Structural changes in human tear lipocalins associated with lipid binding.

Structural and conformational changes in tear lipocalins were detected in association with ligand binding and release. Circular dichroism measurements demonstrated that ligand binding induces beta structure formation, aromatic side chain asymmetry, and a more rigid state in tear lipocalins (TL). The exposure of the tyrosyl component is less in apo-TL than in holo-TL. The sole tryptophan residue, Trp17, is buried in both holo- and apo-TL. The steady state exposure of Trp17 is the same in holo- and apo-TL, but the dynamic exposure is two-fold greater in apo-TL. Maneuvers to unfold the protein with urea or incubation in an acidic environment resulted in increased exposure of aromatic amino acids. Electron paramagnetic resonance studies verified that lipids are liberated from TL in an acidic environment. Acidic pH promotes conformational changes in TL involving aromatic residues, particularly the conserved residue Trp17. These changes are associated with lipid release. The liberation of lipid from the cavity of TL under acidic conditions involves a molten globule state of the protein. We postulate that TL, exposed to the steep surface pH gradient that exists at lipid-aqueous interfaces, would release lipid in association with a molten globule transition. The data suggest a plausible regulatory mechanism for lipid delivery from lipocalins at the tear film surface.

Binding studies of tear lipocalin: the role of the conserved tryptophan in maintaining structure, stability and ligand affinity.

The principal lipid binding protein in tears, tear lipocalin (TL), binds acid and the fluorescent fatty acid analogs, DAUDA and 16-AP at one site TL compete for this binding site. A fluorescent competitive binding assay revealed that apo-TL has a high affinity for phospholipids and stearic acid (Ki) of 1.2 microM and 1.3 microM, respectively, and much less affinity for cholesterol (Ki) of 15.9 of the hydrocarbon chain. TL binds most strongly the least soluble lipids permitting these lipids to exceed their maximum solubility in aqueous solution. These data implicate TL in solubilizing and transporting lipids in the tear film. Phenylalanine, tyrosine and cysteine+ were substituted for TRP 17, the only invariant residue throughout the lipocalin superfamily. Cysteine substitution resulted in some loss os secondary structure, relaxation of aromatic side chain rigidity, decreased binding affinity for DAUDA and destabilization of structure. Mutants of TL, W17Y, and W17F showed a higher binding affinity for DAUDA than wild-type TL. Comparison of the results of the tryptophan 17 substitution in lipocalin with those of tryptophan 19 substitution in beta-lactoglobulin revealed important differences in binding characteristics that reflect the functional heterogeneity within the lipocalin family.

Resolution of ligand positions by site-directed tryptophan fluorescence in tear lipocalin.

The lipocalin superfamily of proteins functions in the binding and transport of a variety of important hydrophobic molecules. Tear lipocalin is a promiscuous lipid binding member of the family and serves as a paradigm to study the molecular determinants of ligand binding. Conserved regions in the lipocalins, such as the G strand and the F-G loop, may play an important role in ligand binding and delivery. We studied structural changes in the G strand of holo- and apo-tear lipocalin using spectroscopic methods including circular dichroism analysis and site-directed tryptophan fluorescence. Apo-tear lipocalin shows the same general structural characteristics as holo-tear lipocalin including alternating periodicity of a beta-strand, orientation of amino acid residues 105, 103, 101, and 99 facing the cavity, and progressive depth in the cavity from residues 105 to 99. For amino acid residues facing the internal aspect of cavity, the presence of a ligand is associated with blue shifted spectra. The collisional rate constants indicate that these residues are not less exposed to solvent in holo-tear lipocalin than in apo-tear lipocalin. Rather the spectral blue shifts may be accounted for by a ligand induced rigidity in holo-TL. Amino acid residues 94 and 95 are consistent with positions in the F-G loop and show greater exposure to solvent in the holo- than the apo-proteins. These findings are consistent with the general hypothesis that the F-G loop in the holo-proteins of the lipocalin family is available for receptor interactions and delivery of ligands to specific targets. Site-directed tryptophan fluorescence was used in combination with a nitroxide spin labeled fatty acid analog to elucidate dynamic ligand interactions with specific amino acid residues. Collisional quenching constants of the nitroxide spin label provide evidence that at least three amino acids of the G strand residues interact with the ligand. Stern-Volmer plots are inconsistent with a ligand that is held in a static position in the calyx, but rather suggest that the ligand is in motion. The combination of site-directed tryptophan fluorescence with quenching by nitroxide labeled species has broad applicability in probing specific interactions in the solution structure of proteins and provides dynamic information that is not attainable by X-ray crystallography.

