Oesophageal rhabdomyoma.

Extracardiac rhabdomyomas are rare benign tumours showing striated muscle differentiation. Seventy percent of these lesions occur in the head and neck region. The most common sites for these lesions are the larynx, pharynx, and the floor of the mouth. There has been only one previous report of a rhabdomyoma of the oesophagus; two further cases are described.

B-cell antigens within normal and activated human T cells.

In this study we compared cell surface staining for human peripheral blood lymphocyte (PBL) CD antigens by flow cytometry, with staining obtained following permeabilization of PBL using the Cytoperm method (Serotec). Six CD antigens (CD20, CD21, CD22, CD32, CD35 and major histocompatibility complex class II antigen) normally found on the surface of B cells, were also found to be expressed within T cells. We also showed, by immunoelectron microscopy, that these inappropriately expressed ('occult') CD antigens are located within cytoplasmic vesicles or within the rough endoplasmic reticulum. Following in vitro activation of T cells a distinct increase in expression of all of these cytoplasmic antigens was observed but staining at the cell surface was, by comparison, weak. We therefore propose that up-regulation of various B-cell CD antigens occurs within the cytoplasm of T cells following activation and that these antigens may be synthesized and released into the fluid-phase as soluble immunoregulatory molecules.

Tuft-to-capsule adhesions and their precursors: differences between the vascular and tubular poles of the human glomerulus.

Human glomerular capillary tufts were removed by microdissection and scanning electron microscopy was used to examine the surface of the capillary tuft and the interior of its Bowman's capsule in order to identify connections between the tuft and capsule. Glomeruli were examined in histologically normal renal cortex from 12 kidneys removed for tumour and 12 renal allografts removed for end-stage rejection. In normal kidney, the glomerular tuft was connected to Bowman's capsule by single podocytes and their processes. At the vascular pole, these were predominantly associated with parietal podocytes which lined Bowman's capsule. At the tubular pole, occasional podocytic processes derived from the capillary tuft bridged Bowman's space and connected to Bowman's capsule where there were no parietal podocytes. These podocytic connections were also found in all rejected transplants, but in addition adhesions were identified which consisted of thicker connections between the tuft and capsule. At the vascular pole, tuft-to-capsule adhesions were found in all 12 kidneys; these were always associated with parietal podocytes. Tubular pole adhesions were identified in ten of the 12 transplants. They were associated with abnormal squamous cells, but not with parietal podocytes. When the capillary tuft herniated into the proximal tubule, the tuft sometimes formed an adhesion with the origin of the proximal tubule. These observations suggest that podocyte connections between the glomerular tuft and Bowman's capsule may be precursors of glomerular adhesions at the vascular pole. Since tuft-to-capsule adhesions at the vascular pole differ morphologically from those at the tubular pole, this may reflect different pathogenetic mechanisms at the opposite poles of the glomerulus.

Glomerular pathology: recent advances.

The last decade has seen significant advances in the fields of cellular and molecular biology and pathology. These have contributed to our understanding of the mechanisms of glomerular disease and indicate possible novel approaches to therapy. This review discusses recent insights into the pathogenesis of glomerular disease, with consideration of the roles of intrinsic glomerular cells, infiltrating inflammatory cells, circulating permeability factors, and antibodies, and recent advances in the molecular pathology of the glomerular basement membrane. Changes in the perception of some well-established glomerular entities such as focal segmental glomerulosclerosis are considered. In addition, a number of newly-recognized specific glomerulopathies including collapsing glomerulopathy, fibrillary and immunotactoid glomerulopathy, fibronectin glomerulopathy, and collagenofibrotic glomerulopathy are briefly reviewed.

Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease.

