Synthesis, structural, and magnetic characterization of linear and bent geometry cobalt(II) and nickel(II) amido complexes: evidence of very large spin-orbit coupling effects in rigorously linear coordinated Co2+.

The complexes M(II){N(H)Ar(Pr(i)(6))}(2) (M = Co, 1 or Ni, 2; Ar(Pr(i)(6)) = C(6)H(3)-2,6(C(6)H(2)-2,4,6-Pr(i)(3))(2)), which have rigorously linear, N-M-N = 180°, metal coordination, and M(II){N(H)Ar(Me(6))}(2) (M = Co, 3 or Ni, 4; Ar(Me(6)) = C(6)H(3)-2,6(C(6)H(2)-2,4,6-Me(3))(2)), which have bent, N-Co-N = 144.1(4)°, and N-Ni-N = 154.60(14)°, metal coordination, were synthesized and characterized to study the effects of the metal coordination geometries on their magnetic properties. The magnetometry studies show that the linear cobalt(II) species 1 has a very high ambient temperature moment of about 6.2 µ(B) (cf. spin only value = 3.87 µ(B)) whereas the bent cobalt species 3 had a lower µ(B) value of about 4.7 µ(B). In contrast, both the linear and the bent nickel complexes 2 and 4 have magnetic moments near 3.0 µ(B) at ambient temperatures, which is close to the spin only value of 2.83 µ(B). The studies suggest that in the linear cobalt species 1 there is a very strong enhanced spin orbital coupling which leads to magnetic moments that broach the free ion value of 6.63 µ(B) probably as a result of the relatively weak ligand field and its rigorously linear coordination. For the linear nickel species 2, however, the expected strong first order orbital angular momentum contribution does not occur (cf. free ion value 5.6 µ(B)) possibly because of π bonding effects involving the nitrogen p orbitals and the d(xz) and d(yz) orbitals (whose degeneracy is lifted in the C(2h) local symmetry of the Ni{N(H)C(ipso)}(2) array) which quench the orbital angular momentum.

Two-coordinate, quasi-two-coordinate, and distorted three coordinate, T-shaped chromium(II) amido complexes: unusual effects of coordination geometry on the lowering of ground state magnetic moments.

The synthesis and characterization of the mononuclear chromium(II) terphenyl substituted primary amido-complexes Cr{N(H)Ar(Pr(i)(6))}(2) (Ar(Pr(i)(6)) = C(6)H(3)-2,6-(C(6)H(2)-2,4,6-(i)Pr(3))(2) (1), Cr{N(H)Ar(Pr(i)(4))}(2) (Ar(Pr(i)(4)) = C(6)H(3)-2,6-(C(6)H(3)-2,6-(i)Pr(2))(2) (2), Cr{N(H)Ar(Me(6))}(2) (Ar(Me(6)) = C(6)H(3)-2,6-(C(6)H(2)-2,4,6-Me(3))(2) (4), and the Lewis base adduct Cr{N(H)Ar(Me(6))}(2)(THF) (3) are described. Reaction of the terphenyl primary amido lithium derivatives Li{N(H)Ar(Pr(i)(6))} and Li{N(H)Ar(Pr(i)(4))} with CrCl(2)(THF)(2) in a 2:1 ratio afforded complexes 1 and 2, which are extremely rare examples of two coordinate chromium and the first stable chromium amides to have linear coordinated high-spin Cr(2+). The reaction of the less crowded terphenyl primary amido lithium salt Li{N(H)Ar(Me(6))} with CrCl(2)(THF)(2) gave the tetrahydrofuran (THF) complex 3, which has a distorted T-shaped metal coordination. Desolvation of 3 at about 70 °C gave 4 which has a formally two-coordinate chromous ion with a very strongly bent core geometry (N-Cr-N= 121.49(13)°) with secondary Cr--C(aryl ring) interactions of 2.338(4) Å to the ligand. Magnetometry studies showed that the two linear chromium species 1 and 2 have ambient temperature magnetic moments of about 4.20 µ(B) and 4.33 µ(B) which are lower than the spin-only value of 4.90 µ(B) typically observed for six coordinate Cr(2+). The bent complex 4 has a similar room temperature magnetic moment of about 4.36 µ(B). These studies suggest that the two-coordinate chromium complexes have significant spin-orbit coupling effects which lead to moments lower than the spin only value of 4.90 µ(B) because λ (the spin orbit coupling parameter) is positive. The three-coordinated complex 3 had a magnetic moment of 3.79 µ(B).