Lipophilin, a novel heterodimeric protein of human tears.

We identified a novel heterodimeric protein, lipophilin AC, in human tears. One of its components, lipophilin A (69 residues; mass, 7575.1; pI, 9.47) was homologous to the C1 and C2 components of prostatein ('estramustine-binding protein'), the major secreted protein of rat prostate. Human lipophilin C (77 residues; mass, 8854.1; pI, 4.94) was homologous to the rat prostatein C3 component and to human mammaglobin, a protein overexpressed in some mammary carcinomas. Tear lipophilins A and C expand the roster of human uteroglobin superfamily members and provide models for exploring these typically steroid-regulated and steroid-binding molecules.

Nonvascular contractile cells in sclera and choroid of humans and monkeys.

PURPOSE: To investigate by histochemistry and immunohistochemistry the distribution and innervation of nonvascular contractile cells in the sclera and choroid of humans and monkeys. METHODS: Globes were obtained from 2 macaque monkeys and 19 human cadavers that ranged in age from fetal life to 94 years. Immunohistochemistry was performed using monoclonal antibody against human smooth muscle (SM) alpha-actin and tyrosine hydroxylase (TH). The nicotinamide-adenine dinucleotide phosphate (NADPH)- diaphorase reaction was used as a marker for nitric oxide synthase. RESULTS: The scleras of all but fetal, newborn, and infant globes exhibited myofibroblasts, amelanotic, fibroblastlike cells having SM alpha-actin immunoreactivity. In the choroid of all but fetal eyes, SM cells were present in the suprachoroidal layer, forming a reticulum of flattened laminae, and in the choriocapillaris where ovoid-to-spindle-shaped SM cells were arrayed in parallel layers immediately adjacent to Bruch's membrane. Contractile cells in the sclera and choroid were most concentrated subfoveally and were sparse anteriorly. Nerve terminals positive for NADPH- diaphorase were colocalized with SM alpha-actin-positive cells in the sclera and choroid, whereas TH-positive nerve terminals colocalized with SM cells in the choroid. Clusters of ganglion cells were present on the posterior surface of globes near SM cells. CONCLUSIONS: The posterior choroid and sclera of humans and monkeys contain nonvascular contractile cells. The presence of nerve terminals and adjacent ganglion cells suggests neural control of these contractile cells. The absence of such contractile cells in fetal, newborn, and infant eyes is an argument against a major role of these cells in promoting ocular enlargement. These contractile cells may instead participate in regulation of refractive state by maintenance of ocular size in the face of intraocular pressure or in intermediate-term regulation of choroidal thickness.

GLUT1 glucose transporter expression in the diabetic and nondiabetic human eye.

