Strial Capillaries Research Articles

A critical evaluation of "leakage" at the cochlear blood-stria-barrier and its functional significance.

The blood-labyrinth-barrier (BLB) is a semipermeable boundary between the vasculature and three separate fluid spaces of the inner ear, the perilymph, the endolymph and the intrastrial space. An important component of the BLB is the blood-stria-barrier, which shepherds the passage of ions and metabolites from strial capillaries into the intrastrial space. Some investigators have reported increased "leakage" from these capillaries following certain experimental interventions, or in the presence of inflammation or genetic variants. This leakage is generally thought to be harmful to cochlear function, principally by lowering the endocochlear potential (EP). Here, we examine evidence for this dogma. We find that strial capillaries are not exclusive, and that the asserted detrimental influence of strial capillary leakage is often confounded by hair cell damage or intrinsic dysfunction of the stria. The vast majority of previous reports speculate about the influence of strial vascular barrier function on the EP without directly measuring the EP. We argue that strial capillary leakage is common across conditions and species, and does not significantly impact the EP or hearing thresholds, either on evidentiary or theoretical grounds. Instead, strial capillary endothelial cells and pericytes are dynamic and allow permeability of varying degrees in response to specific conditions. We present observations from mice and demonstrate that the mechanisms of strial capillary transport are heterogeneous and inconsistent among inbred strains.

Acoustic Trauma Causes Cochlear Pericyte-to-Myofibroblast–Like Cell Transformation and Vascular Degeneration, and Transplantation of New Pericytes Prevents Vascular Atrophy

Acoustic trauma disrupts cochlear blood flow and damages sensory hair cells. Damage and regression of capillaries after acoustic trauma have long been observed, but the underlying mechanism of pathology has not been understood. We show herein that loud sound causes change of phenotype from neural/glial antigen 2 positive/α-smooth muscle actin negative to neural/glial antigen 2 positive/α-smooth muscle actin positive in some pericytes (PCs) on strial capillaries that is strongly associated with up-regulation of transforming growth factor-β1. The acoustic trauma also reduced capillary density and increased deposition of matrix proteins, particularly in the vicinity of transformed PCs. In a newly established invitro three-dimensional endothelial cell (EC) and PC co-culture model, transformed PCs induced thicker capillary-like branches in ECs and increased collagen IV and laminin expression. Transplantation of exogenous PCs derived from neonatal day 10 mouse cochleae to acoustic traumatized cochleae, however, significantly attenuated the decreased vascular density in the stria. Transplantation of PCs pretransfected with adeno-associated virus 1-vascular endothelial growth factor-A165 under control of a hypoxia-response element markedly promotes vascular volume and blood flow, increased proliferation of PCs and ECs, and attenuated loud sound-caused loss in endocochlear potential and hearing. Our results indicate that loud sound-triggered PC transformation contributes to capillary wall thickening and regression, and young PC transplantation effectively rehabilitates the vascular regression and improves hearing.

Estimation of Volume of Stria Vascularis and the Length of Its Capillaries in the Human Cochlea.

Background:The stria vascularis (SV) is a vascularized epithelium that secretes endolymph and is located on the lateral wall of the membranous cochlea. The capillaries of SV directly influence the composition of the endolymph and hence the generation of impulses by the hair-cells that are auditory receptors and thus affect hearing. Therefore, the real morphology of the SV would be very important for understanding the hearing system. There are few reliable reports of the morphology of the human SV.Aims and Objectives:In this research, we have estimated the volume of the SV and total length of strial capillaries in the apical, middle and basal turns of the human cochlea by updated stereological techniques.Methods:The point-counting Cavalieri's method and hemispherical volume probes were applied on stained, 40 μm-thick serial sections of five celloidin-embedded, decalcified cochleae.Results:The mean age of persons at the time of death was 51 ± 15.25 years, the mean volume of the SV was 0.56 ± 0.054 mm3 and the mean length of the SV capillaries was 289.08 ± 72.96 mm. We also estimated the same parameters with different stereological parameters, probes and in differently stained sections and checked the relationship and limits of agreement between different methods by paired t-test and Bland-Altman plot. We found agreement in our results.Conclusion:We provide reliable baseline data on the real morphology of the human SV.

