identified as a basis for subcellular iron deficiency in DCM-induced pluripotent stem cell-derived cardiomyocytes. The clathrin-mediated endocytosis defects were also confirmed in the hearts of patients with DCM with end-stage heart failure. Correction of the TPM1-L185F mutation in DCM patient-derived induced pluripotent stem cells, treatment with a peptide, Rho activator II, or iron supplementation rescued the molecular disease pathway and recovered contractility. Phenocopying the effects of the TPM1-L185F mutation into WT induced pluripotent stem cell-derived cardiomyocytes could be ameliorated by iron supplementation., Conclusions: Our findings suggest that impaired endocytosis and cargo transport resulting in subcellular iron deficiency could be a relevant pathomechanism for patients with DCM carrying inherited mutations. Insight into this molecular mechanism may contribute to the development of treatment strategies and risk management in heart failure., Competing Interests: Disclosures None.

[Figure: see text].

Background: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS-mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking., Methods: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 ( LZTR1 ). We generated induced pluripotent stem cell-derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level., Results: Patients' induced pluripotent stem cell-derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS-mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype., Conclusions: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell-derived cardiomyocytes from NS patients carrying biallelic variants in LZTR1 and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.

Background: Abnormal calcium (Ca 2+ ) release from the sarcoplasmic reticulum (SR) contributes to the pathogenesis of atrial fibrillation (AF). Increased phosphorylation of 2 proteins essential for normal SR-Ca 2+ cycling, the type-2 ryanodine receptor (RyR2) and phospholamban (PLN), enhances the susceptibility to AF, but the underlying mechanisms remain unclear. Protein phosphatase 1 (PP1) limits steady-state phosphorylation of both RyR2 and PLN. Proteomic analysis uncovered a novel PP1-regulatory subunit (PPP1R3A [PP1 regulatory subunit type 3A]) in the RyR2 macromolecular channel complex that has been previously shown to mediate PP1 targeting to PLN. We tested the hypothesis that reduced PPP1R3A levels contribute to AF pathogenesis by reducing PP1 binding to both RyR2 and PLN., Methods: Immunoprecipitation, mass spectrometry, and complexome profiling were performed from the atrial tissue of patients with AF and from cardiac lysates of wild-type and Pln-knockout mice. Ppp1r3a-knockout mice were generated by CRISPR-mediated deletion of exons 2 to 3. Ppp1r3a-knockout mice and wild-type littermates were subjected to in vivo programmed electrical stimulation to determine AF susceptibility. Isolated atrial cardiomyocytes were used for Stimulated Emission Depletion superresolution microscopy and confocal Ca 2+ imaging., Results: Proteomics identified the PP1-regulatory subunit PPP1R3A as a novel RyR2-binding partner, and coimmunoprecipitation confirmed PPP1R3A binding to RyR2 and PLN. Complexome profiling and Stimulated Emission Depletion imaging revealed that PLN is present in the PPP1R3A-RyR2 interaction, suggesting the existence of a previously unknown SR nanodomain composed of both RyR2 and PLN/sarco/endoplasmic reticulum calcium ATPase-2a macromolecular complexes. This novel RyR2/PLN/sarco/endoplasmic reticulum calcium ATPase-2a complex was also identified in human atria. Genetic ablation of Ppp1r3a in mice impaired binding of PP1 to both RyR2 and PLN. Reduced PP1 targeting was associated with increased phosphorylation of RyR2 and PLN, aberrant SR-Ca 2+ release in atrial cardiomyocytes, and enhanced susceptibility to pacing-induced AF. Finally, PPP1R3A was progressively downregulated in the atria of patients with paroxysmal and persistent (chronic) AF., Conclusions: PPP1R3A is a novel PP1-regulatory subunit within the RyR2 channel complex. Reduced PPP1R3A levels impair PP1 targeting and increase phosphorylation of both RyR2 and PLN. PPP1R3A deficiency promotes abnormal SR-Ca 2+ release and increases AF susceptibility in mice. Given that PPP1R3A is downregulated in patients with AF, this regulatory subunit may represent a new target for AF therapeutic strategies.