PURPOSE: The GLUT1 glucose transporter is expressed in endothelial and epithelial barriers, including the retinal capillary endothelium and the retinal pigment epithelium (RPE) of the eye. The present studies were undertaken to determine whether GLUT1 is expressed in additional cell types within the human eye and whether retinal endothelial GLUT1 is aberrantly expressed in diabetic proliferative retinopathy in humans. METHODS: Immunohistochemical staining of sections of human eyes obtained at surgery or autopsy from patients with and without diabetes was performed with polyclonal antisera directed against the human GLUT1 glucose transporter. RESULTS: In the course of this study, an unexpected multicellular localization of GLUT1 in different cellular barriers of the human eye was observed. In the nondiabetic eye, specific staining for GLUT1 was seen in the nerve fiber layer, the ganglion and photoreceptor cell bodies, the capillaries and the RPE of the retina, the basal infoldings of the pigmented and nonpigmented layers of the ciliary body, the capillary endothelium and posterior epithelium of the iris, the corneal epithelium and endothelium, and the endothelium lining of the canal of Schlemm. Müller cells, a type of retinal glial cell identified by morphology and by parallel staining for glial fibrillary acidic protein, also stained intensely positive for GLUT1. The pattern of GLUT1 immunoreactivity in the diabetic eyes was virtually identical to that in the nondiabetic specimens, with the notable exception that the neovascular endothelium of proliferative retinopathy did not stain for GLUT1. CONCLUSIONS: These studies describe the heretofore unrecognized expression of immunoreactive GLUT1 in the ganglion cell layer of the retina, the endothelium lining the canal of Schlemm, the corneal endothelium, and the basal cells of the corneal epithelium of the human eye. The present study also provides evidence for immunoreactive GLUT1 in glial cells of the central nervous system. Because the expression of GLUT1 is characteristic of tissues that possess a barrier function, the absence of GLUT1 immunoreactivity in the neovascular tissue of proliferative diabetic retinopathy suggests that the loss of selective permeability is associated with an absence of facilitated glucose transport in this disorder.

The use of bioerodible polymers and 5-fluorouracil in glaucoma filtration surgery.

A study was performed to examine the effect of a localized and sustained delivery of 5-fluorouracil (5-FU) on the success of glaucoma filtration surgery in 18 rabbits in a prospective, randomized, double-masked and placebo-controlled fashion. A bioerodible polyanhydride composed of bis (p-carboxyphenoxy) propane and sebacic acid was used as the drug carrier. The polymer and 5-FU (20% by weight) were compressed into 3 mm diameter discs, 1 mm thick. The polymer with the 5-FU was randomized to one eye and the fellow eye received the blank polymer. The results showed that intraocular pressures (IOP) were lower in the experimental eyes during the 5th through 17th postoperative days, but eventually both experimental and control eyes returned to preoperative levels. Filtration blebs lasted longer in experimental eyes when compared to control eyes. Implant disappearance occurred after IOP elevations and bleb failure. Eventually, the filtration surgery failed in both the experimental and control rabbit eyes.

Immune response to Staphylococcus aureus endophthalmitis in a rabbit model.

Staphylococcus aureus is an important cause of severe bacterial endophthalmitis. Both immunoglobulin (Ig) G and A antibody titers to ribitol teichoic acid (RTA), the major antigenic determinant of the S. aureus cell wall, were measured by an enzyme-linked immunosorbent assay in serum, tears, aqueous, and vitreous on days 3, 7, 10, 14, 21, and 30 after intravitreal injection of viable S. aureus in rabbits. Clinical examination showed vitreous opacification in all rabbits from days 7-30. Histopathologic examination showed acute inflammation on day 3 and chronic inflammation on days 7-30 in the conjunctiva, cornea, iris, ciliary body, and trabecular meshwork. The vitreous cavity contained neutrophils and necrotic cells on all days. Retinal necrosis was present on days 14-30. Lymphoid follicles with plasma cells were identified in the conjunctiva, ciliary body, and choroid. The vitreous of experimental eyes showed increasing numbers of bacteria from days 3-14, followed by a decrease in numbers on day 21 and absence of viable bacteria on day 30. Increases in IgG antibody levels to RTA were first detected in serum where they were higher than in tears, aqueous, and vitreous until day 14. Vitreous IgG antibody levels to RTA in experimental eyes exceeded all other samples on day 14 and progressively increased thereafter; the other samples declined. The IgA antibody levels were increased in tears on day 14 and in the vitreous of experimental eyes on days 14, 21, and 30. Vitreous IgG antibody levels to RTA were substantially higher than vitreous IgA antibody levels. An inverse correlation was found between vitreous IgG antibody levels and positive vitreous cultures, suggesting that the humoral immune response may be important in the spontaneous sterilization of the vitreous in this model.

Evidence for fibromuscular pulleys of the recti extraocular muscles.