Matrix metalloproteinase-2 and -9 contribute to functional integrity and noise‑induced damage to the blood-labyrinth-barrier.

The cochlear blood-labyrinth barrier (BLB), located in the stria vascularis, is critical for the homeostasis of cochlear solutes and ion transport. Significant disruption to the BLB occurs early during noise-induced hearing loss. Matrix metalloproteinase (MMP)-2 and −9 are important molecules known to be capable of degrading tight junction (TJ) proteins. The TJ proteins are important components of the extracellular matrix (ECM), required to maintain BLB integrity and permeability. Previous studies have demonstrated that MMP-2 and −9, rich in healthy cochlea, serve an essential role in regulating the cochlear response to acoustic trauma. The present study investigated the localization and function of MMP-2 and −9 in the BLB by determining their associated gene expression and activity under normal conditions and after noise exposure. Analysis of gene expression by RNA-sequencing (RNA-seq) revealed expression of 15 MMP-associated genes, including genes for MMP-2 and −9, in healthy stria vascularis. Expression of these MMP genes was dynamically regulated by noise trauma to the cochlea, and accompanied by alterations in tissue inhibitors of metalloproteinases (TIMPs) and the TJ protein zona-occludens 1 (ZO-1). These alterations suggested that MMP-2 and −9 serve an important role in maintaining the integrity of BLB and in response to acoustic trauma. MMP-2, MMP-9 and ZO-1 protein expression levels in the stria vascularis by immunofluorescence, and observed that the stable expression of MMP-2 and −9 in healthy stria was markedly increased following noise exposure, consistent with the RNA-seq results. The compact structure of ZO-1 in the BLB loosened, and strial capillaries exhibited markedly increased leakage of Evans blue dye following acoustic trauma. These data indicated that mediation of MMP-2 and −9 in structural damage to TJ proteins, including ZO-1, may be an important mechanism in the breakdown of the BLB following acoustic trauma. Additionally, these results indicated that MMPs are involved in regulating the integrity and permeability of the BLB, which may provide a theoretical basis for the prevention of noise-induced hearing loss.

Effects of Long-Term Exercise on Age-Related Hearing Loss in Mice.

Nearly two-thirds of adults aged 70 years or older develop significant age-related hearing loss (AHL), a condition that can lead to social isolation and major communication difficulties. AHL is also associated with decreased physical function among older adults. In the current study, we show that regular exercise slowed AHL and cochlear degeneration significantly in a well established murine model. Our data suggest that regular exercise delays the progression of AHL by reducing age-related loss of strial capillaries associated with inflammation.

Histopathologic Evaluation of Vascular Findings in the Cochlea in Patients With Presbycusis.