Objective: Matrix metalloproteinases (MMPs) seem to play a prominent role in atherogenesis. Extracellular MMP inducer (EMMPRIN), a cell surface glycoprotein which stimulates MMP synthesis, has recently been detected in human atheroma. We have investigated the influence of oxidized low-density lipoproteins (oxLDLs) on EMMPRIN expression in human coronary artery smooth muscle cells (HCA-SMCs)., Methods and Results: OxLDL induced a significant increase of EMMPRIN release into HCA-SMC supernatants and a concomitant decrease of cell-associated EMMPRIN. These effects were antagonized by antioxidants as well as by EDTA and the MMP inhibitor GM6001. Western blot analysis demonstrated that MMP-1 and MMP-2 induce the cleavage of the extracellular domain from cell-associated EMMPRIN. MMP-1 and MMP-2 synthesis was upregulated by oxLDL, and, in addition, we have shown that soluble EMMPRIN, isolated from macrophage supernatants, increased MMP-1 and MMP-2 synthesis in HCA-SMC., Conclusions: Our data suggest that oxLDLs stimulate the release of soluble EMMPRIN, at least in part, by MMP-dependent shedding from the cell surface. Additionally, oxLDLs might induce a circular upregulation of matrix degradation because, in turn, soluble EMMPRIN stimulates MMP synthesis in HCA-SMC.

Background: Little is known about the regional distribution of cerebral blood flow (CBF) in nonanesthetized animals during periods of lowered blood pressure. The present investigation addresses the specific reaction patterns of local cerebral blood flow (LCBF) in comparison with mean CBF during graded pressure-controlled hemorrhagic shock in conscious rats., Methods: Conscious rats were subjected to graded pressure-controlled hemorrhage (to 85, 70, 55, or 40 mm Hg) by arterial blood withdrawal. After a period of 30 minutes, blood pressure was stabilized by withdrawal or reinfusion of blood. LCBF was determined autoradiographically by the iodo(14C)antipyrine method in 34 brain structures, and mean CBF was calculated and compared with the values of nonhemorrhaged control animals., Results: Mean CBF remained unchanged except for the group with the lowest blood pressure of 40 mm Hg (decrease in CBF of 28%). Otherwise, LCBF was increased in some brain structures at an unchanged mean CBF. Congruently, at 40 mm Hg, the decrease in mean CBF did not show up in all brain structures, the local pattern of CBF varying between an unchanged and a profoundly decreased CBF. The mean coefficient of variation of CBF was increased with the severity of hemorrhagic shock, which indicates an enhanced heterogeneity of CBF., Conclusion: Because of the substantial heterogeneity in the responses of LCBF to pressure-controlled hemorrhage, autoregulation of CBF during pressure-controlled hemorrhagic shock has to be reconsidered on a regional basis.

Background: -Recent studies have suggested that testosterone has a protective effect in the arterial vascular system. However, little is known about the molecular aspects of the mechanism(s) involved in these processes. The aim of the present study was to investigate the effect of testosterone on neointimal plaque development and on the expression of the vascular androgen receptor. Methods and Results-Neointimal plaque formation was induced by endothelial denudation in the aortas of male New Zealand White rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses. Compared with the non-hormone-treated control group, a significant inhibition of neointimal plaque development (expressed as the intima/media ratio) was found at testosterone concentrations of 10 ng/mL (P:=0.037) and 100 ng/mL (P:=0.012; intima/media ratios: median of controls, 0.25; median of 10 ng/mL testosterone group, 0.15; median of 100 ng/mL testosterone group, 0.16). Associated with this inhibitory effect on plaque size was a 50% increase of the amount of androgen receptor mRNA in the arterial segments treated with testosterone., Conclusion: -The beneficial effects of testosterone on postinjury plaque development underlines, at least in males, the important role of androgens in the vascular system. As our data suggest, the vascular androgen receptor is probably involved in these processes. Further studies are required to characterize the androgen receptor-dependent pathways in the vascular system.

