Interstitial Capillary Research Articles

Characterization of patients with idiopathic interstitial pulmonary disease and capillary and laboratory findings in two health institutions in Medellín, Colombia: A descriptive study

IntroductionInterstitial lung disease (ILD) usually has a poor therapeutic response and prognosis. One of the methods that could help in the diagnosis and optimize the management of these patients is capillaroscopy. The study aimed to determine the clinical and capillaroscopic characteristics of patients with ILD and the frequency of findings suggestive of autoimmune disease. Materials and methodsA descriptive observational study that evaluated patients with ILD treated between 2010 and 2019 without a previous diagnosis of autoimmune disease. An interview, capillaroscopy, and laboratory tests were performed. Results28 patients were evaluated, 16 (57.1%) were women and 17 (60.7%) had hypertension. Three patients (10.7%) reported morning stiffness for more than 60 minutes and there was one unexplained digital edema. There were no telangiectasias, Raynaud’s phenomenon, mechanic’s hands, sclerodactyly or Gottron’s sign, or ANAS titres greater than 1:80. The rest of the laboratory tests were negative in 100% of the patients. In the capillaroscopies, 13 (46.4%) patients had a normal capillaroscopic pattern, and 15 (53.6%) had capillaroscopic abnormalities of undetermined significance. There were none with a pattern of systemic sclerosis or similar. ConclusionsNo laboratory or capillaroscopy findings were found that suggested interstitial disease with autoimmune features, possibly due to the low prevalence of the disease, its high mortality, and underdiagnosis. These findings reinforce the concept of capillaroscopic normality in patients with non-autoimmune ILD and call for an active search for ILD with autoimmune features for prognostic purposes.

Renal Alterations Induced by Chronic Exposure to Therapeutic Doses of Antihypercholestremic Atorvastatin.

Atorvastatin (ATOR) is widely used for the treatment and prevention of hypercholesterolemia and various diseases, such as cardiovascular complications, with little data about the histopathological and ultrastructural renal alterations that might be induced by this drug. The present study was undertaken to investigate the potential toxicity of therapeutic doses of atorvastatin on the microanatomy and ultrastructure of renal tissues from Wistar albino rats. Adult male Wistar albino rats received an oral daily dose of 5 mg/kg bodyweight for 90 consecutive days. Biopsies from both kidneys of each study rat were taken for histopathological and ultrastructural examination. ATOR-treated rats exhibited glomerular, tubular, and interstitial histological alterations, including degeneration, necrosis, hyaline droplets, edema, cortical hemorrhages, mesangial hypercellularity, and blood capillary dilation and congestion. In addition, ATOR exposure increased the activity of glucose-6-phosphate dehydrogenase and alkaline phosphatase with a concurrent reduction in proteins and neutral mucosubstances content of the glomeruli and renal cells. Moreover, ATOR-treated animals demonstrated glomerular ultrastructural alterations, consisting mainly of capillary tuft dilatation, glomerular basement membrane thickening, and mesangial cell proliferation. The renal cells of the proximal tubules demonstrated damaged mitochondria, degenerative cellular changes, endoplasmic reticulum dilatation, lysosomal and autophagosome activation, nuclear alteration, myelin figure formation, and microvilli disorganization. The findings of the present work may indicate that ATOR can induce renal histological, histochemical, and ultrastructural alterations that may affect kidney and other vital organ functions.

Assessment of plasma lyso-Gb3 for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease

PurposeTo assess the utility of globotriaosylsphingosine (lyso-Gb3) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. MethodsA post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)–experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb3 and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb3 and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb3 and kidney interstitial capillary (KIC) globotriaosylceramide (Gb3) inclusions was assessed in treatment-naive patients. ResultsNo significant correlations were identified between changes in lyso-Gb3 and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb3 levels nor the rate of change in lyso-Gb3 levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for ≥24 months. Changes in lyso-Gb3 correlated with changes in KIC Gb3 inclusions in treatment-naive patients. ConclusionsAlthough used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb3 may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.

Migalastat: A Review in Fabry Disease.