Age-related changes in cochlear vessel wall thickness in human temporal bones have not been described previously. To compare thickness of the spiral modiolar artery and strial capillaries and to investigate strial atrophy and vessel loss in temporal bones with and without presbycusis. This retrospective case-control study examined the autopsy reports of 1024 patients in the temporal bone collection at the University of Minnesota. Inclusion criteria consisted of being 60 years or older with sensorineural hearing loss and progression of hearing loss with age (presbycusis group). Age-matched controls had no record of hearing loss. All patients underwent pure-tone audiometry. Exclusion criteria included a history of otologic disease, ototoxic drug use, head or acoustic trauma, or systemic disease. Data were collected from October 1, 2013, to October 1, 2014. Vessel wall thickness in the modiolar artery and strial vessels, the strial area, and number of strial vessels were measured under light microscopy. Among the 1024 autopsy reports examined, 11 patients (19 temporal bones) with presbycusis (7 men and 4 women; age range, 67-88 years; mean [SD] age, 78 [7] years]) and 15 controls (24 temporal bones) (7 men and 8 women; age range, 67-94 years; mean [SD] age, 79 [8] years) met the inclusion criteria. Compared with the control group, the presbycusis group had significantly increased mean (SD) thickness of vessel walls in the modiolar arteries (6.73 [2.39] vs 5.55 [0.86] μm; P = .02) and the strial capillaries in the lower basal (1.57 [0.21] vs 1.39 [0.15] μm; P = .005), upper basal (1.62 [0.28] vs 1.40 [0.13] μm; P < .001), lower middle (1.68 [0.22] vs 1.39 [0.20] μm; P < .001), upper middle (1.74 [0.39] vs 1.40 [0.19] μm; P = .01), and apical (1.70 [0.36] vs 1.47 [0.21] μm; P = .04) turns of the cochlea. Compared with the control group, the presbycusis group had significant loss of strial area in the lower basal (6614 [1559] vs 8790 [1893] μm2; P = .002), upper basal (6387 [2211] vs 9105 [2700] μm2; P < .001), lower middle (5140 [1471] vs 7269 [2181] μm2; P = .003), upper middle, (5583 [1742] vs 7206 [2258] μm2; P = .02), and apical (4286 [1604] vs 6535 [2454] μm2; P < .001) turns of the cochlea; in the vessel area in the lower basal turn (74.65 [127.74] vs 124.92 [89.04] μm2; P = .01); and in the number of vessels in the lower basal (1.00 [0.78] vs 1.94 [0.93]; P = .008) and lower middle (1.00 [0.78] vs 1.94 [0.93]; P = .04) turns of the cochlea. The histopathologic findings of increased thickness of the vascular walls of the modiolar arteries and stria vascularis, increased strial atrophy, and decreased number of strial vessels may have led to decreased cochlear microcirculation. Deficiency in the circulation and perfusion of the cochlea may be a factor in presbycusis.

Degeneration of stria vascularis in age-related hearing loss; a corrosion cast study in a mouse model

Conclusion With age, in a mouse model, degenerative changes to the capillaries of the stria vascularis are observed. These range from a narrowing of vessel lumen to complete degeneration of strial vessels. Other vascular beds in the cochlea are relatively unchanged with age. Strial capillaries at the cochlear base are significantly more affected than those in mid-apical turns.Objectives Previous work suggests that age-related hearing loss is associated with degenerative changes to cochlear vasculature; the term strial presbyacusis is often cited. This study reports on vascular changes observed in a murine model of presbyacusis, analyzed using corrosion cast techniques.Methods A novel corrosion cast technique was developed to compare cochlear vasculature in control mice (non-presbycusic, CD1) and old (> 6 months) C57BL/6 animals. ABR measures indicated a significant age-related threshold elevation in the C57BL/6 mice. Cochlear vascular casts were imaged using scanning electron microscopy, and vessel degeneration was quantified by measuring capillary diameters.Results Corrosion casts of cochlear vasculature in 6–12 month old C57BL/6 mice reveal significant degeneration of stria vascularis. Other capillary beds (spiral ligament and the spiral limbus) appear unchanged. Comparison of strial capillary diameters reveals significantly more damage in basal/lower-turn regions compared with the cochlear mid-turn.

Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.

Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively. S1P is a biologically active lysophospholipid with multiple roles in signalling. The mechanism of action of Spns2 is still elusive in mammals. Here, we report that Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old. We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion. In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries, and reduced expression of several key proteins involved in the generation of the EP (Kcnj10, Kcnq1, Gjb2 and Gjb6), but these changes were likely to be secondary. Permeability of the boundaries of the stria vascularis and of the strial capillaries appeared normal. We also found focal retinal degeneration and anomalies of retinal capillaries together with anterior eye defects in Spns2 mutant mice. Targeted inactivation of Spns2 in red blood cells, platelets, or lymphatic or vascular endothelial cells did not affect hearing, but targeted ablation of Spns2 in the cochlea using a Sox10-Cre allele produced a similar auditory phenotype to the original mutation, suggesting that local Spns2 expression is critical for hearing in mammals. These findings indicate that Spns2 is required for normal maintenance of the EP and hence for normal auditory function, and support a role for S1P signalling in hearing.