PURPOSE: Magnetic resonance imaging (MRI) shows that the paths of recti extraocular muscle (EOM) bellies remain fixed in the orbit during large ocular rotations and across large surgical transpositions of their insertions. These findings imply that recti EOMs pass through pulleys coupled to the orbit and anterior to the muscle bellies, because the insertions must move with the globe. The present study was conducted to locate anatomically and to characterize histologically the pulley tissues. METHODS: High-resolution MRI images were collected from volunteers, using multiple gaze directions to infer the locations of, and occasionally to visualize, recti EOM pulleys. Fresh cadaver orbits were exenterated and dissected to evaluate mechanical and structural properties of the orbital connective tissues. Lipid was cleared from whole specimens to reveal tissue relationships. Other specimens were selectively step- and serial-sectioned for histochemical and immunohistochemical staining. RESULTS: Magnetic resonance imaging demonstrated dense connective tissue structures within posterior Tenon's fascia near the equator of the globe adjacent to the recti EOMs. Histochemistry showed these structures to be pulleys--fibroelastic EOM sleeves consisting of dense bands of collagen and elastin, suspended from the orbit and adjacent EOM sleeves by bands of similar composition. A monoclonal antibody to human smooth muscle alpha-actin demonstrated substantial smooth muscle in the pulley suspensions and in posterior Tenon's fascia. Tenon's fascia itself was seen to be suspended at its periphery from the orbital walls like a drumhead. CONCLUSIONS: The human orbit contains specialized musculofibroelastic tissues in and just posterior to Tenon's fascia that serve as compliant pulleys and determine the pulling directions of recti EOMs. In this sense, the pulleys are the functional origins of the recti EOMs and are determinants of ocular motility.

Necrotizing retinopathy after intraocular inoculation of murine cytomegalovirus in immunosuppressed adult mice.

A light microscopic study was done to investigate retinal changes in healthy and immunosuppressed mice after intraocular inoculation of murine cytomegalovirus (MCMV). A 0.01-ml inoculum containing 10(5) plaque-forming units of MCMV was placed behind the lens in 138 4-week-old Swiss Webster mice. Ninety-eight mice were immunosuppressed with 0.2 mg/g of cyclophosphamide given intraperitoneally at the time of inoculation and 0.1 mg/g of cyclophosphamide every 5 days thereafter. Selected eyes were examined on postinoculation days 5, 10, 15, and 16-20. Evidence of viral infection was most prominent in uveal tissue. Uveal infection developed whether or not animals received cyclophosphamide, but retinal necrosis developed only in immunosuppressed mice. Focal retinal necrosis, primarily involving the outer retinal layers and retinal pigment epithelium, was first observed in an eye examined on day 10. Retinopathy from MCMV was present in three of five eyes (60%) examined on day 15, and in six of 16 eyes (37.5%) examined between days 16-20. Retinal disease was characterized by full-thickness retinal necrosis, scattered cytomegalic cells, intranuclear and intracytoplasmic viral inclusions, and acute and chronic inflammation. These results indicate that MCMV can produce a necrotizing retinopathy in mice and that immunosuppression facilitates infection. Although ocular MCMV infection in immunosuppressed adult mice is a potential model for study of human CMV retinopathy, many differences exist between human CMV and MCMV and between the ocular diseases they produce.

Immune response to Staphylococcus epidermidis-induced endophthalmitis in a rabbit model.