Fabry disease is a rare lysosomal disorder characterized by deficient or absent α-galactosidase A activity resulting from mutations in the GLA gene. Migalastat (Galafold™), a pharmacological chaperone, stabilizes and facilitates trafficking of amenable mutant forms of α-galactosidase A enzyme from the endoplasmic reticulum to lysosomes and increases its lysosomal activity. Oral migalastat is the first pharmacological chaperone approved for treating patients [aged ≥ 18 years (USA and Canada) or ≥ 16 years in other countries] with Fabry disease who have a migalastat-amenable GLA mutation. In the FACETS trial in enzyme replacement therapy (ERT)-naive patients with GLA mutations amenable or non-amenable to migalastat, there was no significant difference between the migalastat and placebo groups for the proportion of patients achieving a ≥ 50% reduction in the number of globotriaosylceramide (GL-3) inclusions/kidney interstitial capillary (KIC) at 6 months [primary endpoint; intent-to-treat (ITT) population]. In the modified ITT population (i.e. patients with migalastat-amenable GLA mutations), relative to placebo, migalastat treatment significantly reduced the mean number of GL-3 inclusions/KIC and plasma lyso-globotriaosylsphingosine levels at 6 months. Among evaluable patients, migalastat maintained renal function and reduced cardiac mass after ≤ 24 months’ therapy. In the ATTRACT trial in ERT-experienced patients, renal function was maintained during 18 months of migalastat or ERT; however, migalastat significantly reduced cardiac mass compared with ERT. Migalastat was generally well tolerated in both of these trials. Given its convenient oral regimen and the limited therapeutic options available, migalastat is an important treatment option for Fabry disease in patients with migalastat-amenable GLA mutations.

Significance of Antibody-Mediated Vascular Rejection (AMVR) on Graft Survival

Introduction Traditionally, endarteritis accepted to associate with cellular rejection. Nevertheless, some of the patients with AMR also had endarteritis at the same time. The risk of graft loss was nine times higher in AMVR than T cell-mediated rejection without endarteritis. However, the importance of the endarteritis on the graft survival in recipients with AMR is controversial. Thus we aimed to understand the prognostic value of the presence of endarteritis in recipients with AMR. Materials and Methods Among 155 recipients 72 (46,5%)had pure AMR (Group 1) while 83 (53,5%) had both AMR and endarteritis (Group 2). Endarteritis graded according to Banff. First indication biopsies of all cases reevaluated and the intensity of interstitial, glomerular and peritubular capillary (PTC) inflammation, neutrophil, macrophage and lymphocyte infiltration graded. HLA-DR expression in the arteries, PTCs, and tubules examined. The loss of DR expression on PTCs accepted as the destruction of PTCs. Follow-up biopsies analyzed for the development of interstitial fibrosis (IF), transplant glomerulopathy (TG) and transplant arteriopathy (TA). Results The extensity of the PTC and arterial C4d expression and the degree of PTC destruction found higher in Group 2 compared to Group 1 (P<.001).The degree of the interstitial eosinophil, plasma, and macrophage infiltration found higher in Group 2 patients than Group 1 (p<.001). Also, the intensity of inflammatory cells and neutrophils in both glomeruli and PTCs found higher in Group 2 compared to Group 1 (p<.001). Compared to Group 1 patients, Group 2 patients showed a higher incidence of IF, TG and TA in follow-up biopsies (p<.01).The development of IF and TG increases with the increasing degree of glomerulitis, PTC-itis, C4d expression and PTC destruction (p<.01). Also, the time of the development of IF and TG decreased with increasing intensity of PTC and interstitial infiltration, glomerulitis, PTC destruction and C4d expression (p<.01). The presence of the eosinophil and macrophage infiltration on the wall of arteries of recipients with AMVR rises the risk of the development of TG and TA (p<.01). Also, patients who had arterial C4d staining had a higher risk of TG, TA and graft loss (p<.001). The response to rejection therapy was lower in Group 2 recipients compared to Group 1 patients (p<.001). Overall the 3- and 5-year graft survival was 98%, and 85% respectively for Group 1 patients while it was 57%, and 27% respectively for Group 2 (p<.001). Conclusion Our results have underlined the importance of the presence of endarteritis in AMR. We showed that the course of AMVR are noticeably different from pure AMR, with AMVR having the worst outcome through leading the early development of IF, TG, and TA via augmenting inflammatory and fibrotic pathways. Thus the development of new treatment strategies for AMVR could salvage many kidney allografts.