TNF-α inhibition using etanercept prevents noise-induced hearing loss by improvement of cochlear blood flow in vivo

Objective: Exposure to loud noise can impair cochlear microcirculation and cause noise-induced hearing loss (NIHL). TNF-α signaling has been shown to be activated in NIHL and to control spiral modiolar artery vasoconstriction that regulates cochlear microcirculation. It was the aim of this experimental study to analyse the effects of the TNF-α inhibitor etanercept on cochlear microcirculation and hearing threshold shift in NIHL in vivo. Design: After assessment of normacusis using ABR, loud noise (106 dB SPL, 30 minutes) was applied on both ears in guinea pigs. Etanercept was administered systemically after loud noise exposure while control animals received a saline solution. In vivo fluorescence microscopy of strial capillaries was performed after surgical exposure of the cochlea for microcirculatory analysis. ABR measurements were derived from the contralateral ear. Study sample: Guinea pigs (n = 6, per group). Results: Compared to controls, cochlear blood flow in strial capillary segments was significantly increased in etanercept-treated animals. Additionally, hearing threshold was preserved in animals receiving the TNF-α inhibitor in contrast to a significant threshold raising in controls. Conclusions: TNF-α inhibition using etanercept improves cochlear microcirculation and protects hearing levels after loud noise exposure and appears as a promising treatment strategy for human NIHL.

The Change of Strial Capillaries in Hemorrhage Shock

The Change of Strial Capillaries in Hemorrhage Shock

Hearing Loss and Cochlear Pathology in a Type II Diabetic Mouse Model

Objective: 1) Determine whether a type II diabetic mouse model demonstrates hearing loss. 2) Examine cochlear ultrastructure of a type II diabetic mouse model for evidence of pathology. Method: The Leprdb/Leprdb (db/db) mouse has a leptin receptor point mutation which manifests as polyphagia, hyperglycemia, and obesity, mimicking type II diabetes. Db/db and wild type mice from the parent strain underwent auditory brainstem response measurements followed by cochlear ultrastructure analysis using scanning and transmission electron microscopy. Results: At 12 weeks of age, the mutant animals demonstrate a profound hearing loss from 8 to 32 kHz, which is in contrast to published data of a 10 dB shift at 8 kHz and 30 dB shift at 16 to 32 kHz for age-matched, wild type C57BL/6J counterparts. In addition, fine structure analysis reveals evidence of morphological alterations in multiple locations within the cochlea, including loss of neuron density in the spiral ganglion, stria vascularis edema, and endothelial abnormalities within strial capillaries. Age-matched controls are without similar ultrastructural changes. Scanning electron microscopy reveals no evidence of hair cell loss or other identifiable abnormalities. Conclusion: This is the first demonstration of cochlear pathophysiology in a genetically derived type II diabetic mouse model. Use of the db/db mouse provides an opportunity to investigate the underlying mechanism of type II diabetes associated hearing loss.

Trafficking of Systemic Fluorescent Gentamicin into the Cochlea and Hair Cells

Aminoglycosides enter inner ear hair cells across their apical membranes via endocytosis, or through the mechanoelectrical transduction channels in vitro, suggesting that these drugs enter cochlear hair cells from endolymph to exert their cytotoxic effect. We used zebrafish to determine if fluorescently tagged gentamicin (GTTR) also enters hair cells via apically located calcium-sensitive cation channels and the cytotoxicity of GTTR to hair cells. We then examined the serum kinetics of GTTR following systemic injection in mice and which murine cochlear sites preferentially loaded with systemically administered GTTR over time by confocal microscopy. GTTR is taken up by, and is toxic to, wild-type zebrafish neuromast hair cells. Neuromast hair cell uptake of GTTR is attenuated by high concentrations of extracellular calcium or unconjugated gentamicin and is blocked in mariner mutant zebrafish, suggestive of entry via the apical mechanotransduction channel. In murine cochleae, GTTR is preferentially taken up by the stria vascularis compared to the spiral ligament, peaking 3 h after intra-peritoneal injection, following GTTR kinetics in serum. Strial marginal cells display greater intensity of GTTR fluorescence compared to intermediate and basal cells. Immunofluorescent detection of gentamicin in the cochlea also revealed widespread cellular labeling throughout the cochlea, with preferential labeling of marginal cells. Only GTTR fluorescence displayed increasing cytoplasmic intensity with increasing concentration, unlike the cytoplasmic intensity of fluorescence from immunolabeled gentamicin. These data suggest that systemically administered aminoglycosides are trafficked from strial capillaries into marginal cells and clear into endolymph. If so, this will facilitate electrophoretically driven aminoglycoside entry into hair cells from endolymph. Trans-strial trafficking of aminoglycosides from strial capillaries to marginal cells will be dependent on as-yet-unidentified mechanisms that convey these drugs across the intra-strial electrical barrier and into marginal cells.

