[Meibomian glands : part IV. Functional interactions in the pathogenesis of meibomian gland dysfunction (MGD)]. / Meibom-Drüsen : Teil IV: Funktionelle Interaktionen in der Pathogenese der Dysfunktion (MGD).

Obstructive dysfunction of the meibomian glands (MGD) is surprisingly frequent in the general population and increases with age. Clinically, the focus is mainly on the consequences at the ocular surface in the sense of an evaporative dry eye syndrome. However, in addition, chronic obstruction of the meibomian glands also leads to degeneration of the secretory gland tissue which can result in a secondary hyposecretion even if the primary obstruction is later resolved by therapeutic approaches.Important influencing factors in the pathogenesis of obstructive MGDs and their interaction during the progression of the disease are systematically analyzed and displayed in a flow diagram. Age, hormonal disturbances and environmental influences, such as contact lenses, as well as qualitative alterations in the composition of the meibomian oil (meibum) lead to hyperkeratinization of the ductal epithelium and increased viscosity of the meibum which result, either alone or in combination, in obstruction of the duct and orifice. This leads to a lack of meibum on the lid margin and tear film with downstream hyperevaporative dry eye syndrome. At the same time, obstruction leads to a stasis of meibum inside the meibomian gland with increased pressure and resulting dilatation of the ducts and in atrophy of the acini with rarefaction of the secretory meibocytes and gland dropout. Stasis can also increase the growth of commensal bacteria, their production of oil degrading enzymes (lipases) and release of toxic mediators. These factors can, in return, act as self-enforcing feedback loops in the sense of vicious circles that aggravate the primary hyperkeratinization and compositional disturbance of meibum and can hence lead to a progressive MGD.

[Meibomian glands : part III. Dysfunction - argument for a discrete disease entity and as an important cause of dry eye]. / Meibom-Drüsen : Teil III: Dysfunktion (MGD) - Plädoyer für ein eigenständiges Krankheitsbild und wichtige Ursache für das trockene Auge.

Meibomian gland dysfunction (MGD), mainly synonymous with posterior blepharitis but typically without prominent inflammatory alterations of the lid margin, is a discrete disease entity and a frequent cause of wetting deficiencies of the ocular surface leading to dry eye disease that deserves increased recognition by clinicians. The history, classification, pathology, influencing factors, diagnostics and therapy are explained and discussed. MGD is mainly based on an obstructive mechanism caused by hyperkeratinization of the excretory duct and/or increased viscosity of the secretion (meibum) with subsequent deficiency of the tear film lipid layer. MGD is influenced by the hormonal status and by chemical and mechanical noxes as well as genetic defects and it occurs more frequently in women and generally increases with age. It results in stasis of meibum inside the glands, dilatation of the ductal system and eventually in atrophy and loss of glandular tissue (gland dropout). Careful investigation of the eyelids and lid margins with eversion, if necessary, should therefore be performed in every case of a wetting defect, notably before fitting contact lenses. Particularly important is the inspection of the meibomian orifices and diagnostic expression by mild mechanical compression of the lid.

[Sex hormones and dry eye]. / Sexualhormone und trockenes Auge.

Among ophthalmic diseases dry eye in its various forms, represents an entity with one of the highest prevalences and at the same time the lowest chance for causal therapy. Since some years there is growing evidence that sex hormones play a key role in the formation and course of the disease and thus provide potentially promising approaches for therapy. The objective of this article is to briefly outline current scientific knowledge on the relationship between androgens, estrogens,and progesterones on the one hand and the lacrimal gland and Meibomian glands respectively.

[Meibomian glands. Part I: anatomy, embryology and histology of the Meibomian glands]. / Meibom-Drüsen. Teil I: Anatomie, Embryologie und Histologie der Meibom-Drüsen.