Injection of parental spleen cells into BDF1 mice results in a graft-vs-host disease (GVHD), the nature of which is critically dependent on the parental haplotype. B6-->BDF1 mice develop a Th1-mediated immunosuppressive lethal GVHD, whereas DBA/2-->BDF1 mice develop a Th2-dependent chronic GVHD, characterized by autoantibody production and glomerulonephritis. In this study we show that neutralizing endogenous IL-12 for a brief period during the initiation of acute GVHD in B6-->BDF1 mice not only confers long term protection from the acute disease, but also permits full repopulation of the recipient with donor B6 lymphocytes. Antibody-treated animals showed normal T cell proliferation in response to Con A stimulation and remained healthy throughout the study. Splenocytes from such mice showed reduced in vitro production of IFN-gamma and enhanced production of IL-5 and IL-10, suggesting a permanent switch from a Th1 to a Th2 cytokine response, comparable to that associated with chronic GVHD in DBA/2-->BDF1 mice. In contrast to DBA/2-->BDF1 mice, however, anti-IL-12-treated B6-->BDF1 mice displayed only mild B cell hyper-responsiveness, as evidenced by a modest increase in serum IgG and IgE levels and moderate levels of anti-dsDNA Abs. Importantly, however, anti-IL-12-treated B6-->BDF1 mice showed no evidence of immune complex-mediated glomerulonephritis. These results demonstrate that neutralizing IL-12 is an effective means of preventing acute GVHD and does not result in the development of chronic GVHD, which might otherwise limit its application.

Demonstration of cytoplasmic CD32 (Fc gamma RII) within human lymphocytes following microwave treatment.

We have recently described a cytoplasmic from of CD32 (Fc gamma RII) within the vast majority of normal human peripheral blood lymphocytes (PBL) including T cells. The function of cytoplasmic CD32 is not known. These flow cytometric studies were conducted using single cell suspensions of PBL that had been pre-fixed and permeabilized using methanol/triton-X-100. In this study we have attempted to visualize cytoplasmic CD32 by immunocytochemistry using normal PBL processed in various ways and have also looked for CD32 within tissue lymphocytes. Weak cytoplasmic CD32 staining was observed in paraffin sections of normal lymphocytes but only when sections were microwave treated. The intensity of staining for CD32 did however, appear to be much stronger within infiltrating lymphocytes found in autoimmune diseases or in rejecting allografts: an observation that suggests that up-regulation of cytoplasmic CD32 may occur when T cells become activated in vivo. Microwave treatment of PBL suspensions was shown to disrupt the outer cell membrane, thus effectively permeabilizing the cell and allowing for the detection of cytoplasmic components, like CD32, by flow cytometry. Microwave treatment may, therefore, afford an alternative method for cell permeabilization and may prove to be a useful method for the study of cytoplasmic molecules in cell suspensions and in paraffin-embedded tissues.

Atubular glomeruli and glomerular cysts--a possible pathway for nephron loss in the human kidney?

Glomerular tufts were removed and scanning electron microscopy was used to study the interior of Bowman's capsule, in order to identify atubular glomeruli. Normal renal cortex was studied from six kidneys removed for tumour and six renal transplants removed for end-stage rejection. Atubular glomeruli occurred in normal renal cortex in less than 1 percent of glomeruli, but were more common in transplant nephropathy, representing up to 61 percent of glomeruli. Glomerular cysts were identified which also lacked a tubular connection. Both atubular glomeruli and glomerular cysts contained a contracted glomerular capillary tuft and in both, Bowman's capsule was lined mostly by parietal podocytes. It is suggested that atubular glomeruli may be precursors of the glomerular cysts. The glomerular tuft may produce filtrate which exits the glomerulus via the parietal podocytes on Bowman's capsule. In normal human kidney, the formation of atubular glomeruli by disconnection from the tubule may represent an alternative pathway for the gradual nephron loss that is associated with ageing. This process may be amplified in disease: disconnection from the tubule may be an important part of irreversible nephron damage in chronic allograft nephropathy.

Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery Doppler waveforms.