Background: 17 beta-Estradiol and phytoestrogens are known to have beneficial effects on the cardiovascular systems of women. The exact mechanisms for how estrogens and phytoestrogens influence the cardiovascular system are not yet understood in detail., Objective: The objective of this study was to investigate whether 17 beta-estradiol and the phytoestrogens Genistein and Daidzein have an effect on post-injury processes in vessel walls., Methods: In this in-vitro experiment, the sex-specific effects of 50 micrograms/ml 17 beta-estradiol (equivalent to 180 mumol/l), and of the isoflavones Genistein (5 and 50 micrograms/ml, equivalent to 18.5 and 185 mumol/l), and Daidzein (5 and 50 micrograms/ml, equivalent to 19.7 and 197 mumol/l) on endothelium-denuded aortas from female and male rabbits after vascular injury were studied. Morphometry and immunohistochemistry were performed for quantitative and qualitative analysis., Results: Neointimal cells were in part positive for alpha-actin staining of smooth muscle cells. Staining with 5'-bromo-2'deoxyuridine plus 2'-deoxycytidine showed that proliferative activity in the neointima had significantly decreased after 28 days for groups that had been treated with 50 micrograms/ml Genistein. Immunofluorescence staining for the expression of nuclear estrogen receptor protein in the arterial wall for aortic rings from female and male rabbits was positive. 17 beta-Estradiol, Genistein, and its analog Daidzein (with no protein tyrosine kinase activity) inhibited formation of neointima sex-independently at equivalent concentrations of 50 micrograms/ml. However, a concentration of 5 micrograms/ml Genistein decreased formation of neointima significantly for aortic rings from male rabbits only, whereas 5 micrograms/ml Genistein increased formation of neointima in rings from female rabbits, which corresponded to the increase in proliferative activity detected after 28 days., Conclusion: Genistein and Daidzein both inhibited proliferation at certain concentrations, so this effect is supposed to be independent from Genistein's protein tyrosine kinase activity. The antiproliferative properties of all three estrogens were observed in the absence of endothelium and therefore are independent from endothelium-mediated effects.

Background: It is not known whether the effects of desflurane on local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) are different from those of other volatile anesthetics., Methods: Using the autoradiographic iodoantipyrine and deoxyglucose methods, LCGU, LCBF, and their overall means were measured in 60 Sprague-Dawley rats (10 groups, n = 6 each) during desflurane and isoflurane anesthesia and in conscious controls., Results: During anesthesia, mean cerebral glucose utilization was decreased compared with conscious controls: 1 minimum alveolar concentration (MAC) desflurane: -52%; 1 MAC isoflurane: -44%; 2 MAC desflurane: -62%; and 2 MAC isoflurane: -60%. Local analysis showed a reduction of LCGU in the majority of the 40 brain regions analyzed. Mean cerebral blood flow was increased: 1 MAC desflurane: +40%; 1 MAC isoflurane: +43%; 2 MAC desflurane and 2 MAC isoflurane: +70%. LCBF was increased in all brain structures investigated except in the auditory cortex. No significant differences (P < 0.05) could be observed between both anesthetics for mean values of cerebral glucose use and blood flow. Correlation coefficients obtained for the relation between LCGU and LCBF were as follows: controls: 0.95; 1 MAC desflurane: 0.89; 2 MAC desflurane: 0.60; 1 MAC isoflurane: 0.87; and 2 MAC isoflurane: 0.68., Conclusion: Differences in the physicochemical properties of desflurane compared with isoflurane are not associated with major differences in the effects of both volatile anesthetics on cerebral glucose utilization, blood flow, and the coupling between LCBF and LCGU.