Synthesis and characterization of the M(II) (M = Ge, Sn, or Pb) phosphinidene dimers {M(µ-PAr')}2 (Ar' = C6H3-2,6-(C6H3-2,6-Pr(i)2)2).

Reaction of M{N(SiMe(3))(2)}(2) (M = Ge, Sn, or Pb) with the sterically encumbered primary phosphine Ar'PH(2) (2), Ar' = C(6)H(3)-2,6-(C(6)H(3)-2,6-Pr(i)(2)), at ca. 200 °C afforded the highly colored phosphinidene dimers {M(µ-PAr')}(2), M = Ge(3), Sn(4), or Pb(5), with disilylamine elimination. The compounds were characterized by single-crystal X-ray crystallography and heteronuclear NMR spectroscopy. The structures of 3, 4, and 5 featured similar M(2)P(2) ring cores, of which 4 and 5 have 50/50 P atom disorder, consistent with either a planar four-membered M(2)P(2) arrangement with anti aryl groups or with an M(2)P(2) ring folded along the M-M axis with syn aryl groups. A syn-folded structure was resolved for the Ge(2)P(2) ring in compound 3. The M-P distances resembled those in M(II) phosphido complexes and are consistent with single bonding. The coordination geometries at the phosphorus atoms are pyramidal. DFT calculations on the gas phase models {M(µ-PMe)}(2) (M = Ge, Sn, Pb) agreed with the syn (M-M folded) structural interpretation of the X-ray data. The synthesis of the bulky phosphine Ar'PH(2) 2 with the use of the aryl transfer agent Ar'MgBr(THF)(2) is also reported. This route afforded a significantly higher yield of product than that which was obtained using LiAr', which tends to result in aryl halide elimination and the observation of insoluble red phosphorus.

Direct spectroscopic observation of large quenching of first-order orbital angular momentum with bending in monomeric, two-coordinate Fe(II) primary amido complexes and the profound magnetic effects of the absence of Jahn- and Renner-Teller distortions in rigorously linear coordination.

The monomeric iron(II) amido derivatives Fe{N(H)Ar*}(2) (1), Ar* = C(6)H(3)-2,6-(C(6)H(2)-2,4,6-Pr(i)(3))(2), and Fe{N(H)Ar(#)}(2) (2), Ar(#) = C(6)H(3)-2,6-(C(6)H(2)-2,4,6-Me(3))(2), were synthesized and studied in order to determine the effects of geometric changes on their unusual magnetic properties. The compounds, which are the first stable homoleptic primary amides of iron(II), were obtained by the transamination of Fe{N(SiMe(3))(2)}(2), with HN(SiMe(3))(2) elimination, by the primary amines H(2)NAr* or H(2)NAr(#). X-ray crystallography showed that they have either strictly linear (1) or bent (2, N-Fe-N = 140.9(2) degrees ) iron coordination. Variable temperature magnetization and applied magnetic field Mossbauer spectroscopy studies revealed a very large dependence of the magnetic properties on the metal coordination geometry. At ambient temperature, the linear 1 displayed an effective magnetic moment in the range 7.0-7.50 mu(B), consistent with essentially free ion magnetism. There is a very high internal orbital field component, H(L) approximately 170 T which is only exceeded by a H(L) approximately 203 T of Fe{C(SiMe(3))(3)}(2). In contrast, the strongly bent 2 displayed a significantly lower mu(eff) value in the range 5.25-5.80 mu(B) at ambient temperature and a much lower orbital field H(L) value of 116 T. The data for the two amido complexes demonstrate a very large quenching of the orbital magnetic moment upon bending the linear geometry. In addition, a strong correlation of H(L) with overall formal symmetry is confirmed. ESR spectroscopy supports the existence of large orbital magnetic moments in 1 and 2, and DFT calculations provide good agreement with the physical data.

Synthesis, characterization and real molecule DFT calculations for neutral organogallium(I) aryl dimers and monomers: weakness of gallium-gallium bonds in digallenes and digallynes.