The abnormal umbilical artery Doppler waveform represented by absent end-diastolic flow velocity (AEDFV) identifies a group of preterm small-for-gestational age fetuses that are at high risk of perinatal death due to chronic fetal hypoxia. The placental ischaemia that results from inadequate trophoblast invasion of spiral arterioles leads to an assumption of placental villous hypoxia, though an alternative explanation is that the placenta fails to adequately transfer oxygen to the fetus from the intervillous space. Because oxygen transport takes place within the terminal villi, we undertook the first detailed studies of villous ultrastructure structure and immunohistochemistry in order to determine the likely origin of fetal hypoxia in this condition. Terminal villi were examined ultrastructurally using transmission electron microscopy and by immunohistochemical localization of matrix molecules (laminin and collagens I, III and IV) and a marker of cell proliferation (MIB-1), in 16 small-for-gestational age pregnancies with AEDFV in the umbilical artery [deemed to have intrauterine growth restriction (IUGR)] and in 16 gestation age-matched controls. Terminal villi from the IUGR cases were smaller in diameter (P < 0.02) and had several abnormal features in comparison with the controls; increased syncytial nuclei (P < 0.01), reduced cytotrophoblast nuclei (P < 0.01), thickened basal lamina (P < 0.01), and increased stromal deposition of collagens and laminin. The amount of proliferating cytotrophoblast was reduced in the IUGR group (P < 0.014) and the degree of capillary erythrocyte congestion within terminal villous capillaries was increased (P < 0.001). Several of the structural differences in the terminal villi of the IUGR group such as reduced cytotrophoblast proliferation and stromal fibrosis are incompatible with the prevailing view of placental hypoxia in IUGR. Rather thickening of the basal lamina and congestion of the capillaries by erythrocytes are predicted to limit oxygen transfer from the intervillous space to the fetus and may represent an equilibration of oxygen tension between intervillous space and the terminal villi. Despite the known reduction in uteroplacental blood flow in IUGR, fetoplacental blood flow is compromised to a far greater extent in the presence of AEDFV such that maternal blood leaving the placenta has a higher oxygen content than under normal circumstances.

A comparative study of the glomerular peripolar cell and the renin-secreting cell in twelve mammalian species.

The peripolar cell is a glomerular epithelial cell situated within Bowman's capsule at its vascular pole. It is believed to be a secretory cell which forms part of the juxtaglomerular apparatus. Scanning electron microscopy was used to perform a comparative study of the morphology and number of peripolar cells in twelve mammalian species. The number of renin-secreting cells in kidney sections stained by renin antibodies and immunocytochemistry was counted. There was a marked inter-species variation in the number, size and appearance of peripolar cells. They were largest and most abundant in sheep and goat and fewest in dog, cow and human. There was no correlation between the numbers of peripolar cells and renin-secreting cells. This does not support the view that the peripolar cell is part of the juxtaglomerular apparatus.

Immune complex deposition in Bowman's capsule is associated with parietal podocytes.

We have recently documented the presence of podocytes lining part of Bowman's capsule at the vascular pole, in adult human kidney. In this study, we describe the deposition of immune complexes in Bowman's capsule in association with these parietal podocytes. We examined 1 year's consecutive human renal biopsies (n = 170). Transmission electron microscopy (TEM) revealed 18 cases in which parietal podocytes were present. Of these 18, there were 11 cases of glomerulonephritis, in which immune complexes were demonstrated in the capillary tuft by both TEM and direct immunofluorescence microscopy. In seven of these 11 cases, TEM showed immune complex-type deposits in Bowman's capsule, always associated with parietal podocytes. These deposits were similar in size, appearance, and distribution to the deposits in the capillary tuft. By contrast, non-specific electron densities within Bowman's capsule were found beneath both squamous parietal cells and parietal podocytes. In four cases, Bowman's capsule also showed focal positive immunostaining for complement components and/or fibrinogen. Both parietal and visceral podocytes showed similar fusion of pedicles. We suggest that filtration through parietal podocytes may be responsible for immune complex deposition and subsequent damage to the vascular pole of the glomerulus in human renal disease.

Crescentic glomerulonephritis: experience of a single unit over a five year period.

Crescentic glomerulonephritis is a well defined pathological lesion occurring in a range of renal and systemic diseases. We have retrospectively reviewed the aetiology, clinical features and outcome in 60 patients presenting over a five and a half year period. Most patients were elderly (median age 61 years, range 16-84 years). The majority presented with severe renal impairment, 32 requiring dialysis at admission. The degree of glomerular crescent formation on biopsy was closely related both to initial dialysis dependence and the ensuing response to immunosuppression. Forty-three patients received immunosuppressive treatment. A beneficial response was seen in 40% of patients requiring dialysis, and in 88% of those with less severe renal impairment. A high early mortality was apparent (30% within three months), exclusively affecting elderly patients (all > 60 years), with advanced renal failure (all dialysis dependent), the majority of whom (15 out of 18) had been immunosuppressed. The results suggest that the benefits of immunosuppression in this group may be outweighed by the complications of treatment.

Peripolar cells and other granulated epithelial cells in renal biopsies.

