Increased Basement Membrane Thickness Research Articles

Modifications of physical and functional integrity of the blood-brain barrier in an inducible mouse model of neurodegeneration

The inducible p25 overexpression mouse model recapitulate many hallmark features of Alzheimer's disase including progressive neuronal loss, elevated Aβ, tau pathology, cognitive dysfunction, and impaired synaptic plasticity. We chose p25 mice to evaluate the physical and functional integrity of the blood-brain barrier (BBB) in a context of Tau pathology (pTau) and severe neurodegeneration, at an early (3 weeks ON) and a late (6 weeks ON) stage of the pathology. Using in situ brain perfusion and confocal imaging, we found that the brain vascular surface area and the physical integrity of the BBB were unaltered in p25 mice. However, there was a significant 14% decrease in cerebrovascular volume in 6 weeks ON mice, possibly explained by a significant 27% increase of collagen IV in the basement membrane of brain capillaries. The function of the BBB transporters GLUT1 and LAT1 was evaluated by measuring brain uptake of d-glucose and phenylalanine, respectively. In 6 weeks ON p25 mice, d-glucose brain uptake was significantly reduced by about 17% compared with WT, without any change in the levels of GLUT1 protein or mRNA in brain capillaries. The brain uptake of phenylalanine was not significantly reduced in p25 mice compared with WT. Lack of BBB integrity, impaired BBB d-glucose transport have been observed in several mouse models of AD. In contrast, reduced cerebrovascular volume and an increased basement membrane thickness may be more specifically associated with pTau in mouse models of neurodegeneration.

Age-related ultrastructural neurovascular changes in the female mouse cortex and hippocampus

Blood-brain barrier (BBB) breakdown occurs in aging and neurodegenerative diseases. Although age-associated alterations have previously been described, most studies focused in male brains; hence, little is known about BBB breakdown in females. This study measured ultrastructural features in the aging female BBB using transmission electron microscopy and 3-dimensional reconstruction of cortical and hippocampal capillaries from 6- and 24-month-old female C57BL/6J mice. Aged cortical capillaries showed more changes than hippocampal capillaries. Specifically, the aged cortex showed thicker basement membrane, higher number and volume of endothelial pseudopods, decreased endothelial mitochondrial number, larger pericyte mitochondria, higher pericyte–endothelial cell contact, and increased tight junction tortuosity compared with young animals. Only increased basement membrane thickness and pericyte mitochondrial volume were observed in the aged hippocampus. Regional comparison revealed significant differences in endothelial pseudopods and tight junctions between the cortex and hippocampus of 24-month-old mice. Therefore, the aging female BBB shows region-specific ultrastructural alterations that may lead to oxidative stress and abnormal capillary blood flow and barrier stability, potentially contributing to cerebrovascular diseases, particularly in postmenopausal women.

Unique mechanisms of connective tissue growth factor regulation in airway smooth muscle in asthma: Relationship with airway remodelling.

Neovascularization, increased basal membrane thickness and increased airway smooth muscle (ASM) bulk are hallmarks of airway remodelling in asthma. In this study, we examined connective tissue growth factor (CTGF) dysregulation in human lung tissue and animal models of allergic airway disease. Immunohistochemistry revealed that ASM cells from patients with severe asthma (A) exhibited high expression of CTGF, compared to mild and non‐asthmatic (NA) tissues. This finding was replicated in a sheep model of allergic airways disease. In vitro, transforming growth factor (TGF)‐β increased CTGF expression both in NA‐ and A‐ASM cells but the expression was higher in A‐ASM at both the mRNA and protein level as assessed by PCR and Western blot. Transfection of CTGF promoter‐luciferase reporter constructs into NA‐ and A‐ASM cells indicated that no region of the CTGF promoter (−1500 to +200 bp) displayed enhanced activity in the presence of TGF‐β. However, in silico analysis of the CTGF promoter suggested that distant transcription factor binding sites may influence CTGF promoter activation by TGF‐β in ASM cells. The discord between promoter activity and mRNA expression was also explained, in part, by differential post‐transcriptional regulation in A‐ASM cells due to enhanced mRNA stability for CTGF. In patients, higher CTGF gene expression in bronchial biopsies was correlated with increased basement membrane thickness indicating that the enhanced CTGF expression in A‐ASM may contribute to airway remodelling in asthma.