A series of stable aryl gallium(I) terphenyl derivatives was synthesized and characterized spectroscopically, structurally and by density functional calculations. Dimeric structures with trans-bent planar CGaGaC core arrangements were observed for [(GaAr*-4-tBu)(2)] (7, Ar*-4-tBu = C(6)H(2)-2,6(C(6)H(2)-2,4,6-iPr(3))(2)-4-tBu) and [(GaAr*-4-CF(3))(2)] (8, Ar*-4-CF(3) = C(6)H(2)-2,6(C(6)H(2)-2,4,6-iPr(3))(2)-4-CF(3)), whereas monomeric structures featuring one coordinate gallium were observed for the more crowded complexes [:GaAr*-3,5-iPr(2)] (10, Ar*-3,5-iPr(2) = C(6)H-2,6(C(6)H(2)-2,4-6-iPr(3))(2)-3,5-iPr(2)) and [GaAr'-3,5-iPr(2)] (11, Ar'-3,5-iPr(2) = C(6)H-2,6(C(6)H(3)-2,6-iPr(2))(2)-3,5-iPr(2)). Complexes 7 and 8 dissociate to monomers in hydrocarbon solution and their electronic spectra closely resemble those of 10 and 11 as well as those of [Ar'GaGaAr'] (Ar' = C(6)H(3)-2,6(C(6)H(3)-2,6-iPr(3))(2)) and [(GaAr*)(n)] (Ar* = C(6)H(3)-2,6(C(6)H(2)-2,4,6-iPr(3))(2)). The calculations showed that the binding energies of the compounds are weak, resemble closed-shell interactions and average approximately 5 kcal mol(-1), as in [Ar*GaGaAr*] with a lowest value of approximately -2 kcal mol(-1) for monomeric 10 and a highest value approximately 9 kcal mol(-1) for the least crowded species [Ar'GaGaAr']. The weak bonding in the complexes supports the view that the GaGa bonding in the previously published doubly reduced Na(2)[Ar*GaGaAr*] and Na(2)[Ar'GaGaAr'] is also weak and is consistent with approximate single bonding.

Isomeric forms of heavier main group hydrides: experimental and theoretical studies of the [Sn(Ar)H]2 (Ar = terphenyl) system.

A series of symmetric divalent Sn(II) hydrides of the general form [(4-X-Ar')Sn(mu-H)]2 (4-X-Ar' = C6H2-4-X-2,6-(C6H3-2,6-iPr2)2; X = H, MeO, tBu, and SiMe3; 2, 6, 10, and 14), along with the more hindered asymmetric tin hydride (3,5-iPr2-Ar*)SnSn(H)2(3,5-iPr2-Ar*) (16) (3,5-iPr2-Ar* = 3,5-iPr2-C6H-2,6-(C6H2-2,4,6-iPr3)2), have been isolated and characterized. They were prepared either by direct reduction of the corresponding aryltin(II) chloride precursors, ArSnCl, with LiBH4 or iBu2AlH (DIBAL), or via a transmetallation reaction between an aryltin(II) amide, ArSnNMe2, and BH3.THF. Compounds 2, 6, 10, and 14 were obtained as orange solids and have centrosymmetric dimeric structures in the solid state with long Sn...Sn separations of 3.05 to 3.13 A. The more hindered tin(II) hydride 16 crystallized as a deep-blue solid with an unusual, formally mixed-valent structure wherein a long Sn-Sn bond is present [Sn-Sn = 2.9157(10) A] and two hydrogen atoms are bound to one of the tin atoms. The Sn-H hydrogen atoms in 16 could not be located by X-ray crystallography, but complementary Mössbauer studies established the presence of divalent and tetravalent tin centers in 16. Spectroscopic studies (IR, UV-vis, and NMR) show that, in solution, compounds 2, 6, 10, and 14 are predominantly dimeric with Sn-H-Sn bridges. In contrast, the more hindered hydrides 16 and previously reported (Ar*SnH)2 (17) (Ar* = C6H3-2,6-(C6H2-2,4,6-iPr3)2) adopt primarily the unsymmetric structure ArSnSn(H)2Ar in solution. Detailed theoretical calculations have been performed which include calculated UV-vis and IR spectra of various possible isomers of the reported hydrides and relevant model species. These showed that increased steric hindrance favors the asymmetric form ArSnSn(H)2Ar relative to the centrosymmetric isomer [ArSn(mu-H)]2 as a result of the widening of the interligand angles at tin, which lowers steric repulsion between the terphenyl ligands.