Endocochlear potential depends on Cl− channels: mechanism underlying deafness in Bartter syndrome IV

Human Bartter syndrome IV is an autosomal recessive disorder characterized by congenital deafness and severe renal salt and fluid loss. It is caused by mutations in BSND, which encodes barttin, a beta-subunit of ClC-Ka and ClC-Kb chloride channels. Inner-ear-specific disruption of Bsnd in mice now reveals that the positive potential, but not the high potassium concentration, of the scala media depends on the presence of these channels in the epithelium of the stria vascularis. The reduced driving force for K(+)-entry through mechanosensitive channels into sensory hair cells entails a profound congenital hearing loss and subtle vestibular symptoms. Although retaining all cell types and intact tight junctions, the thickness of the stria is reduced early on. Cochlear outer hair cells degenerate over several months. A collapse of endolymphatic space was seen when mice had additionally renal salt and fluid loss due to partial barttin deletion in the kidney. Bsnd(-/-) mice thus demonstrate a novel function of Cl(-) channels in generating the endocochlear potential and reveal the mechanism leading to deafness in human Bartter syndrome IV.

Estrogen-Related Receptor β/NR3B2 Controls Epithelial Cell Fate and Endolymph Production by the Stria Vascularis

In the mammalian inner ear, endolymph is produced and resorbed by a complex series of epithelia. We show here that estrogen-related receptor beta (ERR-beta; NR3B2), an orphan nuclear receptor, is specifically expressed in and controls the development of the endolymph-producing cells of the inner ear: the strial marginal cells in the cochlea and the vestibular dark cells in the ampulla and utricle. Nr3b2(-/-) strial marginal cells fail to express multiple ion channel and transporter genes, and they show a partial transformation toward the fate of the immediately adjacent Pendrin-expressing epithelial cells. In genetically mosaic mice, Nr3b2(-/-) strial marginal cells produce secondary alterations in gene expression in the underlying intermediate cells and a local loss of strial capillaries. A systematic comparison of transcripts in the WT versus Nr3b2(-/-) stria vascularis has identified a set of genes that is likely to play a role in the development and/or function of endolymph-producing epithelia.

血管条血管の特徴―血管の透過性について―

When the cochleas of guinea pigs were fixed after decapitation, HRP leakage from the strial capillaries was observed with blood sludge. HRP was transported to the extracapillary space by many pinocytotic vesicles and marginal folds. However, when the cochleas were fixed before decapitation, blood sludge was not observed in the strial capillaries and leakage of HRP from the capillaries was not observed 10 minutes after HRP injection. Thereafter, the level of HRP leakage increased with time. It was noted that capillary permeability to HRP at the basal turn was lower than that of the upper three turns. HRP leakage was not observed in the capillaries of the spiral ligament even beyond one hour after injection.As a result of severe hemorrhagic shock in guinea pigs, blood sludge appeared in strial capillaries and capillary permeability to HRP increased. However, in moderate hemorrhagic shock, both blood sludge and accentuation of capillary permeability did not occur.After the inoculation of endotoxin in the middle ear, a large amount of HRP leaked out of the capillaries through the opened endothelial cell junctions.After vibration administered to auditory ossicle is by a drill, the permeability of the strial capillaries to HRP also increased. High permeability was thought to be caused by damage to the strial endothelial cells. HRP leakage initially took place through the tubules in the endothelial cytoplasm, and HRP leaked in to the extracapillary space when the cell membranes were damaged by vibration. Administration of the steroid inhibited HRP leakage from the strial capillaries.The stria vascularis became markedly edematous after the administration of furosemide, while capillary permeability to HRP was decreased.From the above, the route of HRP leakage is different depending on the type of stimulation, even if it occurs alongside increased capillary permeability.