Increased accumulation of dendritic cells in celiac disease associates with increased expression of autophagy protein LC3

Celiac disease (CD) an immune-mediated disorder associates with accumulation of dendritic cell (DC) in duodenal mucosa. Autophagy has recently been implicated in autoantigen formation. However, its role in CD is still unknown. To examine role of autophagic protein LC3 expressed by activated DC in CD. Thirty CD patients were analyzed at initial presentation and after 6 months of gluten-free diet (GFD). Duodenal biopsies were studied for histological changes and CD11c, CD86, and MAP1LC3A expressions by double immunohistochemistry (IHC). Masson's trichrome (MT) staining was used to assess basement membrane (BM) thickness and Oil Red O (ORO) staining for mucosal lipid deposit. Polymerase chain reaction (PCR) was performed for HLA-DQ system. Statistical analysis was done using paired and unpaired t test, chi-square test, Fisher's exact test, and McNemar-Bowker test. A P-value <0.05 was considered statistically significant. HLA-DQ2 and HLA-DQ8 alleles were present in all studied patients. Increased BM thickness was observed in 63% and 73% had ORO-positive lipid in surface lining epithelium. Pre-treatment biopsies showed increased DCs expressing LC3, which were significantly less in follow-up biopsies. The follow-up biopsies had shown significant reduction in BM thickness and ORO. Histological improvement in duodenal biopsies was associated with reduction in activated DCs expressing autophagic protein, which probably play important role in pathogenesis of an autoimmune disorder like CD.

Diabetic nephropathy: Progression and pathophysiology

Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects ~30% of type 1 and type 2 diabetic patients. This review focuses on the progression and pathophysiological aspects of the condition. The natural history of diabetic nephropathy is characterized by specific renal morphological and functional alterations. Features of early diabetic renal changes are microalbuminuria (30-300mg/day), glomerular hyperfiltration, glomerular and renal hypertrophy, increased basement membrane thickness, and mesangial expansion with the accumulation of extracellular matrix proteins such as collagen, fibronectin, and laminin. Advanced diabetic nephropathy is characterized by macroalbuminuria ( >300mg/day), a progressive decline in glomerular filtration rate, decreasing creatinine clearance, glomerulosclerosis, and interstitial fibrosis. Although poor glycemic control is an important risk factor, glycemia does not fully explain why only a subset of diabetic patients progress to end stage renal disease. Several decades of extensive research has elucidated various pathways to be implicated in the development of diabetic kidney disease such as systemic and glomerular hypertension, advanced glycation endproducts and the aldose reductase system. Furthermore, hemodynamic factors, the reninangiotensin system, the endothelin system, the intracellular signaling molecule protein kinase C, transforming growth factor-s, growth hormone, insulin like growth factors, vascular endothelial growth factor, and platelet-derived growth factor are believed to be involved in the pathogenesis. Thus, there are clearly many points at which therapeutic approaches could be tried to provide renoprotection in diabetes. It is likely that due to its complexity, targeting multiple points in altered metabolism in the diabetic kidney will be more successful in attenuating the development of diabetic nephropathy, rather than a single approach.

Increased basement membrane thickness, pericyte ghosts, and loss of retinal thickness and cells in dopamine beta hydroxylase knockout mice

Diabetes can cause damage to sympathetic nerves, and we have previously shown that experimental sympathectomy can produce capillary abnormalities in the retina similar to those seen in early diabetes. We postulate that the diabetes-induced loss of the sympathetic system, and at least in part the sympathetic neurotransmitter norepinephrine (NE), contributes to the development of retinal vascular and neural abnormalities in diabetes. Thus, we predict that non-diabetic animals that lack NE will develop microvascular and neural changes that are similar to those that are characteristic of diabetic retinopathy. To test this, retinas from non-diabetic dopamine beta hydroxylase (Dbh, Dbh−/−) knockout mice and their littermate controls were assessed for diabetic-like capillary and neural changes at 5 months of age. Genetic deletion of Dbh resulted in a significant decrease in retinal thickness and number of cells in the retinal ganglion cell layer (central retinal region). In addition, the number of pericyte ghosts and the basement membrane of retinal capillaries were significantly increased in the Dbh−/− mice. These results provide evidence that loss of sympathetic neurotransmission may contribute to the microvascular and neural changes of diabetic retinopathy. Restoration of sympathetic neurotransmission may be a new target for therapeutic intervention to inhibit the early phases of diabetic retinopathy.