Alveolar macrophage-derived chemotactic factor: kinetics of in vitro production and partial characterization.

Alveolar macrophages are the initial phagocytic cells that encounter foreign material and particulates deposited in the terminal airways. We have examined a mechanism by which these cells, after phagocytic challenge, may control or amplify the inflammatory response in lung parenchyma. Normal human alveolar macrophages (AM) were studied from eight subjects. With in vitro culture, AM produced and released two substances into culture media which have potent chemoattractant activity for blood polymorphonuclear granulocytes (PMN) and negligible activity for mononuclear cells. Release of these factors is maximally stimulated by aggregated human immunoglobulin (Ig)G or zymosan particles; however, simple adhesion of the macrophages to plastic surfaces is also sufficient to stimulate release of these chemotactic substances. The larger substance (10,000 daltons) is immunologically distinct from C5a and interacts with a different PMN membrane receptor than that known to exist for formyl-methionyl-leucyl-phenylalanine. Its chemotactic activity is sensitive to the enzymatic effect of trypsin. Although producing a single elution peak on gelfiltration chromatography, electrofocusing in polyacrylamide gels yielded five peaks of radioactivity. Chemotactic activity was localized to a fraction with a pI = 5.0. The smaller molecular weight substance has been less well characterized. Thus, the human AM can produce at least two factors which attract PMN and this capability may augment the local inflammatory response in the lung.

A donor-stabilization strategy for the preparation of compounds featuring P=B and As=B double bonds.

A new class of heavier group 15 compounds demonstrating multiple bonding with boron has been synthesized using a simple donor-stabilization protocol.

Physician practice variation in assignment of return interval.

BACKGROUND: Recent shifts in reimbursement toward capitation makes appointment availability a significant resource and stimulates us to understand primary care physician (hereafter referred to as "provider") behavior concerning appointment assignment. The results of prior studies suggest significant provider variability in this area. OBJECTIVE: To examine the influences on assigning patient revisit intervals in the ambulatory setting. METHODS: Survey regarding general care issues of hypothetical diabetic and hypertensive patients seen in an ambulatory setting was given to 62 providers in the Internal Medicine Program at the Tulane University Internal Medicine Residency Program and outpatient clinics, New Orleans, La. Measurements evaluated included survey responses for demographics (sex, year of birth, year of graduation from medical school, and level of training) and practice style (decision to change therapy, order tests, and recommended return appointment interval in weeks) variables. RESULTS: The response rate was 89% (56 providers). Most respondents were men (n = 39). Wide variation was noted in assignment of reappointment interval with mean return intervals for the scenarios ranging from 2.2 to 20.5 weeks. Significant influences on provider practice included patient stability (P<.001), the decision to change therapy (P = .001), and the decision to order tests (P = .001). All correlated with an earlier return appointment. Some providers exhibited test-ordering tendencies across scenarios. Sex was a significant provider independent variable and was not influenced by other study variables. Female providers assigned earlier reappointment intervals for their patients. CONCLUSIONS: Wide variation exists among practitioners with similar training background and practice setting. As expected, patient stability was a major determinant of assigned return interval. Test-ordering behaviors may consume appointments inappropriately and may be a productive area for efforts to reduce provider variability. The influence of the provider's sex on scheduling follow-up appointments warrants further investigation.

Retroviral vector-modified bone marrow stromal cells secrete biologically active factor IX in vitro and transiently deliver therapeutic levels of human factor IX to the plasma of dogs after reinfusion.