The Meibomian glands are large sebaceous glands that are located as separate gland strands in parallel arrangement within the tarsal plates of the eyelids. Their oily product (meibum) is secreted by a holocrine mechanism during which the secretory cells (meibocytes) are completely transformed into the meibum after synthesis and accumulation of lipids. After production in the gland acini, meibum is transported through the ductal system via the connecting duct (ductule) and the central duct towards the orifice at the free lid margin close to the inner lid border. The embryological development of the Meibomian glands takes place during the differentiation of the eyelids in the sealing phase of the eyelids. They are not directly associated with hair follicles but share important similarities in embryology, structure and keratinization potency with the cilia. Similar to the sebaceous glands Meibomian glands are regulated via sex hormones and androgens have a supporting function whereas estrogens act antagonistically. However, in contrast to other sebaceous glands they also have a distinct innervation, apart from sympathetic and sensory primarily by parasympathetic fibers that share the innervation pattern of the lacrimal glands. The anatomy, embryology and histology of the Meibomian glands are explained here, mainly with respect to humans, in an extensive review.

[Meibomian glands. Part II: physiology, characteristics, distribution and function of meibomian oil]. / Meibom-Drüsen. Teil II: Physiologie, Eigenschaften, Verteilung und Funktion des Meibom-Ols.

The oily secretion (meibum) of the Meibomian glands forms the superficial layer of the pre-ocular tear film and reduces evaporation of the aqueous phase. Meibum is a complex mixture of various lipids and minor protein components as well as other components of the secretory meibocytes, which form a clear liquid at body temperature. The exact composition and functions of meibum are still partly unknown, in particular the interaction of the water insoluble non-polar lipids with the polar, partly water soluble, lipids and potentially with proteins, which altogether interact to maintain the connection with the underlying aqueous tear phase. Meibum is transported within the gland by the force of secretory pressure from continuous secretion and by muscular action of the orbicularis muscle and Riolans muscles during blinking. After delivery of meibum onto the posterior lid margin the oil moves from the posterior lid margin reservoir onto the tear meniscus and is pulled as a thin layer onto the pre-ocular tear film every time the lid opens. During lid closure it is compressed and a small part is continuously renewed. Meibum also has a barrier function against the spillage of tears over the inner border of the lid and against the entry of skin lipids (sebum) from the free lid margin.

[Eye-associated lymphoid tissue (EALT) is continuously spread throughout the ocular surface from the lacrimal gland to the lacrimal drainage system]. / Augen-assoziiertes lymphatisches Gewebe (EALT) durchzieht die Augenoberfläche kontinuierlich von der Tränendrüse bis in die ableitenden Tränenwege.

INTRODUCTION: Components of the mucosal immune system (MALT) have been identified in the conjunctiva (as CALT) and the lacrimal drainage system (as LDALT). Their structural and functional relation with the established immune protection by the lacrimal gland is unclear. MATERIAL AND METHODS: Macroscopically normal and complete tissues of the conjunctiva, lacrimal drainage system and lacrimal gland from human body donors were investigated by analysis of translucent whole mounts, and using histology, immunohistology as well as scanning and transmission electron microscopy. RESULTS: A typical diffuse lymphoid tissue, composed of effector cells of the immune system (T-lymphocytes and IgA producing plasma cells) under an epithelium that contains the IgA transporter SC, is not isolated in the conjunctiva and lacrimal drainage system. It is anatomically continuous from the lacrimal gland along its excretory ducts into the conjunctiva and from there via the lacrimal canaliculi into the lacrimal drainage system. Lymphoid follicles occur in a majority (about 60%) and with bilateral symmetry. The topography of CALT corresponds to the position of the cornea in the closed eye. CONCLUSION: These results show that the MALT of the lacrimal gland, conjunctiva and lacrimal drainage system constitute an anatomical and functional unit for immune protection of the ocular surface. Therefore it should be integrated as an "eye-associated lymphoid tissue" (EALT) into the MALT system of the body. EALT can detect ocular surface antigens by the lymphoid follicles and can supply other organs and the ocular surface including the lacrimal gland with specific effector cells via the regulated recirculation of lymphoid cells.

[Dry eye disease as a complex dysregulation of the functional anatomy of the ocular surface. New concepts for understanding dry eye disease]. / Das trockene Auge als komplexe Fehlregulation der funktionellen Anatomie der Augenoberfläche. Neue Impulse zum Verständnis des trockenen Auges.

