SLEEP-GOAL: A multicenter success criteria outcome study on 302 obstructive sleep apnoea (OSA) patients.

OBJECTIVE: To demonstrate SLEEP-GOAL as a more holistic and comprehensive success criterion for Obstructive Sleep Apnoea (OSA) treatment. METHODS: A prospective 7-country clinical trial of 302 OSA patients, who met the selection criteria, and underwent nose, palate and/or tongue surgery. Pre- and post-operative data were recorded and analysed based on both the Sher criteria (apnoea hypopnea index, AHI reduction 50% and <20) and the SLEEP-GOAL. RESULTS: There were 229 males and 73 females, mean age of 42.4±17.3 years, mean BMI 27.9±4.2. The mean VAS score improved from 7.7±1.4 to 2.5±1.7 (p<0.05), mean Epworth score (ESS) improved from 12.2±4.6 to 4.9±2.8 (p<0.05), mean body mass index (BMI) decreased from 27.9±4.2 to 26.1±3.7 (p>0.05), gross weight decreased from 81.9±14.3kg to 76.6±13.3kg. The mean AHI decreased 33.4±18.9 to 14.6±11.0 (p<0.05), mean lowest oxygen saturation (LSAT) improved 79.4±9.2% to 86.9±5.9% (p<0.05), and mean duration of oxygen <90% decreased from 32.6±8.9 minutes to 7.3±2.1 minutes (p<0.05). The overall success rate (302 patients) based on the Sher criteria was 66.2%. Crosstabulation of respective major/minor criteria fulfilment, based on fulfilment of two major and two minor or better, the success rate (based on SLEEP-GOAL) was 69.8%. Based solely on the Sher criteria, 63 patients who had significant blood pressure reduction, 29 patients who had BMI reduction and 66 patients who had clinically significant decrease in duration of oxygen <90% would have been misclassified as "failures". CONCLUSION: AHI as a single parameter is unreliable. Assessing true success outcomes of OSA treatment, requires comprehensive and holistic parameters, reflecting true end-organ injury/function; the SLEEP-GOAL meets these requirements.

EUFOREA Rhinology Research Forum 2016: report of the brainstorming sessions on needs and priorities in rhinitis and rhinosinusitis.

The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016.

[Regional anesthesia and timely treatment for neuropathy in patients with pyonecrotic forms of the diabetic foot].

Regional anesthesia was studied for its impact on the functional status of a peripheral nerve in 20 patients with purulent diseases of the lower extremities in the presence of diabetes mellitus. The impact of conservative therapy on the peripheral nerve was also studied in these patients. There was no negative impact of regional methods of anesthesia on the function of the nerve, its improvement due to treatment with alpha-lipoic acid and serotonin adipinate.

Ultrastructure and organization of the cutaneous microvasculature in normal and pathologic states.

The cutaneous microvasculature is organized into upper and lower horizontal plexuses with the dermal capillary loops arising from the upper plexus. The arteriolar and venular sides of the microvasculature can be identified by the ultrastructure of the mural basement membrane material. Collecting venules present in the lower dermis contain valves. Periadventitial cells (veil cells) are present around all microvessels. Their size and number appear to correlate with the quantity of mural basement membrane material found in cutaneous vessels in diabetes, actinic damage, and chronological aging. The contractile cells of the vascular wall surround the endothelial cell tube in a manner suggesting specific functions. The smooth muscle cells in the arteriolar segment form a sleeve, whereas each pericyte in the postcapillary venular simultaneously makes many contacts with several underlying endothelial cells. The common telangiectases can be explained by abnormalities in this organization and ultrastructure rather than by neovascularization or random anastomoses. The macular telangiectases seen in scleroderma, generalized essential telangiectasia, and nevus flammeus are produced by dilatation of the postcapillary venules of the upper horizontal plexus. Cherry angiomas are produced by spherical and tubular dilatations of capillary loops in dermal papillae with tortuous cross-connections between individual loops. Angiokeratomas of Fabry and Fordyce have the ultrastructure of collecting venules that contain valves, and appear to represent the ectopic development or placement of small valve-containing collecting veins. The cutaneous lesions of hereditary hemorrhagic telangiectasia represent arteriovenous communications.

Three-dimensional reconstructions of objects from serial sections using a microcomputer graphics system.

A computer graphics system for constructing 3-dimensional models of tissues from serial sections has been designed around a Motorola 68000 CPU. The system consists of a Dual Systems 16-bit microcomputer running the UNIX operating system. A Scion Corporation MicroAngelo color graphics system drives the color monitor. Three-dimensional imaging is enhanced by hidden line removal and area filling by color. A computer-drawn model of a cherry angioma is compared with a previously constructed physical model of the same angioma to illustrate how the system operates.

Three-dimensional reconstruction of endothelial cell gaps in psoriatic vessels and their morphologic identity with gaps produced by the intradermal injection of histamine.