Canine bone marrow stromal cells (BMSCs), transduced ex vivo with retroviral vectors, expressed and secreted biologically active human and canine coagulation factor IX (hFIX and cFIX) in vitro, and on autologous reinfusion expressed hFIX into the circulation of normal (nonhemophiliac) dogs. Human FIX, when expressed in vitro by BMSCs of two dogs at 1.22 and 1.39 microg/10(6) cells/24 hr in medium supplemented with vitamin K, respectively, exhibited 28.1 and 27.3% normal biological activity as determined on the basis of a one-stage clotting assay. BMSCs of two additional dogs expressed 1.54 and 4.81 microg of cFIX/10(6) cells/24 hr in vitamin K-supplemented medium and the expressed cFIX possessed 58.4 and 32.9% normal activity, respectively. Between 2.33 and 3.35 x 10(8) transduced BMSCs, expressing 1.22 and 2.61 microg of hFIX/10(6) cells/24 hr or 3.24 and 7.82 microg of cFIX/10(6) cells/24 hr were reintroduced into the four donor dogs by intravenous infusion. Human FIX was detected in plasma for 7 or 12 days after BMSC reinfusion, with peak levels of 85.8 and 233.0 ng/ml observed at 2 days. Canine anti-hFIX antibodies, which were detected as early as 2-4 days after reinfusion of BMSCs expressing hFIX, may have masked potentially longer duration expression in vivo. Peak plasma levels of hFIX represented 2.1 and 5.8% normal human hFIX levels. When adjusted for percent normal one-stage clotting activity determined in vitro, these levels represented 0.6 and 1.6% normal human hFIX activity levels. Thus, we have demonstrated that retroviral vector-modified BMSCs can deliver human therapeutic levels of hFIX to the circulation of dogs.

Systemic delivery of human growth hormone or human factor IX in dogs by reintroduced genetically modified autologous bone marrow stromal cells.

Canine bone marrow stromal cells were expanded to numbers in excess of 10(9) cells from the initial 10-20 ml of marrow aspirates and transfected to express high levels of human growth hormone (hGH) in vitro. Ex vivo-modified marrow stromal cells were used in a gene therapy model system for the systemic delivery of transgene products in dogs. Adherent bone marrow stromal cell cultures, established and expanded from iliac crest marrow aspirates from each of 8 dogs, were transfected with a hGH gene plasmid expression vector and shown to express from 0.54-3.84 micrograms/10(6) cells per 24 hr hGH in vitro. The transfected plasmid vector does not possess a eukaryotic origin of replication nor does it possess sequences required for efficient integration into the host cell genome. As such, expression was expected to be transient. Transfected cells were autologously reintroduced into each dog by either infusion into a foreleg vein or directly into iliac crest marrow. In two cases, the stromal cells were cryopreserved following transfection, and subsequently thawed and infused. In one case, the expanded stromal cells were first cryopreserved, and then thawed, recultured, transfected, and infused. Reintroduced cell numbers ranged from 2.2 x 10(7) to 2.6 x 10(9), with total hGH expression capacities ranging from 62 to 1,400 micrograms/24 hr. Plasma of each of the dogs contained detectable hGH for a mean of 3.1 days (SD +/- 0.8 day) ranging from 2 to 5 days following reinfusion of cells. Peak plasma levels ranged from 0.10 to 1.76 ng/ml. Similar hGH expression values, based upon total expression capacity of the cells infused and dog body weight, were obtained for all dogs. Vector-modified stromal cells were detectable, by polymerase chain reaction (PCR) analysis, in the peripheral circulation following reinfusion in all 4 dogs analyzed. In 3 of the dogs, modified stromal cells were detected for 8.5-15 weeks. In addition, modified stromal cells were detected in iliac crest marrow of 2 dogs for 9 and 13 weeks, respectively, following reinfusion. In another experiment, cultured bone marrow stromal cells were transfected with a human factor IX (hFIX) plasmid vector. Modified cells (5.57 x 10(8)), with a total hFIX expression capacity of 281 micrograms/24 hr, were reinfused, resulting in detectable hFIX in plasma continuously for 9 days with a peak level of 8 ng/ml on day 1. These results demonstrate that the ex vivo bone marrow stromal cell system is a potentially powerful method by which to deliver secreted transgene product to the systemic circulation of large animals.

Implications of hypercalcemia with respect to diagnosis and treatment of lung cancer.

This study had two objectives. The first was to determine if hypercalcemia presents as an isolated finding in patients with lung cancer prior to the development of abnormalities on chest radiography. The second was to correlate the presence of hypercalcemia with survival after surgical therapy. A review of clinical material over a seven-year period yielded 67 patients with diagnoses of hypercalcemia and lung cancer. No patient presented with surgically curable lung cancer associated with hypercalcemia. A review of the literature disclosed only four cases in which a putative cure occurred in the presence of hypercalcemia. Review of the clinical material and the literature revealed no instance in which hypercalcemia per se led to the diagnosis of clinically occult lung cancer. Hypercalcemia was almost always associated with large tumor masses. Median survival after the discovery of hypercalcemia complicating carcinoma of the lung was one month.