Expression and Distribution of Laminin Chains in the Testis for Patients With Azoospermia

The aim of our study was to investigate the relationships between the expression of laminin in the testis and spermatogenesis, and the basement membrane (BM) of testicular tubules in fertile and infertile men. Testicular tissue samples were collected from the testes of 9 patients with obstructive azoospermia (OA), 9 patients with maturation arrest (MA), and 15 patients with Sertoli cell-only syndrome (SCO). In testicular tissue, laminin was identified by staining with polyclonal antibodies. Serum follicle-stimulating hormone (FSH), lutenizing hormone (LH), and testosterone were determined by chemiluminescence assays. In seminal plasma, laminin was estimated using a double-antibody enzyme immunoassay. BM thickness was significantly correlated with testicular tubule diameter (r = -0.49, P = .004) and FSH (r = 0.52, P = .008). The beta2 chain of laminin was most expressed on the inner BM of testicular tubules. The laminin index for the beta2 chain in SCO was significantly higher than in OA (P < .0001) and MA (P = .03). The mean seminal laminin levels in SCO were significantly lower than in OA (P < .001). We demonstrated that overabundance of the beta2 chain of laminin is associated with increased BM thickness and is possibly related to spermatogenic dysfunction.

Mucosal Remodeling in Chronic Rhinosinusitis

Despite pathophysiologic similarities, mucosal remodeling is well described in asthma but not chronic rhinosinusitis (CRS). This study attempts to identify mucosal remodeling in CRS and correlate it with clinical information. Charts and histopathology from 53 CRS patients who underwent functional endoscopic sinus surgery were reviewed. Clinical data and basement membrane (BM) thickness were recorded. BM thickness was graded as 0 (no thickening), 1 (mild thickening), 2 (moderate thickening), or 3 (marked thickening). Control mucosae from ten patients without CRS were analyzed for comparison. Duration of CRS symptoms positively correlated with BM thickness (p = 0.007). Also, patients with a markedly thickened BM (score of 3) had a significantly greater duration of CRS symptoms (120 months) compared to patients with a thinner BM (score < or =2) (33 months) (p = 0.010). Markedly thickened BM was associated with increased coincidence of asthma (p = 0.019) and aspirin sensitivity (p = 0.003). No correlation was found between BM thickness and preoperative Lund-MacKay score. There was no statistically significant difference between markedly thickened BM and thinner BM with respect to coincidence of polyps, course of preoperative systemic steroids, estimated blood loss at surgery, and number of prior surgeries. Increased BM thickness is correlated with prolonged duration of symptoms and the coincidence of asthma. This may indicate paranasal sinus remodeling akin to that which occurs in the bronchioles of persistent asthmatic sufferers.

Combined effects of moderately elevated blood glucose and locally produced TGF- 1 on glomerular morphology and renal collagen production

There is a correlation between renal graft rejection and blood glucose (BG) levels. Furthermore, diabetic patients may develop non-diabetic renal diseases, which in some circumstances progress rapidly. Since transforming growth factor-beta1 (TGF-beta) levels are elevated in many renal diseases, the accelerated progression may be due to interactions between glucose and locally produced TGF-beta1. Therefore, we investigated the effect of mild hyperglycaemia on glomerular morphology and collagen production in TGF-beta1 transgenic mice. To achieve BG concentrations of approximately 15 mmol/l in TGF-beta1 transgenic and non-transgenic mice, we used multiple streptozotocin (STZ) injections, and after 8 weeks, we measured the changes in glomerular morphology and total collagen content. We also analysed extracellular matrix (ECM) and protease mRNA levels using real-time polymerase chain reaction (PCR) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK) expression by immunohistochemistry. Mild hyperglycaemia alone had no effect on glomerular structure or ECM deposition. Over-expression of TGF-beta1 increased basement membrane thickness (BMT) and the mesangial volume fraction. Furthermore, it augmented ECM, Matrix metalloproteinase-2 (MMP), MMP-9, plasminogen activator inhibitor-1 (PAI) and tissue inhibitor of metalloproteinase-1 (TIMP) gene expression and pERK1/2 immunostaining. Elevated BG in combination with TGF-beta1 resulted in enlargement of glomerular volume, total mesangial volume and renal collagen content. Moreover, high BG exaggerated TGF-beta1-induced changes in the BMT, MMP-2 and TIMP-1 expression and pERK1/2 staining. Even moderate elevations in BG accelerate the progression of those kidney diseases in which TGF-beta1 is involved. This emphasizes the importance of strict BG control in renal transplant patients and diabetic patients with renal malfunctions unrelated to diabetes.