The peripolar cell is a recently described glomerular epithelial cell which is situated within Bowman's capsule at the vascular pole. It contains cytoplasmic granules which contain plasma proteins, although it may also have a secretory function. The relationship between peripolar cells, other granulated glomerular epithelial cells and tubular epithelial cells is unclear. We have studied 242 biopsies from 19 types of renal disease for peripolar cells, other granulated epithelial cells and granulated tubular epithelial cells. Peripolar cells were most numerous in mesangioproliferative glomerulonephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis and lupus nephropathy. Other granulated glomerular epithelial cells were most prominent in diffuse lupus nephropathy, focal glomerulonephritis, acute vascular transplant rejection, crescentic glomerulonephritis and mesangioproliferative glomerulonephritis. Granulation of the tubular epithelium was most prominent in minimal change nephrotic syndrome and amyloidosis. It is likely that the granules in tubular epithelial cells represent lysosomes containing plasma proteins which have been absorbed from the tubular fluid. However, granulation of glomerular cells may represent a more specific response to glomerular damage. In addition, peripolar cells are prominent in only certain diseases, suggesting a specialized function.

Non-granulated peripolar cells exist in the rat glomerulus.

The peripolar cell is a unique cell type in the mammalian glomerulus. Peripolar cells are said to be identifiable during light microscopy by their cytoplasmic granules and by their position at the vascular pole; and during scanning electron microscopy by their distinctive surface morphology. We used both techniques to count peripolar cells in 6 normal rat kidneys. Scanning microscopy revealed that 55(+/- 5)% of glomeruli contained at least one peripolar cell whereas light microscopy revealed granulated peripolar cells in only 4(+/- 2)% of glomeruli. Vascular poles which contained peripolar cells previously identified by scanning were then examined by light and by transmission electron microscopy. Serial sections through these peripolar cells demonstrated the absence of cytoplasmic granules. Our observations suggest that the majority of peripolar cells in the rat contain no granules.

The glomerular peripolar cell: a review.

There is now morphological evidence from several species that the peripolar cell is a distinctive glomerular cell which may have a secretory function, although a secretory product has not been identified. Peripolar cells, like other glomerular epithelial cells, probably absorb plasma proteins from the glomerular filtrate. Peripolar cells may participate in regulation of sodium balance and the changes in renal function which occur at the time of birth. They are ideally situated to monitor the composition of the glomerular filtrate and/or the calibre of the glomerular arterioles. The relationship between peripolar cells and other granulated glomerular epithelial cells must be clarified, however their morphology and unique anatomical site is suggestive of a specialised function.

The muscle findings in the neuroleptic malignant syndrome associated with lysergic acid diethylamide.

A detailed pathological description of the muscle findings in a case of the neuroleptic malignant syndrome (NMS) following ingestion of lysergic acid diethylamide (LSD) is given, including the first ultrastructural analysis. Focal necrosis, oedema, and hypercontraction of fibres with glycogen and lipid depletion, were identified, all of which had resolved completely a year later. The findings are compared with those in malignant hyperthermia. It is suggested that the results support the view that in NMS, the muscle rigidity is due to central mechanisms and, in both this disorder and malignant hyperthermia, it is responsible for the hyperpyrexia and its life-threatening complications.

The effect of conversion from cyclosporin to azathioprine on renin-containing cells in renal allograft biopsies.

Renal biopsies were examined from 17 renal transplant recipients before and after conversion from cyclosporin to azathioprine, and in 17 patients who remained on cyclosporin. All patients had stable renal function. We used an immunoperoxidase technique with an antiserum to human renin to identify renin-containing cells. We demonstrated hyperplasia of renin-containing cells in patients treated with cyclosporin. Numbers of renin-containing cells decreased after conversion to azathioprine. We suggest that local activation of the intrarenal renin-angiotensin system could mediate the effects of cyclosporin on renal haemodynamics. This could play a role in the pathogenesis of cyclosporin nephrotoxicity and cyclosporin hypertension.

Mitochondrial abnormalities in the postviral fatigue syndrome.

We have examined the muscle biopsies of 50 patients who had postviral fatigue syndrome (PFS) for from 1 to 17 years. We found mild to severe atrophy of type II fibres in 39 biopsies, with a mild to moderate excess of lipid. On ultrastructural examination, 35 of these specimens showed branching and fusion of mitochondrial cristae. Mitochondrial degeneration was obvious in 40 of the biopsies with swelling, vacuolation, myelin figures and secondary lysosomes. These abnormalities were in obvious contrast to control biopsies, where even mild changes were rarely detected. The findings described here provide the first evidence that PFS may be due to a mitochondrial disorder precipitated by a virus infection.