Proteins of the respiratory tract after heart-lung transplantation.

Heart-lung transplant recipients represent a unique population who experience episodic lung injury caused by infection or rejection. We hypothesized that the proteins in the respiratory lining fluids of these patients might reflect and provide insights into the in vivo immunologic and inflammatory events that occur in the transplanted lung. Structural, inflammatory, and immune proteins were quantitated in 57 samples of BAL fluid recovered from 17 heart-lung recipients when infections, rejection, or neither was present. Protein levels were compared with those of normal subjects and between the clinical transplant groups. When neither infection nor rejection was present, levels of albumin, fibronectin, and immunoglobulins G, M, and A were all higher in the transplanted lungs as compared with the normal lungs. These findings suggest that a new steady state of these proteins is established in the transplanted lungs. When infection or rejection was present, there was a further significant increase in albumin, fibronectin, IgG, and especially C5a in the transplanted lungs. These findings suggest that at least some elements of host defense remain intact in the posttransplantation period despite the use of immunosuppressive drugs and a HLA-incompatible microenvironment. The profiles of recovered alveolar proteins did not, however, help to differentiate infection from rejection. This is disappointing because distinguishing between infection and rejection without examination of lung tissue remains an unresolved and important clinical problem. Nevertheless these data provide new insights into organ tolerance and defense of the newly transplanted lung from infection or rejection.

Association of acidic fibroblast growth factor and untreated low grade rejection with cardiac allograft vasculopathy.

Acidic fibroblast growth factor (aFGF) is a potent growth factor for vascular smooth muscle cells and may mediate vasculopathy in cardiac allografts subjected to chronic immunological injury. Therefore, we examined cardiac expression of aFGF, the number of rejection episodes, and other potential risk factors in 32 heart transplant patients who underwent intravascular ultrasound (IVUS) for detection of cardiac allograft vasculopathy (CAV). As defined by IVUS, CAV was present in 21 patients and absent in 11 patients (follow-up time: 52 +/- 21 vs. 51 +/- 12 months, respectively, P = NS). The level of aFGF in myocardial biopsies obtained at the time of IVUS was measured by semiquantitative reverse transcriptase polymerase chain reaction and expressed as the aFGF:GAPDH ratio. Higher level of aFGF were associated with CAV (mean aFGF:GAPDH ratio was 1.45 +/- 0.99 in patients with vs. 0.18 +/- 0.12 in patients without CAV [P < 0.001]). A strong association was found between high levels of cardiac aFGF and CAV, as 18 of 19 patients (95%) with high levels of aFGF (aFGF:GAPDH > 1) but only 3 of 13 patients with low levels of aFGF had CAV (P < 0.001). The relative risk of high level of aFGF for CAV was 4.1. Untreated low grade rejection (ISHLT I), but not treated high grade rejection (ISHLT > 2), was also associated with CAV (average number of untreated low grade rejection episodes was 3.5 +/- 1.8 in patients with vs. 2.1 +/- 1.0 in patients without CAV [P = 0.04]). Among other risk factors examined (age, sex, serum cholesterol, blood pressure, CMV infection, dose of immunosuppressants, and ischemic time), only triglycerides were higher in patients with than those without CAV (P = 0.003). We conclude that increased cardiac production of aFGF is significantly associated with CAV, which suggests that aFGF may serve as an important mediator in CAV. Untreated low grade rejection also poses an increased risk for CAV.

Biologic activity of purified cotton bract extracts in man and guinea pig.

Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers never before exposed to cotton bract. The response is similar to that of textile workers who inhale cotton dust. Approximately 60% of volunteers respond to bract extract with significant decreases in lung function, and these volunteers show an increased number of lymphocytes present in their lungs. Following inhalation of bract, the percent of polymorphonuclear leukocytes increases. Macrophages obtained by bronchoalveolar lavage from volunteers pre-challenged with bract extract release increased amounts of chemotactic factor and superoxide anion. Efforts to detect release of histamine and leukotrienes in volunteers following challenge with bract show no increase in urinary histamine and no significant release of leukotrienes in lung lavage fluid. Purified extracts exhibit chemotactic activity in vitro. They also contract guinea pig ileal longitudinal muscle in vitro. This preparation contains mast cells but no basophils, and the H-1 blocker, mepyramine blocks the contraction. Purified bract extracts contain no histamine or endotoxin but other contractors of smooth muscle may be present. The purified extract exhibits spectral, fluorescent, and radioimmune assay properties similar to a leukotriene B-like component. Cotton bract appears to have direct as well as cell-mediated activities.