Background: Compared to isoflurane, knowledge of local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) during sevoflurane anesthesia is limited., Methods: LCGU, LCBF, and their overall means were measured in Sprague-Dawley rats (8 groups, n=6 each) during sevoflurane and isoflurane anesthesia, 1 and 2 MAC, and in conscious control animals (2 groups, n=6 each) using the autoradiographic 2-[14C]deoxy-D-glucose and 4-iodo-N-methyl-[14C]antipyrine methods., Results: During anesthesia, mean cerebral glucose utilization was decreased: control, 56+/-5 micronmol x 100 g(-1) x min(-1); 1 MAC isoflurane, 32+/-4 micromol x 100 g(-1) x min(-1) (-43%); 1 MAC sevoflurane, 37+/-5 micromol x 100 g(-1) x min(-1) (-34%); 2 MAC isoflurane, 23+/-3 micromol x 100 g(-1) x min(-1) (-58%); 2 MAC sevoflurane, 23+/-5 micromol x 100 g(-1) x min(-1) (-59%). Local analysis showed a reduction in LCGU in the majority of the 40 brain regions analyzed. Mean cerebral blood flow was increased as follows: control 93+/-8 ml x 100 g(-1) x min(-1); 1 MAC isofurane, 119+/-19 ml x 100 g(-1) x min(-1) (+28%); 1 MAC sevoflurane, 104+/-15 ml x 100 g(-1) x min(-1) (+12%); 2 MAC isoflurane, 149+/-17 ml x 100 g(-1) x min(-1) (+60%); 2 MAC sevoflurane, 118+/-21 ml x 100 g(-1) min(-1) (+27%). LCBF was increased in most brain structures investigated. Correlation coefficients obtained for the relationship between LCGU and LCBF were as follows: control 0.93; 1 MAC isoflurane, 0.89; 2 MAC isoflurane, 0.71; 1 MAC sevoflurane, 0.83; 2 MAC sevoflurane, 0.59)., Conclusion: Mean and local cerebral blood flows were lower during sevoflurane than during isoflurane anesthesia. This difference cannot be explained by differing changes in glucose utilization because glucose utilization was decreased to the same extent in both groups.

Forty-three ambulatory patients with locally advanced or metastatic bronchogenic adenocarcinoma were sequentially treated with two potentially mutually non-cross-resistant chemotherapy regimens. A new regimen, MVPF (mitomycin-c, vinblastine, procarbazine, and 5-fluorouracil), was given until progressive disease occurred. Then, a second regimen--MOCC (methotrexate, vincristine [Oncovin], cyclophosphamide, and CCNU)--was initiated. At further progression, regional disease patients received radiotherapy, whereas extensive disease patients received Phase II agents. Of the 43 patients entered on the study, 40 were evaluable. Three patients withdrew early due to poor tolerance of the regimen. The response rate for MVPF was 33% (12 of 40 PR, 1 of 40 CR) compared to a 4% (1 of 23 PR) response for MOCC (difference: p < or = .03), for a total response rate of 35%. Although there was an initial improvement in survival for responders (31.7 weeks) versus nonresponders (15.7 weeks) at the 75th percentile (p < or = .05), there was no significant difference in median survival. The hematologic toxicity was equivalent for both groups, whereas nonhematologic toxicity revealed a high incidence of nausea and vomiting in the MVPF group. It is concluded that this approach lent itself well to ambulatory care, and MVPF could be considered an alternative to cyclophosphamide-based regimens. However, the absence of a meaningful CR rate and lack of influence of response on median survival were factors limiting its effectiveness.

Involving community members into plans and projects is especially salient in initiating and maintaining nurse-managed centers. Nowhere is community involvement more crucial than in establishing a nursing practice in an isolated rural setting. The authors share their first-hand experiences in community interaction in establishing the state-funded health center.