Cuneyt Yilmaz

Diminished alveolar microvascular reserves in type 2 diabetes reflect systemic microangiopathy.

OBJECTIVE—Alveolar microvascular function is moderately impaired in type 1 diabetes, as manifested by restriction of lung volume and diffusing capacity (DLCO). We examined whether similar impairment develops in type 2 diabetes and defined the physiologic sources of impairment as well as the relationships to glycemia and systemic microangiopathy. RESEARCH DESIGN AND METHODS—A cross-sectional study was conducted at a university-affiliated diabetes treatment center and outpatient diabetes clinic, involving 69 nonsmoking type 2 diabetic patients without overt cardiopulmonary disease. Lung volume, pulmonary blood flow (Q̇), DLCO, membrane diffusing capacity (measured from nitric oxide uptake [DLNO]), and pulmonary capillary blood volume (VC) were determined at rest and exercise for comparison with those in 45 healthy nonsmokers as well as with normal reference values. RESULTS—In type 2 diabetic patients, peak levels of oxygen uptake, Q̇ and DLCO, DLNO, and VC at exercise were 10–25% lower compared with those in control subjects. In nonobese patients (BMI <30 kg/m2), reductions in DLCO, DLNO, and VC were fully explained by the lower lung volume and peak Q̇, but these factors did not fully explain the impairment in obese patients (BMI >30 kg/m2). The slope of the increase in VC with respect to Q̇ was reduced ∼20% in patients regardless of BMI, consistent with impaired alveolar-capillary recruitment. Functional impairment was directly related to A1C level, retinopathy, neuropathy, and microalbuminuria in a sex-specific manner. CONCLUSIONS—Alveolar microvascular reserves are reduced in type 2 diabetes, reflecting restriction of lung volume, alveolar perfusion, and capillary recruitment. This reduction correlates with glycemic control and extrapulmonary microangiopathy and is aggravated by obesity.

Subclinical Lung Disease, Macrocytosis, and Premature Graying in Kindreds With Telomerase (TERT) Mutations

BACKGROUND Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. METHODS We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. RESULTS Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (Dlco), impaired recruitment of Dlco with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. CONCLUSIONS TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations.

Significant blood resistance to nitric oxide transfer in the lung

Lung diffusing capacity for nitric oxide (DLNO) is used to measure alveolar membrane conductance (DMNO), but disagreement remains as to whether DMNO=DLNO, and whether blood conductance (thetaNO)=infinity. Our previous in vitro and in vivo studies suggested that thetaNO<infinity. We now show in a membrane oxygenator model perfused with whole blood that addition of a cell-free bovine hemoglobin (Hb) glutamer-200 solution increased diffusing capacity of the circuit (D) for NO (DNO) by 39%, D for carbon monoxide (DCO) by 24%, and the ratio of DNO to DCO by 12% (all P<0.001). In three anesthetized dogs, DLNO and DLCO were measured by a rebreathing technique before and after three successive equal volume-exchange transfusions with bovine Hb glutamer-200 (10 ml/kg each, total exchange 30 ml/kg). At baseline, DLNO/DLCO=4.5. After exchange transfusion, DLNO rose 57+/-16% (mean+/-SD, P=0.02) and DLNO/DLCO=7.1, whereas DLCO remained unchanged. Thus, in vitro and in vivo data directly demonstrate a finite thetaNO. We conclude that the erythrocyte and/or its immediate environment imposes considerable resistance to alveolar-capillary NO uptake. DLNO is sensitive to dynamic hematological factors and is not a pure index of conductance of the alveolar tissue membrane. With successive exchange transfusion, the estimated in vivo thetaNO [5.1 ml NO.(ml blood.min.Torr)(-1)] approached 4.5 ml NO.(ml blood.min.Torr)(-1), which was derived from in vitro measurements by Carlsen and Comroe (J Gen Physiol 42: 83-107, 1958). Therefore, we suggest use of thetaNO=4.5 ml NO.(min.Torr.ml blood)(-1) for calculation of DM(NO) and pulmonary capillary blood volume from DLNO and DLCO.

Eliminating the Reaching Phase From Variable Structure Control

In this paper, we present a variable structure control method that eliminates the reaching phase. The approach is based on modifying the sliding domain equations through the use of exponential functions. In addition, the proposed method insures optimal convergence parameters with respect to the tracking errors and control effort.