Association between neutrophil concentration in bronchoalveolar lavage fluid and recent losses in diffusing capacity in men formerly exposed to asbestos.

It has been observed widely that some individuals exposed to asbestos will experience continued losses of lung function after asbestos exposure ceases. Unfortunately, there are few data on factors that determine clinical course, limiting the clinician's ability to determine prognosis in an individual case and restricting the possibility for testing or targeting any potential intervention to alter the course among the millions at risk. In an attempt to address this question, we studied a volunteer population of 50 such men from among a stable, heterogeneous population of asbestos-exposed workers who had been continuously followed in our occupational medicine clinics for up to 12 years (mean, 6.3 years); most had some clinical or roentgenographic sign of asbestos effect, pleural or parenchymal. Each subject was reexamined clinically, functionally, and roentgenographically. Asbestos and tobacco exposure histories were carefully reviewed with the subjects and quantified based on these reports and available data regarding the various work environments from which they came. Subsequently, each underwent a bronchoalveolar lavage to assess cellularity and levels of various proteins. The levels of risk factors, clinical findings, and biologic parameters from lavage were examined for their relationship to serial changes in lung function during the period over which they had been previously followed. Results of the study demonstrate that serial changes in lung function were not closely related to level or length of prior exposure, smoking behavior, chest roentgenographic findings, or lung volumes. Progressive loss of diffusing capacity for carbon monoxide (Dco) was significantly associated with two factors: level of neutrophil concentration in lavage fluid (0.043 +/- 0.016 ml/min/mm Hg/yr drop for each 0.1 x 10(4) neutrophils per milliliter, p = 0.02) and the level of Dco itself (0.17 +/- 0.07 ml/min/mm Hg/yr drop for each 10 percent decrease in percent Dco predicted, p = 0.01). The relationship with neutrophil concentration was statistically independent of the association with Dco itself and stronger; it persisted when loss of Dco was adjusted for baseline value. Lung volume changes were not associated with any predictor variables, alone or in combination. We conclude that the presence of neutrophils in bronchoalveolar lavage fluid is associated with recent disease progression that may have implications in studies of the mechanisms of asbestos-associated disease and in clinical treatment of patients at risk.

The relationship between large airway inflammation and airway metaplasia.

To assess the role of acute inflammatory cells in large airways in the pathogenesis of metaplasia, we performed BAL (divided into aliquots) and mucosal biopsies on asbestos workers. They had evidence of asbestos-related lung injury. We found that acute inflammatory cells were significantly increased in the first aliquot. Ex-smokers had a greater percentage of PMN compared with nonsmokers and current smokers. The subjects were subgrouped with respect to biopsy-detected metaplasia. There was no difference between these groups for percentage or total number of PMN in the first aliquot. However, subjects with metaplasia had significant reduction in FEV1/FVC compared with those without. We conclude that there are significant differences in cells between the first and subsequent aliquots. Although inflammatory stimuli may be important in the pathogenesis of metaplasia, PMN present in the first aliquot could not be related to the severity of the metaplastic changes in these workers.

Relationship of the ventilatory response to cotton bract extract and the cells and proteins of the lung.

Many healthy subjects who have had no exposure to cotton textile dusts will experience significant reductions in expired flow rate following an inhalational challenge with an aqueous extract of cotton bracts (CBE). Differences noted among individuals in the magnitude of the bronchial response to a standardized preparation of CBE suggest variable airway reactivity. The mechanism of this response and the reasons for its variability among these naive subjects are unknown. We have studied this problem by performing bronchoalveolar lavage on 13 volunteer subjects with no history of textile dust exposure. Two to three months later, a bronchial provocation with aqueous CBE was performed by an investigator blinded to the lavage results. Subjects with greater than 20 percent drop in flow rate at 40 percent of vital capacity during a partial forced expiration (MEF 40 percent [P]) following CBE had a reduction in total recoverable alveolar macrophages, with a resultant increase in the percentage of recoverable lymphocytes. The magnitude of response (MEF 40 percent [P]) correlated directly with the measured lymphocyte percentage (r = 0.69 p less than 0.01) and inversely with the total numbers of recovered cells.