Treatment of Fabry’s Disease with the Pharmacologic Chaperone Migalastat

BackgroundFabry’s disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes.MethodsThe initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry’s disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes.ResultsThe primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were –0.30±0.66 and −1.51±1.33 ml per minute per 1.73 m2 of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (−7.7 g per square meter; 95% confidence interval [CI], −15.4 to –0.01), particularly when left ventricular hypertrophy was present (−18.6 g per square meter; 95% CI, −38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased.ConclusionsAmong all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].)

Ultrasound-Mediated Microbubble Destruction Increases Renal Interstitial Capillary Permeability in Early Diabetic Nephropathy Rats

Diabetic nephropathy (DN) is defined as persistent proteinuria corresponding to a urinary albumin excretion rate >300 μg/mg in the absence of other non-diabetic renal diseases. The aim of this study was to determine if ultrasound (US)-mediated microbubble (MB) destruction could increase renal interstitial capillary permeability in early DN rats. Diabetes was induced with streptozotocin. DN rats presented with mild micro-albuminuria 30 d after onset of diabetes. DN rats (N = 120) were divided into four groups that received Evans blue (EB) followed by: (i) no treatment (control group); (ii) continuous ultrasonic irradiation for 5 min (frequency = 7.00 MHz, mechanical index = 0.9, peak rarefactional pressure = 2.38 MPa: US group); (iii) microbubble injection (0.05 mL/kg: MB group); and (iv) both ultrasound and microbubble injection (US + MB group). Another 8 DN rats were subjected to ultrasound and microbubbles and then injected with EB after 24 h (recovery group). EB content, EB extravasation and E-selectin mRNA and protein expression significantly increased, and interstitial capillary walls became discontinuous in the US + MB group. Neither hemorrhage nor necrosis was observed on renal histology. Urine samples were collected 24 h post-treatment. There was no hematuria, and the urinary albumin excretion rate did not increase after ultrasound-microbubble interaction detected by urinalysis. EB content returned to the control group level after 24 h, as assessed for the recovery group. In conclusion, ultrasound-mediated microbubble destruction locally increased renal interstitial capillary permeability in DN rats, and should be considered a therapy for enhancing drug and gene delivery to the kidney in the future.

Phase 3 FACETS study of migalastat HCl for Fabry disease: post hoc GLA mutation-based identification of subjects likely to show a drug effect