Although Staphylococcus epidermidis is the most common cause of postoperative pseudophakic endophthalmitis, little is known about the immune response to S. epidermidis-induced endophthalmitis. Using a rabbit model, the immune response to an intravitreal injection of 7000 S. epidermidis (group 1) or 30,000 S. epidermidis (group 2) organisms was investigated. Clinical evaluations showed that rabbits in group 2 had a more severe inflammatory reaction in the conjunctiva, cornea, iris, and vitreous than those in group 1. The inflammatory reaction in group 1 largely resolved by day 30; group 2 continued to show a severe inflammatory response. Histopathologic findings correlated with clinical findings, with rabbits in group 2 showing a more severe inflammatory reaction in both the anterior and posterior segments of the globe. Positive vitreous cultures for S. epidermidis were present in rabbits in group 1 on days 3, 7, 10, 14, and 21 but not thereafter. However, group 2 had higher vitreous colony counts at days 3, 7, and 14 and negative vitreous cultures thereafter. Neither group showed delayed hypersensitivity to S. epidermidis antigens (evaluated by skin tests). Serum immunoglobulin (Ig) G antibody levels to phenol-inactivated S. epidermidis and glycerol teichoic acid (GTA) increased progressively, reached a peak at days 10-14, and then declined in both groups. Serum IgA antibody levels to these antigens were not detected. Group 2 had a more prolonged IgG antibody response in vitreous and aqueous than group 1. Tear fluid showed the weakest IgG and IgA antibody response to S. epidermidis and GTA. S. epidermidis-induced endophthalmitis was associated with a humoral but not a delayed hypersensitivity response to this organism.

Complement system and host defense against staphylococcal endophthalmitis.

PURPOSE: The authors studied the role of the complement system in host defense against Staphylococcus epidermidis and S. aureus endophthalmitis. METHODS: Guinea pigs in the S. epidermidis model received an intravitreal injection of 7000 viable organisms, and guinea pigs in the S. aureus model received 50 viable organisms. The experimental animals in each model were decomplemented with intraperitoneal (IP) injections of cobra venom factor, whereas the control animals received IP injections of normal saline. Mean log bacterial counts in the vitreous and mean serum complement titers were compared in the experimental and control animals in each model on days 1, 2, 3, and 7. RESULTS: In the S. epidermidis model, mean log bacterial counts in the vitreous were significantly higher in the experimental group than the control group on days 1 and 2 (P < 0.01) and on day 3 (P < 0.05). Mean serum complement titers were significantly lower in the experimental group at all days (P < 0.01). In the S. aureus model, mean log bacterial counts in the vitreous were significantly higher in the experimental group than the control group on day 2 (P < 0.05) and day 3 (P < 0.01). Mean serum complement titers were significantly lower in the experimental group on days 1, 2, and 3 (P < 0.01), but not on day 7. CONCLUSION: These results suggest that decomplemented guinea pigs show impaired host defense to S. epidermidis and S. aureus endophthalmitis and that this defense is restored as complement levels approach normal.

Immunopathologic features of Staphylococcus aureus endophthalmitis in the rat.

PURPOSE: To study the clinical, histopathologic, and immunologic responses to Staphylococcus aureus endophthalmitis in rats. METHODS: Experimental Lewis rats received an intravitreal injection of viable S. aureus (65 organisms), and control rats received sterile saline. The clinical scores, cellular infiltrate, delayed hypersensitivity reaction in skin tests, and serum and vitreous enzyme-linked immunosorbent assay titers of immunoglobulin (Ig) M, IgG, and IgA to ribitol teichoic acid (RTA), the major antigenic determinant of S. aureus cell wall, were measured and compared on days 3, 7, 10, 14, 21, and 30. The differences were statistically assessed using Mann-Whitney nonparametric t-tests and analysis of variance. RESULTS: The red reflex was abolished in the majority of rats between days 3 and 21. Ocular inflammation resolved by day 30. The vitreous of eyes injected with S. aureus showed bacterial growth on days 3 and 7, followed by a decrease in numbers on days 10 and 14 and disappearance on days 21 and 30. In the vitreous, a peak neutrophil count was observed at day 3 that rapidly declined by day 7. The number of lymphocytes and plasma cells peaked on day 3 but declined more slowly. Plasma cells and Mott cells were seen on days 10 and 14, suggesting intraocular antibody production. IgM titers to RTA increased progressively in serum and vitreous, reached a peak on day 21, and declined on day 30. A weak IgG but absent IgA response to RTA was observed in serum and vitreous. S. aureus endophthalmitis was not associated with delayed hypersensitivity to the bacteria in skin tests. CONCLUSIONS: S. aureus endophthalmitis is associated with the infiltration of neutrophils, lymphocytes, monocytes, and plasma cells in vitreous. Neutrophils, the predominant infiltrating cells, may be involved in bactericidal activity and opsonophagocytosis. In rat staphylococcal endophthalmitis, IgM rather than IgG may be the protective antibody.