Distribution of type IV collagen subtypes in human testes and their association with spermatogenesis

Objective To evaluate the expression of type IV collagen [α1(IV) to α6(IV)] in testes and the association with spermatogenesis. Design Retrospective immunohistochemical study. Setting Division of Urology, Department of Organs Therapeutics, Faculty of Medicine, in a university hospital. Patient(s) Testicular biopsy specimens were obtained from 24 patients with varicocele, 5 with Sertoli cell-only syndrome (SCO), and 5 normal volunteers. Intervention(s) Collection of testicular tissue and blood and semen sampling. Main outcome measure(s) Expression of type IV collagen subtypes assessed by immunohistochemistry and clinical parameters such as seminogram and hormonal findings. Result(s) In normal testes, the α1(IV) chain was seen in the basement membrane (BM) of seminiferous tubules as strongly stained irregular, wavy double lines, and the α2(IV) chain was slightly detected, whereas other testes showed little staining. In patients with varicocele and Sertoli cell-only syndrome, the BM was thicker and α1(IV) and α2(IV) chains were stained more intensely in the BM of seminiferous tubules than in normal testes. The expression of α1(IV) chain, not α2(IV), significantly correlated positively with the BM thickness, and negatively with sperm concentration, tubular diameter, and Johnsen score. Conclusion(s) Overabundance of the α1(IV) chain is associated with increased BM thickness and possibly related to spermatogenic dysfunction.

Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a comparison between upper and lower airways

Local airway inflammation and airway remodelling are considered important in the clinical expression of allergic asthma. The aim of this study was to compare airway inflammation and remodelling in nasal and bronchial mucosa of subjects with allergic rhinitis with or without asthma. Four experimental groups were formed: allergic asthma and rhinitis (n = 19); allergic rhinitis, no asthma (n = 18); atopic subjects, no asthma, no rhinitis (n = 8) and non-allergic healthy control subjects (n = 16). Blood samples, nasal and bronchial biopsy specimens were collected during stable disease. Immunohistochemistry was performed for eosinophils (MBP), mast cells (CD117) and vascular endothelium (CD31). Epithelial loss, reticular basement membrane (RBM) thickness and subepithelial vascularity was assessed with a computer-assisted image analysis system. In nasal and bronchial mucosa, numbers of eosinophils were significantly higher in rhinitis patients with and without asthma than in asymptomatic atopics (P < 0.05) and controls (P < or = 0.01). In bronchial mucosa, the RBM was significantly thickened in rhinitis patients with and without asthma compared to asymptomatic atopics (P < 0.05) and controls (P < 0.01), while in nasal mucosa no differences were seen. Patients with asthma and rhinitis had increased numbers of blood eosinophils (P = 0.05) and skin test reactivity (P = 0.01) compared to patients with rhinitis only. No significant differences could be found between the investigated groups with respect to serum IL-5 and eotaxin levels, the number of mucosal mast cells and the degree of epithelial loss and subepithelial vascularity. Epithelial desquamation was significantly increased in the bronchial mucosa compared to nasal mucosa, not only in asthmatics (P < 0.001), but also in atopics without asthma and rhinitis (P = 0.02). This study shows that allergic inflammation, increased basement membrane thickness and epithelial desquamation are present in the lower airways of atopic subjects, even before the onset of clinical symptoms. Despite the presence of inflammatory cells, no structural changes could be assessed in nasal mucosa of allergic patients.

Diabetic Glomerulopathy in Young IDDM Patients

The clinical course of diabetic nephropathy may be described in stages; the normo-, micro- and macroalbuminuric stage. The basis for its development is the diabetic glomerulopathy in which accumulation of basement membrane (BM) material is pivotal. Normoalbuminuric patients have normal or slightly increased BM thickness; microalbuminuric patients show further BM thickening and mesangial expansion, formation of new capillaries, arteriolar and interstitial changes. The degree of diabetic glomerulopathy may be predicted by long-term glycemic control, diabetes duration and glomerular filtration rate (GFR). A slight decline in GFR in microalbuminuric patients is associated with increases in BM thickness, capillary diameter and interstitial volume fraction. In turn, the degree of early diabetic glomerulopathy may predict the level of microalbuminuria several years later. Improved metabolic control, even to not normal levels, retards the increase of BM thickness and matrix volume in microalbuminuric adolescents. If matrix accumulation may be prevented diabetic nephropathy will not develop. Morphometric analyses may thus be useful in evaluating the effect of intervention, also during shorter periods and at early stages.

Is reactive airways dysfunction syndrome a variant of occupational asthma?