Noninvasive quantification of heterogeneous lung growth following extensive lung resection by high-resolution computed tomography

To quantify the in vivo magnitude and distribution of regional compensatory lung growth following extensive lung resection, we performed high-resolution computed tomography at 15- and 30-cmH(2)O transpulmonary pressures and measured air and tissue (including microvascular blood) volumes within and among lobes in six adult male foxhounds, before and after balanced 65% lung resection ( approximately 32% removed from each side). Each lobe was identified from lobar fissures. Intralobar gradients in air and tissue volumes were expressed along standardized x,y,z-coordinate axes. Fractional tissue volume (FTV) was calculated as the volume ratio of tissue/(tissue + air). Following resection compared with before, lobar air and tissue volumes increased 1.8- to 3.5-fold, and whole lung air and tissue volumes were 67 and 90% of normal, respectively. Lobar-specific compliance doubled post-resection, and whole lung-specific compliance normalized. These results are consistent with vigorous compensatory growth in all remaining lobes. Compared with pre-resection, post-resection interlobar heterogeneity of FTV, assessed from the coefficient of variation, decreased at submaximal inflation, but was unchanged at maximal inflation. The coefficient of variation of intralobar FTV gradients changed variably due to the patchy development of thickened pleura and alveolar septa, with elevated alveolar septal density and connective tissue content in posterior-caudal and peripheral regions of the remaining lobes; these areas likely experienced disproportional mechanical stress. We conclude that HRCT can noninvasively and quantitatively assess the magnitude and spatial distribution of compensatory lung growth. Following extensive resection, heterogeneous regional mechanical lung strain may exceed the level that could be sustained solely by existing connective tissue elements.

Solving frictionless rocking block problem with multiple impacts

In this paper, we present a solution to the frictionless multiple impact problems that may arise in the rocking blocks. We use an approach based on the impulse–momentum methods, the energetic coefficient of restitution and the impulse correlation ratio. Subsequently, we present the results of an experimental study that is used to compare the results predicted by the proposed method with the experimental outcomes.

Separating in vivo mechanical stimuli for postpneumonectomy compensation: physiological assessment

Following right pneumonectomy (PNX), the remaining lung expands and its perfusion doubles. Tissue and microvascular mechanical stresses are putative stimuli for initiating compensatory lung growth and remodeling, but their relative contributions to overall compensation remain uncertain. To temporally isolate the stimuli related to post-PNX lung expansion (parenchyma deformation) from those related to the sustained increase in perfusion (microvascular distention and shear), we replaced the right lung of adult dogs with a custom-shaped inflated prosthesis. Following stabilization of perfusion and wound healing 4 mo later, the prosthesis was either acutely deflated (DEF group) or kept inflated (INF group). Physiological studies were performed pre-PNX, 4 mo post-PNX (inflated prosthesis, INF1), and again 4 mo postdeflation (DEF) compared with controls with simultaneous INF prosthesis (INF2). Perfusion to the remaining lung increased ~76-113% post-PNX (INF1 and INF2) and did not change postdeflation. Post-PNX (INF prosthesis) end-expiratory lung volume (EELV) and lung and membrane diffusing capacities (DL(CO) and DM(CO)) at a given perfusion were 25-40% below pre-PNX baseline. In the INF group EELV, DL(CO) and DM(CO) remained stable or declined slightly with time. In contrast, all of these parameters increased significantly after deflation and were 157%, 26%, and 47%, respectively, above the corresponding control values (INF2). Following delayed deflation, lung expansion accounted for 44%-48% of total post-PNX compensatory increase in exercise DL(CO) and peak O(2) uptake; the remainder fraction is likely attributable to the increase in perfusion. Results suggest that expansion-related parenchyma mechanical stress and perfusion-related microvascular stress contribute in equal proportions to post-PNX alveolar growth and remodeling.

Long-term post-pneumonectomy pulmonary adaptation following all-trans-retinoic acid supplementation