Fabry disease is caused by more than 800 different mutations in the GLA gene that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), resulting in accumulation of globotriaosylceramide (GL-3) and end-organ damage. Migalastat HCl (1-deoxygalactonojirimycin HCl, AT1001, GR181413A) is an investigational pharmacological chaperone that selectively binds and stabilizes α-Gal A, leading to increased cellular levels and greater lysosomal activity. Previously, a “research” human embryonic kidney (HEK) cell-based in vitro assay was developed to identify migalastat-responsive mutant forms of αGal A. The FACETS study (NCT00925301) compared migalastat to placebo in subjects with GLA mutations categorized as “amenable” to migalastat based on the research in vitro assay available at study initiation. The primary endpoint of this study was the percent change from baseline in kidney interstitial capillary (IC) GL-3 inclusions (responder analysis, 50% reduction threshold), which was not met. Meanwhile, a GLP-validated assay was created (“GLP HEK assay”) and testing of all mutant forms was completed before unblinding of the 6-month data. Approximately 90% of mutations remained in the same category of “amenable” or “non-amenable” using the same predefined in vitro criteria. However, 15 of 67 subjects enrolled in the study express mutant forms of α-Gal A considered to be nonamenable based on the GLP HEK assay, including 8 subjects with mutation R342Q. These 15 subjects may not be sufficiently responsive to migalastat, and may have impacted the previously reported study results. To explore the effect of migalastat in subjects with GLP HEK amenable mutations only, a post hoc analysis of the change from baseline (difference) in kidney IC GL-3 inclusions was conducted using an ANCOVA model with covariate adjustment for the baseline value and treatment-by-baseline interaction. Analysis of the quantitative difference and inclusion of baseline values in the analysis is the most appropriate measure of an effect on kidney IC GL-3 as many values were low at baseline. This analysis was first applied to all subjects in themITT population (n = 30 per group). Themean change from baseline in the migalastat group was a decrease of 0.22 ± 0.11 inclusions per capillary (IPC) (-66 inclusions per 300), and the placebo group showed an increase of 0.06 ± 0.09 IPC (+18 per 300); p = 0.052. The data were also analyzed for subjects with GLP HEK amenable mutations only (n = 25 migalastat, n = 21 placebo). The change from baseline in the migalastat group was a decrease of 0.31 ± 0.12 IPC (-93 per 300), while the placebo group showed an increase of 0.10 ± 0.13 IPC (+30 per 300); p = 0.0024. These findings were observed in the presence of a significant treatmentby-baseline interaction. This analysis demonstrates a measurable drug effect on change from baseline in kidney IC GL-3 inclusions during the first 6 months of treatment with migalastat, which is more pronounced in subjects with GLP HEK amenable mutations and higher baseline values. Additional data will be presented to support use of the GLP HEK assay to identify Fabry disease subjects with mutations that are most likely to demonstrate a drug effect with migalastat HCl.

Effect of mesenchymal stem cells on renal injury in rats with severe acute pancreatitis

The aim of this study was to preliminarily investigate the effect of bone marrow mesenchymal stem cells (MSCs) on structural change of capillary endothelial barrier and expression variation of aquaporin 1 (AQP1) in kidney at the onset of renal injury caused by severe acute pancreatitis (SAP). Ninety male Sprague-Dawley (SD) rats were divided into the control group, the SAP group in which animals received induction of SAP and the MSCs-treated group in which SAP-induced animals were injected with MSCs. They were further subdivided according to the time point that the animals were killed; 6 h, 12 h and 24 h after the closure of the incision, serum, pancreatic and renal samples were collected, respectively. The level of serum amylase (AMY), creatinine (Cr) and blood urea nitrogen (BUN) were analysed, the change of pancreatic histology was assessed, the structural change of the renal interstitial capillaries was evaluated using the transmission electron microscope (TEM) and the location and expression of AQP1 in kidney were analysed using immunohistochemistry, quantitative polymerase chain reaction and Western blot. The outcomes showed that the level of serum AMY, Cr, BUN elevated, the damage of pancreatic tissue and renal capillary endothelial barrier was aggravated and the expression of AQP1 was reduced significantly after induced pancreatitis. But after treatments with MSCs, the elevation of AMY, Cr and BUN was inhibited, the damage of pancreatic tissue and renal interstitial capillary barrier was alleviated and the down-regulation of AQP1 was reversed. In summary, the MSCs therapy could alleviate renal injury in rats with SAP, the mechanism of which might be related to reduction of the damage to renal interstitial capillary endothelial barrier, and up-expression of AQP1 in kidney.

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild-type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1α and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD(cl1)) cell line increased TGF-β1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1α and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions.

Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta during enzyme replacement therapy in patients with Fabry disease