Pathological alterations of strial capillaries in dominant white spotting W/ Wv mice

Dominant white spotting W/ W v and W v/ W v mice are well-known mutants that lack strial intermediate cells in their cochlea and manifest hereditary sensorineural hearing loss. We recently reported marked thickening of and IgG deposition on the basement membrane of strial capillaries in W/ W v mutant mice, similar to observations made in aged animals and in animals with autoimmune sensorineural hearing loss. The present study aimed to clarify the age-dependent changes in these pathological findings of strial capillaries in the W/ W v mice. Male WBB6F1 +/+ and dominant white spotting W/ W v mutant mice were sacrificed by transcardiac perfusion with paraformaldehyde solution. The cochlear ducts were isolated and subjected to light- and electron-microscopy, immunohistochemistry, immunoelectron microscopy. Alternatively, lanthanum chloride tracer examination in the isolated cochlear ducts was performed in order to compare the permeability of the strial capillaries between +/+ and W/ W v mice. In the W/ W v mice, thickening of and IgG deposition on the basement membrane of strial capillaries were observed as early as 1 week after birth and became more noticeable with age. Deposited IgG was preferentially localized to the thickened basement membrane and was also observed in partially the intercellular space between adjacent of endothelial cells. In addition, pinocytotic vesicles both in the apical and basal lesions of such cells also showed IgG deposition. Lanthanum chloride was retained along apical plasma membrane of the endothelial cells in the +/+ mice but penetrated through the endothelial layer in the W/ W v mice. These results indicate that active transport via pinocytotic vesicles as well as increased permeability of strial capillaries in the W/ W v mice occur in the early stage after birth, resulting in the morphological alterations in the strial capillaries of these mice.

Dystroglycan expression in the mouse cochlea

Viable dominant spotting (W v/W v) mice have a c-kit gene mutation, which impedes the migration of neural crest cells to the developing cochlea where they normally differentiate into intermediate cells (ICs). A prominent pathological feature shared by these mutants and the aging human and gerbil cochlea is thickening of the basement membrane (BM) of strial capillaries. Atrophy of strial capillaries in the aging gerbil has been associated with changes in the expression of dystroglycan (DG), a cell-surface receptor that regulates BM assembly. Here we evaluated the expression of DG in W v/W v mutant and C57BL/6J wild-type mice to investigate the possible role of ICs in regulating strial capillary BM homeostasis. The DG gene product was identified in lateral wall dissections from both W v/W v mutant and wild-type mice by reverse transcription-polymerase chain reaction. Subunit-specific antibodies were employed to localize the α and β subunits of the DG heterodimer. Some sites in both wild-type and mutant mice, such as the subepithelial BM lining the scala media and regions of contact between selected epithelial cells, expressed α-DG alone. Other sites such as the perineural BM and the perivascular BM subtending strial capillaries and capillaries in the central portion of the auditory nerve coexpressed α- and β-DG. The strong diffuse staining for α-DG along the basolateral membrane of strial marginal cells disappeared with advancing strial degeneration in abnormal turns of W v/W v mutants. Variations in staining intensity for both α- and β-DG also occurred in the subendothelial BM of strial capillaries in turns lacking ICs and appeared to correspond with the degree of capillary atrophy. The results support the possibility that ICs play a role in the homeostasis of the strial capillary BM.