INTRODUCTION: Dry eye disease is a disorder of the tear film that results in epithelial damage and in a disruption of the normal homeostasis at the ocular surface. It is widespread and causes symptoms ranging from discomfort to blindness. METHODS: A review of the existing literature was used to compare different past and recent concepts for the understanding of dry eye disease with a focus on aspects of the integrating functional anatomy of the ocular surface. RESULTS: The understanding of the pathogenesis of dry eye disease has proceeded from the mere recognition of a lack of tears to a consideration of their quality and to the concept of wetting of the ocular surface. However, several other aspects as epithelial differentiation, innervation, hormonal status or immune protection contribute to the intact functional anatomy of the ocular surface. Recently it has been recognized that immunologically regulated mechanisms of inflammation represent a primary or secondary pathogenetic factor for dry eye disease. This is conceivably regulated by the cells of the physiological mucosal immune defence system, the eye-associated lymphoid tissue (EALT). Androgens represent an important trophic factor for the ocular surface and their deficiency predisposes to inflammation. CONCLUSION: Dry eye disease represents a complex dysregulation of the functional anatomy of the ocular surface that can start from different alterations (e.g. insufficient secretion, defects in wetting or innervation). Immune-based inflammation is able to interconnect and negatively reinforce these different pathomechanisms, resulting in a vicious circle.

Lacrimal drainage-associated lymphoid tissue (LDALT): a part of the human mucosal immune system.

PURPOSE: Mucosa-associated lymphoid tissue (MALT) specifically protects mucosal surfaces. In a previous study of the human conjunctiva, evidence was also found for the presence of MALT in the lacrimal sac. The present study, therefore, aims to investigate its morphology and topographical distribution in the human lacrimal drainage system. METHODS: Lacrimal drainage systems (n = 51) obtained from human cadavers were investigated by clearing flat wholemounts or by serial sections of tissue embedded in paraffin, OCT compound, or epoxy resin. These were further analyzed by histology, immunohistochemistry, and electron microscopy. RESULTS: All specimens showed the presence of lymphocytes and plasma cells as a diffuse lymphoid tissue in the lamina propria, together with intraepithelial lymphocytes and occasional high endothelial venules (HEV). It formed a narrow layer along the canaliculi that became thicker in the cavernous parts. The majority of lymphocytes were T cells, whereas B cells were interspersed individually or formed follicular centers. T cells were positive for CD8 and the human mucosa lymphocyte antigen (HML-1). Most plasma cells were positive for IgA and the overlying epithelium expressed its transporter molecule secretory component (SC). Basal mucous glands were present in the lacrimal canaliculi and in the other parts accompanied by alveolar and acinar glands, all producing IgA-rich secretions. Primary and secondary lymphoid follicles possessing HEV were present in about half of the specimens. CONCLUSIONS: The term lacrimal drainage-associated lymphoid tissue (LDALT) is proposed here to describe the lymphoid tissue that is regularly present and belongs to the common mucosal immune system and to the secretory immune system. It is suggested that it may form a functional unit together with the lacrimal gland and conjunctiva, connected by tear flow, lymphocyte recirculation, and probably the neural reflex arc, and play a major role in preserving ocular surface integrity.

Conjunctiva-associated lymphoid tissue in the human eye.