PurposeFabry disease, a genetic deficiency of α-galactosidase A, is characterized by pathogenic cellular accumulation of globotriaosylceramide. During clinical trials, recombinant human α-galactosidase A (agalsidase beta; Fabrazyme®, Genzyme Corporation, Cambridge, MA), infused intravenously at 1.0 mg/kg every 2 weeks for 6 months, cleared or reduced globotriaosylceramide in renal, cardiac, and dermal microvascular endothelia and other cells, with results sustained for up to 5 years in most patients evaluated. This study explored whether a lower dose could maintain globotriaosylceramide clearance achieved with 1.0 mg/kg. MethodsCellular globotriaosylceramide levels were assessed histologically in kidney and skin biopsies from 21 adult Fabry males treated for 6 months at 1.0 mg/kg/2 weeks followed by 18 months at 0.3 mg/kg/2 weeks. ResultsIn kidney interstitial capillary endothelium, the primary endpoint, globotriaosylceramide clearance was achieved in 100% of patients with 1.0 mg/kg and maintained in 90% with 0.3 mg/kg. In seven other renal cell types and superficial dermal capillary endothelium, globotriaosylceramide reduction or clearance was maintained with 0.3 mg/kg in ∼70% of patients. ConclusionsA lower dose of agalsidase beta may be sufficient in some, but not all, patients with Fabry disease to maintain the cellular globotriaosylceramide clearance achieved with 1.0 mg/kg/2 weeks. Long-term clinical effects of transitioning to the lower dose have not been evaluated.

Acute kidney injury after hepatic ischemia and reperfusion injury in mice

Hepatic ischemia reperfusion (IR) is the leading cause of acute liver failure (ALF) during the perioperative period and patients with ALF frequently develop acute kidney injury (AKI). There is no effective therapy for AKI associated with ALF because pathomechanisms are incompletely characterized, in part due to the lack of an animal model. In this study, we characterize a novel murine model of AKI following hepatic IR. Mice subjected to ∼70% liver IR not only developed acute liver dysfunction, but also developed severe AKI 24 h after liver injury. Mice subjected to liver IR developed histological changes of acute tubular injury including focal proximal tubular cell necrosis involving the S3 segment, cortical tubular ectasia, focal tubular simplification and granular bile/heme cast formation. In addition, there was focal interstitial edema and hyperplasia of the juxtaglomerular apparatus. Inflammatory changes in the kidney after hepatic IR included neutrophil infiltration of the interstitium and upregulation of several proinflammatory mRNAs (tumor necrosis factor-α, keratinocyte-derived cytokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, intercellular adhesion molecule-1). In addition, marked renal endothelial cell apoptosis was detected involving peritubular interstitial capillaries, accompanied by increased renal vascular permeability. Finally, there was severe disruption of renal proximal tubule epithelial filamentous-actin. Our results show that AKI rapidly and reproducibly develops in mice after hepatic IR and is characterized by renal tubular necrosis, inflammatory changes and interstitial capillary endothelial apoptosis. Our murine model of AKI after liver injury closely mimics human AKI associated with ALF and may be useful in delineating the mechanisms and potential therapies for this common clinical condition.

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

In 1984, Loskutoff et al. ([1][1]) purified plasminogen activator inhibitor-1 (PAI-1) from conditioned media of cultured endothelial cells. This 50-kd glycoprotein is the primary physiologic inhibitor of the serine proteases tissue-type and urokinase-type plasminogen activators (tPA and uPA,

Interstitial capillary changes in lithium nephropathy: effects of antihypertensive treatment

Histopathological changes were investigated in the tubulointerstitium and in the capillaries of male Wistar rats with lithium-induced nephropathy using stereological methods. Two antihypertensive drugs with opposite effects on the renin-angiotensin system, an ACE inhibitor (angiotensin converting enzyme inhibitor) and a thiazide diuretic, modified the nephropathy. Generally, there was a significant positive correlation between the reduction in GFR (glomerular filtration rate) and the reduction in the volume of intact tubular structures and interstitial capillaries. A significant negative correlation was seen between the reduction in GFR and the increase in tubulocapillary distance and the absolute volume of interstitial connective tissue, respectively. Treatment with perindopril, and to some extent hydrochlorothiazide, reversed the rise in systolic blood pressure associated with lithium-induced nephropathy but did not affect the progression to terminal uraemia, the structural renal changes or the mortality. In conclusion, severe tubular and capillary changes are seen in this model of chronic renal failure. Tubular atrophy is associated with a decrease in interstitial capillaries and with an increase in the tubulocapillary distance. Systemic hypertension or activation of the renin-angiotensin system may not be important factors for the progression to terminal renal failure.