Tear lipocalins: potential lipid scavengers for the corneal surface.

PURPOSE: To investigate the dynamic effect of tear lipocalins (TLs), the major lipid-binding protein in tears, at aqueous-cornea and lipid-aqueous interfaces, and their potential contribution to surface tension in the tear film. METHODS: Human apo- and holo-TLs were applied to the aqueous subphase in a Langmuir trough, and changes in surface pressure were measured. Changes in the contact angle of tear components were observed on Teflon and ferric-stearate-treated surfaces. A nitroxide-labeled derivative of lauric acid and a fluorescence-labeled derivative of palmitic acid were used to monitor the dynamic interaction of lipid removed from a hydrophobic surface by the major tear components in solution. RESULTS: TLs increase the surface pressure at the aqueous-air interface by penetrating, spreading, and rearranging on the surface. Apo-TLs show a longer diffusion-dependent induction time than holo-TLs due to more extensive oligomerization of the apoprotein. Kinetic analysis of relaxation time suggests that apo-TLs have more rapid surface penetration and rearrangement than holo-TLs, indicative of a more flexible structure in apo-TLs. TLs reduce the contact angle of solutions on lipid films, a property that is greater with TLs than other tear proteins. TLs, unlike lysozyme and lactoferrin, remove labeled lipids from hydrophobic surfaces and deliver them into solution. CONCLUSIONS: TLs are potent lipid-binding proteins that increase the surface pressure of aqueous solutions while scavenging lipids from hydrophobic surfaces and delivering them to the aqueous phase of tears. These data suggest important functional roles for TLs in maintaining the integrity of the tear film.

Bacterial endophthalmitis following sutureless cataract surgery.

We examined a patient who developed group G streptococcal endophthalmitis following phacoemulsification with intraocular lens implantation and sutureless wound closure. Pathologic examination of the enucleated globe 1 month after surgery revealed an intense suppurative reaction centered in the anterior chamber and an open surgical wound filled with fibrinopurulent granulation tissue. Inadequate draping, a high number of instruments passing into and out of the eye during surgery, and wound testing for water tightness with viscoelastic substance in the eye were observed on a videotape of the surgery.

Bilateral endogenous Fusarium endophthalmitis associated with acquired immunodeficiency syndrome.

A 51-year-old man with acquired immunodeficiency syndrome and cytomegalovirus retinitis had bilateral endogenous fungal endophthalmitis. Cultures yielded Fusarium species. Histopathologic examination showed a severe necrotizing acute and granulomatous reaction, with numerous fungal elements in the retina and uveal tract. Fungal elements were seen in the lens, sclera, and emissarial vessels. Angiopathic infiltration by fungus and widespread thrombosis produced retinal and choroidal infarction. In some areas, fungal infection coexisted with cytomegalovirus retinitis. The bilateral distribution suggests hematogenous seeding of the eyes. The eye findings were the first clinically apparent manifestations of fungal disease in this patient.

Ocular involvement in patients with posttransplant lymphoproliferative disorder.

OBJECTIVES: To describe ocular disease in 3 patients with posttransplant lymphoproliferative disorder (PTLD) and to identify the frequency of such ocular involvement. METHODS: Medical record reviews. Using Kaplan-Meier analysis, we calculated the frequency of ocular involvement among pediatric patients with systemic PTLD after liver transplantation. RESULTS: Each patient had bilateral anterior chamber cells. Biopsy of an iris nodule from a patient who had undergone cardiac transplantation confirmed the diagnosis of PTLD, but no signs of systemic PTLD were found. The other 2 patients had systemic PTLD after liver transplantation; 1 presented with iris nodules in both eyes and a subretinal mass in the left eye, while the other had bilateral anterior chamber cells only. Ocular signs improved slowly after reduction of immunosuppressive drug therapy. Ophthalmological examinations were performed on 22 of 25 pediatric patients with PTLD after liver transplantation; 2 had ocular disease. Kaplan-Meier analysis indicated a 20% risk of ocular involvement at 3 years after development of PTLD (95% confidence intervals, 0%-50%). CONCLUSIONS: Posttransplant lymphoproliferative disorder should be considered in the differential diagnosis of uveitis after organ transplantation. Anterior chamber cells and iris nodules are the most common ocular signs, but the posterior segment can be involved. Ocular involvement can occur without evidence of systemic disease and can be asymptomatic. Reduction of immunosuppressive drug therapy is an appropriate treatment.