PURPOSE: Mucosa-associated lymphoid tissue (MALT) represents a part of the immune system located at mucosal surfaces. Its presence in the human eye is the point in question in the current study. Its occurrence, components, topography, and probable functional significance in the human conjunctiva and lacrimal drainage system were investigated. METHODS: Fifty-three complete conjunctival sacs were obtained from cadaveric eyes, prepared as flat wholemounts, stained, optically cleared, observed in total thickness, and sectioned for light microscopic histology, immunohistochemistry, and electron microscopy. Eight lacrimal sacs and adhering canaliculi were prepared accordingly. RESULTS: Lymphoid tissue was mainly observed in the palpebral conjunctiva, more pronounced in the upper than in the lower lid. It occurred in different forms: 1) In all specimens, diffuse lymphoid tissue of lymphocytes and plasma cells, most of which were IgA positive, formed a thin layer in the lamina propria. The overlying epithelium produced secretory component. 2) In approximately three fifths of the conjunctival sacs, organized follicular accumulations were embedded in this layer. They had a lenticular shape, were composed of B lymphocytes, and were apically covered by lymphoepithelium. 3) Both types could be associated with the conjunctival crypts. Lymphoid tissue with similar characteristics, including secondary follicles, was also observed inside the lacrimal drainage system. High endothelial venules were present in all types of lymphoid tissue. CONCLUSIONS: Human conjunctiva and lacrimal drainage system show an associated lymphoid tissue (suggesting the term conjunctiva-associated lymphoid tissue [CALT]) that contains all components necessary for a complete immune response. Expression of immunoglobulins and secretory component indicates that the conjunctiva belongs to the secretory immune system.

A fiberoptic reflection densitometer with cardiac output calculator.

A catheter-tip densitometer for indocyanine green is described consisting of a cardiac catheter containing optical fibers, an incandescent light source, a light detection unit and a processing unit. Half of the optical fibers guide the light to the blood at the tip of the catheter, the other half the back-scattered (reflected) light to the detection unit. In the detection unit the light is measured by two silicium barrier layer photocells after it has been split into two beams by a beam splitter. In the measuring channel the light passes an 800 nm filter before reaching the photocell. When fiberoptic catheters with glass fibers are employed, the other channel, used for compensation of non-specific effects such as blood flow variations, contains no filter, thus measuring light in a broad spectral band. It is shown that in this way compensation of flow effects may be about two times better than when a 920 nm filter is used. When using plastic optical fibers a 950 nm filter must be used, because above lambda = 850 nm plastic fibers transmit only a band around that wavelength (950 nm). At zero dye concentration the densitometer output or ratio of compensating and measuring photocell output R/R800 is almost insensitive to changes in haemoglobin concentration. When the blood contains dye, however, the influence of haemoglobin concentration is considerable. The densitometer output R/R800 is linearly related to dye concentration up to 50 mg . 1-1, the output R920/R800 up to 30 mg . 1(-1). The output R/R800 decreases with decreasing oxygen saturation; the slope of the calibration line, however, appears to be unaffected. The processing unit also contains an analog cardiac output calculator consisting of an integrator and a divider. Central dye dilution curves recorded from the pulmonary artery after injection of dye into the right atrium or a caval vein come down to the baseline. At this moment the reading of a digital voltmeter displaying the divider output calibrated in 1 . min-1 can be held and the reading taken.

A fiberoptic reflection oximeter.

A catheter tip oximeter is described consisting of a cardiac catheter containing optical fibers, and incandescent light source, a light detection unit and a processing unit. Half of the optical fibers guide the light to the blood at the tip of the catheter, the other half the backscattered (reflected) light to the detection unit. The detection unit contains a dichroic mirror, transmitting most of the light with lambda less than 800 nm and reflecting most of the light with lambda greater than 900 nm, thus splitting the light into two beams. These pass through interference filters with nominal wavelengths of 640 and 920 nm respectively, and are focused on silicium barrier layer photocells. The photocell signals are amplified and fed into a divider giving the ratio of measuring (R640) and compensating (R920) photocell output. The relationship between log R640/R920 and oxygen saturation is represented by a slightly curved line. The relation may be linearized by subtracting a constant voltage from the divided output before taking the logarithm. The slope of the calibration line is dependent on the total haemoglobin concentration. Nonetheless an average calibration line can be used between 70 and 100% oxygen saturation. For 78 measurements of pig blood samples in this range (haemoglobin concentration between 96 and 161 g.1(-1)), the standard deviation of the difference between the fiberoptic oximeter and a Radiometer OSM1 oxygen saturation meter was 1.9% saturation, for 152 samples over the entire saturation range the standard deviation of the difference was 3.1% saturation. The influence of the flow velocity of blood on the light reflection depends on wavelength as well as on oxygen saturation. Therefore, complete compensation for the flow effect is not possible by simple means.