Interstitial Capillary in Normal and in Transplanted Kidneys: An Ultrastructural Study

Knowledge about the normal structure and pathology of interstitial capillary is limited. Splitting and multilayering of the basal membrane (BM), as a marker of chronic rejection, has been published in association with transplant glomerulopathy. The authors investigated the ultrastructural features of the interstitial capillary basal membrane in normal (15 biopsies) and in transplanted kidneys (27 biopsies from 21 patients), expressing transplant glomerulopathy (8 biopsies from 6 patients), acute tubulo-interstitial rejection (9 biopsies from 6 patients), and recurrent or de novo glomerulonephritis (10 biopsies from 8 patients). All biopsies were fixed in 1%OsO 4, embedded in Epon, and examined by electron microscope. Measurements of the interstitial capillary BM were made. The BM of interstitial capillary of intact kidney was a homogenous continuous structure, 88 nm in width on average. Thickening with diffuse multilayering of BM was most intensive in patients with transplant glomerulopathy, and much less intensive in patients with acute tubulointerstitial rejection and in patients with recurrent or de novo glomerulonephritis. These findings may provide the first information about the morphology of the normal basal lamina of interstitial capillary and support the diagnostic value of interstitial capillary changes in chronic rejection.

Assessment of Hindered Settling of Fluid Mudlike Suspensions

A formula for the hindered settling velocity of fluid mudlike suspensions is determined based on Darcy's equation for pore water seepage in a consolidating particulate matrix, in which the specific permeability is obtained by assuming interstitial capillary flow to be described by the Hagen-Poiseuille equation. Sediment-specific parameters in the velocity formula are evaluated from a series of experiments in which initially suspended mixtures of dense fine-grained sediments and water at different salinities were allowed to settle. From the results it is concluded that the essential physical process by which hindered settling occurs appears to be well captured by treating settling and consolidation in a unified way.

A mathematical model of polymeric controlled drug release and transport in the brain

A two-dimensional finite-element model was developed to simulate the transport and clearance of drugs released from polymers into the brain. This computer model includes the effects of diffusion and bulk flow of interstitial fluid, metabolism and capillary uptake, and is responsive to various controlled release scenarios and anatomical variation. The capability of this model is illustrated by examining the transport of three compounds of interest for neurological applications.

The role of carbon dioxide in the development of pulmonary insufficiency

The effects of carbon dioxide (PCO2 = 40 versus PCO2 = 20) on pulmonary function changes during 2 hours of hemorrhagic hypotension followed by resuscitation are evaluated in 21 dogs. Pulmonary hemodynamics, mechanics, gas exchange, functional residual capacity, and morphology are studied. In the preshock period, hypocapnia is associated with a decreased cardiac output, increased dead space, and increased alveolar-arterial (A-a) gradiant (room air). During the period of hypotension, all parameters in both groups changed similarly. After resuscitation, the A-a gradients in the two groups further widened. Following the return to control levels of normocapnia in all animals, the group which had been hypocapnic during the hypotensive episode continued to show increased shunting (20 versus 13 percent, p less than 0.05). These results correlated well with cinemicroscopic findings, which showed the normocapnic group to have less interstitial edema and better capillary flow.

An analysis of interstitial fluid pressure in the web of the bat wing

A mathematical theory of interstitial fluid motion and capillary exchange is developed in order to understand and explain measurements of capillary and interstitial fluid pressure in the bat wing, in which a high degree of vasomotor activity occurs. As a result of precapillary sphincter activity, fluid is alternately filtered and reabsorbed from the capillary, and previous studies of related steady problems by the author suggest that the interstitial fluid pressure should oscillate with time. Wiederhielm and Weston did not observe such fluctuations when they measured tissue pressures near the capillaries. This apparent paradox is resolved in the present paper by including unsteady effects. It is shown that pressure oscillations are predicted, but because of the very high vasomotor frequency they die out within a very short distance from the capillary wall. The capillary pressure measurements of Wiederhielm and Weston are also explained in terms of precapillary sphincter activity.