Background: Reactive airways dysfunction syndrome (RADS) or irritant-induced asthma is a syndrome that leaves subjects with asthma-like symptoms after one or more exposures to a high concentration of an irritant substance. The degree of reversibility of airway obstruction in subjects with RADS is nevertheless unknown, as is the degree of associated lesions at the airway level. Methods: We compared the acute reversibility of forced expiratory volume in 1 second (FEV 1) after inhalation of albuterol (200 μg) in 15 subjects with RADS (12 cases caused by chlorine inhalation) with that of 30 subjects with occupational asthma (OA) caused by various agents. They were paired according to baseline airway obstruction (61% and 63% of predicted value in the RADS and OA groups), requirement for medication (bronchodilator only- 7 of 15 subjects with RADS and 14 of 30 subjects with OA-as compared with bronchodilator + inhaled steroids in 8 of 15 subjects with RADS and 16 of 30 subjects with OA, respectively), and interval since removal from exposure (means of 30 and 24 months in the RADS and OA groups). In addition, five nonsmokers with RADS who had not received inhaled steroids underwent bronchoscopy with lavage and bronchial biopsies less than 2 years after the exposure. Results: The percentage increase in FEV 1 over baseline after inhalation of albuterol was 10% ± 9% in the RADS group and 19% ± 16% in the OA group ( p = 0.005). Only 2 of 15 subjects (13%) with RADS and 12 of 30 subjects (40%) with OA showed an improvement in FEV 1 of 20% or greater after inhalation of albuterol. Bronchoalveolar lavage showed an increased number of cells with a predominance of lymphocytes, and biopsy specimens showed increased basement membrane thickness in the five subjects with RADS who underwent bronchoscopy. Conclusion: Subjects with RADS are generally left with less airway reversibility than those with OA. We suggest that this difference is secondary to distinct pathologic changes.

Late ultrastructural effects of heavy ions and gamma irradiation in the gastrointestinal tract of the mouse

The irradiated gastrointestinal tract of LAF1 mice was examined one year following a single dose (1000 rad) of either 12C heavy ions or 60Co gamma rays. Qualitative ultrastructural analysis of the gastrointestinal tract of mice exposed to heavy ions or gamma irradiation did not show any discernible differences. In the stomach of irradiated mice, parietal cells contained numerous lysosomes; the gastric chief cells occasionally contained myelin figures. The epithelial cells of the small intestine, especially jejunum and ileum, showed several changes: (1) increased vacuolation was seen both inter- and intra-cellularly, (2) epithelial cell projections penetrated the basal lamina and were in contact with underlying mesenchymal cells, (3) occasional Paneth cells contained intracellular vacuoles consisting of fibrillar and granular material. In the large intestine occasional signs of degeneration were observed. Qualitative analysis of stromal elements of the gut in irradiated mice indicated the presence of damage to capillary endothelial cells, smooth muscle cells and some nerve processes. The amount of basement membrane (BM) around capillaries and small vessels was increased; the same phenomenon was observed to affect the nerve processes, but with less severity. Quantitative analysis of the basement membrane thickness around capillaries in irradiated vs. control mice showed significant differences. Basement membrane thickness around capillaries in the gastric mucosa and duodenum did not differ significantly in any of the treatment groups. In jejunum, the gamma treated animals exhibited significantly higher BM thickness when compared to unirradiated controls. In ileum, only 12C-heavy ion treated animals showed thicker BM when compared to their respective controls. In colon, both 12C- and 60Co-treated animals showed increased BM thickness when compared to controls.

Quantitative macroscopic and histological study of testicular hypoplasia in Bos indicus strain bulls

Forty-six bulls between 17 and 23 months old were used in an investigation of testicular hypoplasia in Bos indicus strain bulls. Testes diagnosed as either unilaterally or bilaterally hypoplastic or normal were obtained at castration and were examined macroscopically and by quantitative histological methods. Estimations of sperm per gram of testis (spg) were made on these 46 bulls and two others. Testis weight was greatest in the 'normal of unilateral' group (106 g). The mean epididymis:testis weight ratio was 0.12 and did not differ significantly between groups. Increased basement membrane thickness, increased vacuolation and giant cells were not features of testicular hypoplasia per se. Seminiferous tubule diameter varied from 118 micrometer in bilaterally hypoplastic testes to 171 micrometer in normal testes. A mean tubule diameter of about 150 micrometer was considered useful for differentiating hypoplastic from normal testes in young post-puberal B indicus crossbred bulls. There was a significant correlation between tubular diameter and spg (r = 0.68, P less than 0.001) suggesting that tubular diameter measurements in histological sections could be used to predict sperm production. Although there was good agreement between clinical diagnosis and spg values, high spg values were found in several small testes which were considered hypoplastic on clinical examination. Examination of both unilaterally and bilaterally hypoplastic testes showed an interesting variation in the ratio of nucleus to cytoplasm in the interstitial cells. This was significantly (p less than 0.05) lower in the testes of normal bulls than in the other clinical groups.