Adrenal pathology in the acquired immune deficiency syndrome.

Adrenal pathology was examined in 41 autopsied patients with the acquired immune deficiency syndrome. This represents the largest series and the first study with quantitation of adrenal cortical necrosis. In 32 cases clinical data were analyzed for features of adrenal insufficiency. Common clinical findings included vomiting, diarrhea, fever, hypotension, and hyponatremia. None of the 32 patients showed characteristic skin hyperpigmentation. Two patients were suspected premortem to have adrenal insufficiency. In one of these patients, adrenocorticotrophic hormone (ACTH) stimulation resulted in an adequate rise in plasma cortisol values. In the other patient, the baseline plasma cortisol value was elevated and failed to rise significantly after ACTH stimulation. Pathologic findings included widespread lipid depletion, infection by cryptococcus, and acid-fast organisms consistent with Mycobacterium avium-intracellulare, involvement by Kaposi's sarcoma, and necrotizing adrenalitis due to cytomegalovirus (CMV). A point-counting method was used to quantitate adrenal cortical and medullary necrosis. Necrosis due to CMV was greater in the medulla than the cortex. The maximum amount of adrenal cortical necrosis in any case was 70%. The degree of cortical necrosis was less than that usually associated with adrenal insufficiency.

Clinical and pathologic findings of the liver in the acquired immune deficiency syndrome (AIDS).

Clinical data and histologic sections of the liver, including immunohistochemical studies for hepatitis B surface and core antigens, were reviewed in 42 autopsy cases of the acquired immune deficiency syndrome (AIDS). Hepatomegaly, elevation of serum transaminases, and mild elevation of alkaline phosphatase were commonly observed clinical and biochemical abnormalities. Mildly elevated alkaline phosphatase and normal bilirubin levels were present in patients with Mycobacterium avium-intracellulare (MAI) infection, cytomegalovirus (CMV) infection, and Kaposi's sarcoma (KS). Histologic sections demonstrated liver involvement by MAI in eight cases; KS in six cases; cryptococcus in three cases; and CMV in two cases. One case of MAI infection was associated with marked central vein sclerosis, a finding previously unreported. Thirty-two (76%) of 42 cases had serologic or pathologic evidence of hepatitis exposure. Two patients had histologic evidence of chronic active hepatitis. The pathologic processes involving the liver appeared to be secondary to the infections and neoplasms for which this population is susceptible and did not significantly contribute to morbidity or mortality. No findings specific or pathognomic for AIDS were identified in the liver.

Secretory lipophilins: a tale of two species.

Secretory lipophilins are "lipid-loving" proteins that are major constituents of several mammalian secretions, including the prostatic fluid of rats and the tears of humans and rabbits. These proteins form covalent heterodimers that are stabilized by three intramolecular cystine disulfide bonds. The heterodimers, some of which are glycosylated, may undergo additional non-covalent assembly to form tetramers. The peptide components found in secretory lipophilins are from two subfamilies: lipophilins A/B and lipophilin C. The C subfamily members described in this report are three rabbit and one human lipophilin, plus human mammaglobin and the C3 subunit of rat prostatein. Human A/B and C lipophilins are expressed by many tissues and are especially prominent in endocrine-responsive organs. The gene for human lipophilin B resides at chromosome 10q22-23. This region harbors the PTEN/MMAC1 gene and is believed to contain additional tumor suppressor genes. Although the functions of secretory lipophilins are imperfectly understood, their abundance in glandular secretions and in hormone-responsive tissues suggests that they deserve considerably more attention than they have received to date.