Dystroglycan expression in the developing and senescent gerbil cochlea

Dystroglycan (DG) forms part of a cell surface laminin receptor complex and is believed to play a critical role in the assembly and homeostasis of basement membranes (BM). The receptor complex is made up of α- and β-DG subunits and is found in muscle, epithelial and nerve tissue. In the cochlea, DG may be involved in the abnormal accumulation of laminin seen in the thickened BM of strial capillaries with age. This excess deposition of laminin is thought to lead to capillary necrosis and contribute to degeneration of the stria vascularis (SV). Here we assessed the presence and distribution of DG in the developing, mature and senescent gerbil cochlea in order to ascertain whether altered patterns of expression are a factor in age-related pathology. Western blots of proteins isolated from the entire cochlea demonstrated the presence of the α-DG subunit. mRNA encoding DG was identified in microdissected specimens of the lateral wall and the combined organ of Corti/modiolus by RT-PCR analysis. Immunohistochemical experiments localized α-DG in epithelial BMs and regions of epithelial cell–cell contact with no intervening BM in the developing and mature cochlea. Immunoreactive α-DG was present in the BM underlying strial capillaries and in vessels of the central portion of the auditory nerve, but was not detected in any other vessels in the cochlea. Age-related changes in α-DG expression were observed only in the SV where a marked decrease in α-DG immunoreactivity was seen in the BM of strial capillaries as well as throughout the SV. The results demonstrate the selective expression of α-DG in both BM and non-BM sites in the mature cochlea and suggests its involvement in both developmental and aging processes.

Degeneration of the stria vascularis during development in melanocyte-deficient mutant rats (Ws/Ws rats).

Developmental changes in the stria vascularis of white spotting (Ws) rats were examined by scanning and transmission electron microscopes and by diaminobenzidine-staining techniques. The stria of Ws/Ws homozygote rats was found to have both pigmented and non-pigmented portions. While the pigmented portions possessed intermediate cells in the same manner as the stria of wild +/+ rats, the non-pigmented portions lacked the cells. Examination at 1, 2, 3, 4, 6, 8 and 14 weeks after birth revealed a progressive degeneration in the marginal cells and strial capillaries in the non-pigmented portions. At 1 week, no significant differences were seen in the marginal cells of any of the rats examined. At 2 weeks, the basolateral infoldings of the marginal cells were seen to be well developed and adult-like in the pigmented portions of Ws/Ws rats and in +/+ rats. In the non-pigmented portions, the basolateral infoldings of the marginal cells appeared well developed; however, vacant spaces were seen around the basolateral infoldings. At 3 weeks, the basolateral infoldings of the marginal cells in the non-pigmented portions had become more atrophic, and the empty spaces around the basolateral infoldings had enlarged. Also, the marginal cells themselves had become flatter or thinner. These findings became more prominent at 4 weeks and 6 weeks. At 8 weeks and 14 weeks after birth, the marginal cells appeared markedly flat, and no basolateral infoldings were seen in the non-pigmented portions. Pigmented portions of the stria in Ws/Ws rats, on the other hand, showed normal development throughout this period. A DAB-staining examination of the stria capillary net in Ws/Ws rats showed it to be well developed at 3 weeks in both pigmented and non-pigmented portions. At 8 weeks, a thickening of the capillary basement membrane was apparent. The above findings lead the authors to believe that intermediate cells play an important role in the development and maintenance of marginal cells and the strial capillary system.

Nephrotoxicity of Combined Treatment with Cisplatin and Gentamicin in the Guinea Pig: Glomerular Injury Findings

The drugs cisplatin and gentamicin are given consecutively to various cancer patients suffering from infections. Little information exists about the ultrastructural alterations of kidney glomeruli caused by treatment with these drugs. Renal glomeruli of guinea pigs treated with cisplatin alone and in combination with gentamicin were studied by transmission electron microscopy. The findings revealed foci of damage induced by cisplatin and especially by cisplatin/gentamicin in all glomerular components: glomerular capillaries, including their endothelial cells; basement membrane, epithelial podocytes, mesangial cells, and parietal cells of Bowman's capsule. The damage was expressed by endothelial cytoplasmic extrusions into the vascular lumen, thickening and lamination of capillary basement membrane, focal foot process fusion of podocytes, vacuolization in cytoplasm of endothelial cells of epithelial podocytes and of parietal cells, and the presence of lipid bodies and myeloid bodies in all glomerular cell types. Additionally, injurious effects to cytoplasmic organelles such as mitochondria, nuclei, and endoplasmic reticulum were observed. The results indicate that cisplatin alone and in combination with gentamicin is toxic to renal glomerular tissue. Since these drugs were previously found toxic for strial capillaries in the inner ear and since the main glomerular component is the glomerular capillaries, potential vascular damage and vascular complications in different body systems have to be taken into consideration when these drugs are needed in clinical use.