Further views on the basement membrane controversy.

Although it has been claimed often that increased basement membrane thickness is an important factor in diabetic nephropathy, there is no direct evidence that it is associated necessarily with increased permeability or elevated glomerular filtration rate [1] and it should be noted that both changes could follow increased hydrostatic pressure. Hydrostatic pressure and capillary wall structure were thought to be involved in the extravasation of plasma proteins in diabetic microangiopathy [2]. The pressure dependence of human skin capillary permeability was demonstrated by Landis more than 40 years ago [3]. More recently, increased filtration pressure was linked causally with the increased glomerular filtration rate and elevated filtration fraction of diabetic nephropathy [4]. On the other hand, Viberti [5] expressed the view that basement membrane thickness and permeability to plasma proteins were 'somewhat independent'. Recent accepted concepts of basement membrane permeability are based upon a pore theory [6] in which the basement membrane is considered as a semi-permeable membrane containing cylindrical pores of 3.54.2 nm radius, or rectilinear slits of 3.6 nm half width [7]. The permeability of the membrane is believed to be determined by the interaction of particles with the anionic charge barrier on the basement membrane and endothelium [8, 9]. Alternative concepts of basement membrane structure treat it either as a hydrated gel through which filtration occurs by diffusion [10]: or a 'felted fibril' concept in which increased permeability was explained by the slackening of the fibrils when hydrostatic pressure fell [11]. It is noteworthy that these concepts provide no explanation of how cells or larger motile parasite larvae pass through basement membranes without leaving evidence of their passage. In 1980 a new concept was put forward that basement membranes are thixotropic gels which are capable of undergoing localised, reversible deformation under the effect of pressure [12]. Such gels would have the dispersed phase disposed as an irregular lattice which contained the dispersion medium (water). Solutions and small particles of about 2 nm radius or less would pass freely through the lattice, but larger particles would be able to traverse the membrane only if they had sufficient energy to deform the lattice, which reformed after the passage of the particles. In a recent study by Ota et al. [13] ultra-high magnification electron microscopy of unfixed glomerular basement membrane has revealed a sponge-like lattice without large pores or fibrils but which had interstices of similar size to that proposed in the thixotropic gel model [12]. Technical difficulties have prevented direct assessment of pressure-permeability relationships of basement membranes although indirect observations provide support for the idea that basement membranes are pressure dependent. Stolte et al. showed a straight line relationship between pressure and the amount of albumin filtered in perfused rat kidneys [14]. Mice with spontaneous lupus nephritis developed high molecular weight proteinuria in association with elevated systolic blood pressure [15]. Mogensen found that the use of antihypertensive drugs inhibited the progression of diabetic nephropathy as interpreted by altered glomerular filtration rate in five out of six patients [16]. In serial studies of diabetic urines, we have observed that some samples contained a range of plasma proteins, demonstrable by the use of sodium dodecyl sulphate polyacrylamide gel electrophoresis. Similar urinary protein profiles have been found in other types of human nephropathy, in murine lupus nephritis and in exercise proteinuria induced in subjects with normal renal function [unpublished observations]. The similarity of the protein profiles may be

Evaluation of Skeletal Muscle Capillary Basement Membrane Thickness in Congestive Heart Failure

Although it has been demonstrated that during isotonic grip exercise patients with chronic congestive heart failure have an abnormally reduced forearm oxygen consumption resulting from a depressed forearm flood flow, there may be additional etiologies of this abnormality. To explore this possibility biopsies of the pronator teres muscle were taken in eight control subjects with normal cardiac hemodynamics and in seven severely decompensated chronic congestive heart failure subjects. Each sample was fixed, stained, and photomicrographs of the sections were obtained and the capillary basement membrane thickness determined. The control capillary basement membrane thickness was 3028 plus or minus 187 A (mean plus or minus SEM) compared to the congestive heart failure thickness of 4924 plus or minus 538 A (pless than .01). It is possible that the increased basement membrane thickness in congestive heart failure may result from or actually cause the depressed oxygen consumption by altering diffusion.