In adult dogs following right pneumonectomy (PNX) and receiving all-trans-retinoic acid (RA) supplementation for 4 mo, we found modestly enhanced alveolar-capillary growth in the remaining lung without enhanced resting lung function (J Appl Physiol 96: 1080-1089 and 96: 1090-1096, 2004). Since alveolar remodeling progresses beyond this period and the lipid-soluble RA continues to be released from tissue stores, we hypothesized that RA supplementation may exert additional long-term effects. To examine this issue, adult male litter-matched foxhounds underwent right PNX followed by RA supplementation (2 mg/kg po 4 days/wk, n = 6) or placebo (n = 4) for 4 mo. Cardiopulmonary function was measured at rest and during exercise at 4 and 20 mo post-PNX. The remaining lung was fixed under a constant airway pressure for morphometric analysis. Comparing RA treatment to placebo controls, there were no differences in aerobic capacity, cardiopulmonary function, or lung volume at rest or exercise. Alveolar-capillary basal lamina thickness and mean harmonic thickness of air-blood diffusion barrier were 23-29% higher. The prevalence of double-capillary profiles remained 82% higher. Absolute volumes of septal interstitium, collagen fibers, cells, and matrix were 32% higher; the relative volumes of other septal components and alveolar-capillary surface areas expressed as ratios to control values were up to 24% higher. Thus RA supplementation following right PNX modestly and persistently enhanced long-term alveolar-capillary structural dimensions, especially the deposition of interstitial and connective tissue elements, in such a way that caused a net increase in barrier resistance to diffusion without improving lung mechanics or gas exchange.

Separating in vivo mechanical stimuli for postpneumonectomy compensation: imaging and ultrastructural assessment

Following right pneumonectomy (PNX), the remaining lung expands and its perfusion more than doubles. Tissue and microvascular mechanical stresses are putative stimuli for compensatory lung growth and remodeling, but their relative contribution remains uncertain. To temporally separate expansion- and perfusion-related stimuli, we replaced the right lung of adult dogs with a customized inflated prosthesis. Four months later, the prosthesis was either acutely deflated (DEF) or kept inflated (INF). Thoracic high-resolution computed tomography (HRCT) was performed pre- and post-PNX before and after prosthesis deflation. Lungs were fixed for morphometric analysis ∼12 mo post-PNX. The INF prosthesis prevented mediastinal shift and lateral lung expansion while allowing the remaining lung to expand 27-38% via caudal elongation, associated with reversible capillary congestion in dependent regions at low inflation and 40-60% increases in the volumes of alveolar sepal cells, matrix, and fibers. Delayed prosthesis deflation led to further significant increases in lung volume, alveolar tissue volumes, and alveolar-capillary surface areas. At postmortem, alveolar tissue volumes were 33% higher in the DEF than the INF group. Lateral expansion explains ∼65% of the total post-PNX increase in left lung volume assessed in vivo or ex vivo, ∼36% of the increase in HRCT-derived (tissue + microvascular blood) volume, ∼45% of the increase in ex vivo septal extravascular tissue volume, and 60% of the increase in gas exchange surface areas. This partition agrees with independent physiological measurements obtained in these animals. We conclude that in vivo signals related to lung expansion and perfusion contribute separately and nearly equally to post-PNX growth and remodeling.

Progressive adaptation in regional parenchyma mechanics following extensive lung resection assessed by functional computed tomography

In adult canines following major lung resection, the remaining lobes expand asymmetrically, associated with alveolar tissue regrowth, remodeling, and progressive functional compensation over many months. To permit noninvasive longitudinal assessment of regional growth and function, we performed serial high-resolution computed tomography (HRCT) on six male dogs (∼9 mo old, 25.0 ± 4.5 kg, ±SD) at 15 and 30 cmH(2)O transpulmonary pressure (Ptp) before resection (PRE) and 3 and 15 mo postresection (POST3 and POST15, respectively) of 65-70% of lung units. At POST3, lobar air volume increased 83-148% and tissue (including microvascular blood) volume 120-234% above PRE values without further changes at POST15. Lobar-specific compliance (Cs) increased 52-137% from PRE to POST3 and 28-79% from POST3 to POST15. Inflation-related parenchyma strain and shear were estimated by detailed registration of corresponding anatomical features at each Ptp. Within each lobe, regional displacement was most pronounced at the caudal region, whereas strain was pronounced in the periphery. Regional three-dimensional strain magnitudes increased heterogeneously from PRE to POST3, with further medial-lateral increases from POST3 to POST15. Lobar principal strains (PSs) were unchanged or modestly elevated postresection; changes in lobar maximum PS correlated inversely with changes in lobar air and tissue volumes. Lobar shear distortion increased in coronal and transverse planes at POST3 without further changes thereafter. These results establish a novel use of functional HRCT to map heterogeneous regional deformation during compensatory lung growth and illustrate a stimulus-response feedback loop whereby postresection mechanical stress initiates differential lobar regrowth and sustained remodeling, which in turn, relieves parenchyma stress and strain, resulting in progressive increases in lobar Cs and a delayed increase in whole lung Cs.