Association between acute inflammatory cells in lavage fluid and bronchial metaplasia.

In epidemiologic studies, airway disease and parenchymal injury are known morbid outcomes of occupational exposure to asbestos. However, the relationship of inflammatory events considered to be responsible for parenchymal injury to the subsequent development of airway injury is unknown. To assess this we performed bronchoalveolar lavage (BAL) and airway biopsies on a population of subjects with exposure to asbestos in the workplace. As an index of airway injury, we employed histologic metaplasia seen in mucosal biopsy specimens. Lung BAL fluid was analyzed for two potentially relevant protein markers and for inflammatory cells recovered from the lower respiratory tract. We related metaplasia to demographic features of this study population (eg, smoking history and asbestos exposure data) and also to the protein and cellular markers recovered by BAL. We studied 50 workers and detected keratinizing metaplasia in 15 and varying lesser abnormalities in the other 28. Cigarette smoking was not associated with the presence of metaplasia (p less than 0.2). Smoking status was associated with an increase in BAL cells (p less than 0.02); however, neither the percent nor concentration of acute inflammatory cells was significantly increased. Acute inflammatory cells (percent and cells per milliliter of BAL fluid) were significantly increased among the subjects with severe metaplasia compared with other study subjects. This increase was true of both neutrophils and eosinophils and the sum of these two (p less than 0.02). Stratification of subjects by smoking status demonstrated a persistent association of inflammatory cells with metaplasia. By logistic regression analysis, polymorphonuclear leukocytes per milliliter and eosinophils per milliliter were significantly related to the presence of metaplasia in two independent models (odds ratios, 9.9 and 7.6, respectively). Cigarette smoking and other demographic or BAL variables were not significantly associated with metaplasia in these models.

Coronary blood flow and distribution in right ventricular hypertrophy.

Myocardial blood flow and distribution in animals with righ ventricular (RV) hypertrophy have not been studied extensively in the experimental laboratory. This study was carried out to investigate whether or not ischemia can be induced in the hypertrophied right ventricle. Ten adult foxhounds underwent banding of the pulmonary artery. One year later coronary flow and distribution were studied by use of radioactive microspheres. Myocardial oxygen supply and demand were estimated by planimetry of aortic and RV pressure tracings. Data were obtained in the control state, during atrial pacing to a heart rate of 200 +/- 4 beats/min (mean +/- SD), during aorta-right atrial shunting to reduce mean aortic pressure to 60 +/- 6mm Hg, and during aortic constriction to produce a mean aortic pressure of 145 +/- 8mm Hg. RV weight/body weight ratio was 2.2 +/- 0.2 gm/kg(normal, 1.3 +/- 0.1 gm/kg) (p less than 0.001). RV free wall thickness was 11.3 +2- 0.7 mm (normal, 6.7 +/- 0.4 mm) (p less than 0.001). At rest, RV oxygen supply/demand ration was 4.7, and the RV subendocardial/subepicardial (Endo/Epi) flow ratio was 0.93. During atrial pacing, RV supply/demand was 54% of control (p less than 0.01), RV Endo/Epi ratio was 1.00 (p less than 0.05), and right coronary artery (RCA) resistance was 59% of control (p less than 0.01). Aorto-right atrial shunting resulted in an RV supply/demand ratio of 31% of control (p less than 0.01), RV Endo/Epi ratio of 0.95, and RCA resistance of 45% of control (p less than 0.01). During aortic constriction, RV supply/demand ratio was 132% of control (p less than 0.05), RV Endo/Epi ratio was 0.92, and RCA resistance was 146% of control (p less than 0.01). Phasic RCA flowmeter tracings demonstrated an increased proportion of diastolic flow in the study animals as compared to normal animals. In conclusion, myocardial blood flow and distribution in the hypertrophied right ventricle remained normal at rest and during hemodynamic stress. Compensatory mechanisms which maintain normal flow and distribution may include changes in RCA resistance and phasic flow patterns. Under the imposed conditions, RV ischemia and failure did not occur.