Endothelial cell gaps in psoriatic vessels and histamine-induced gaps in forearm skin of normal controls were reconstructed in 3 dimensions by a computer graphics system. The gaps in psoriatic vessels were present within the cell, at the intercellular junction, or concurrently at both sites. Histamine-induced gaps were found at the intercellular junction or at both intracellular and intercellular locations. The gaps were linear to oval and often contained cytoplasmic processes from one of the endothelial cells, suggesting that gap formation represents a cellular injury rather than a purely physiologic reversible phenomenon.

Ultrastructure and three-dimensional reconstruction of several macular and papular telangiectases.

Eight types of telangiectases were studied by light and electron microscopy and by 3-dimensional reconstruction from photomicrographs. Five were macular: mat telangiectasia of scleroderma, generalized essential telangiectasia, nevus flammeus, and 2 macular types not previously described. Three were papular: cherry angioma, angiokeratoma (Fabry), and angiokeratoma (Fordyce). The macular telangiectases were produced by dilatation of postcapillary venules of the upper horizontal plexus. There was no evidence of neovascularization or vascular malformation. The walls of the dilated venules were thickened by the peripheral deposition of basement membrane-like material admixed with reticulin fibers. The ultrastructure and configuration of the papular telangiectases were different. The cherry angioma was produced by spherical and tubular dilatations of capillary loops in dermal papillae. Each abnormally dilated loop was connected to the neighboring loop or loops by tortuous vascular channels. The vessels in the upper horizontal plexus were not involved. Ultrastructurally, the cherry angiomas were composed of both venous capillaries and postcapillary venules whose walls were thickened in a manner identical to that observed in the macular telangiectases. The angiokeratomas of Fabry and Fordyce were also produced by vascular abnormalities predominantly involving the dermal papillae. Ultrastructurally these vessels were similar to the small collecting veins which are normally found at the dermal-subcutaneous interface. Thus, the papular telangiectases also arose by alterations of the existing microvasculature rather than by proliferation of new vessels with random anastomoses. Reconstruction of the upper horizontal plexus from normal skin showed an undulating network of arterioles and their accompanying postcapillary venules. A 3-layered plexus arranged as venules, arterioles, and venules was not found.

Ultrastructure of the human dermal microcirculation. IV. Valve-containing collecting veins at the dermal-subcutaneous junction.

Valve-containing collecting veins 70-120 micron in diameter were found at the interface of the dermis and fat. Two cusped valves with sinuses were found at most points where 25- to 50-micron venules entered these larger veins as well as in the lumens of the larger veins unrelated to branch points. The walls of these valve-containing veins in their narrowest portions were composed of smooth muscle cells, collagen fibers, and homogeneous-appearing basement membrane material. As the vessel became wider, elastic fibers first appeared just inside the most peripheral layer of smooth muscle cells, and gradually occupied the spaces between all the layers of smooth muscle cells. However the subendothelial zone was frequently devoid of elastic fibers. The valves were always pointed in the direction of the larger vessel as would be expected in a collecting vein. Recent experiments by other workers have demonstrated that the capillary blood flow in human nail-fold capillaries is pulsatile, thereby providing physiologic reasons for the presence of valve-containing veins at the dermis-fat interface.

Studies in cutaneous aging: I. The elastic fiber network.

We studied by light and electron microscopy the elastic fibers in he sun exposed and sun protected skin of normal and psoriatic individuals of different ages in order to separate the changes of actinic damage from those of chronological aging. The sun exposed skin showed 2 types of elastic fiber abnormalities-one related to actinic damage and the other to chronological aging. The sun protected buttock skin showed only the latter. From ages 30 to 70, a minority of the elastic fibers exhibited abnormalities that appeared to represent a process of fiber disintegration. After age 70, the majority of elastic fibers showed these abnormalities. These abnormalities were present without accompanying inflammatory cells. Also, there was morphological evidence of continuing synthesis of elastic fibers during the lifetime of these subjects, except that from ages 50-93, the fibers appeared to be loosely, rather than compactly, assembled. Incubation of dermal slices from buttock skin of young adults with porcine pancreatic elastase and bovine chymotrypsin produced elastic fiber degradation that closely simulated the changes that were observed in aged sun protected skin. We propose that one of the features of cutaneous aging is a slow, spontaneous, progressive degradative process inherent in the elastic fiber that can be enzymatically accelerated from decades to hours by elastase and chymotrypsin.

Studies in cutaneous aging: II. The microvasculature.

We studied by light and electron microscopy the microcirculatory vessels in the sun exposed and sun protected skin of normal and psoriatic individuals in order to separate the features of actinic damage from those of chronological aging. In actinically damaged skin, the vascular walls of postcapillary venules and of arterial and venous capillaries were thickened by the peripheral addition of a layer of basement membrane-like material. The veil cells which were intimately related to these layers often had dilated cisternae of rough endoplasmic reticulum containing electron dense material. In 3 of 8 individuals, 70, 70 and 72 yr old, the buttock skin showed mold vascular wall thickening. In 5 other patients, 59-88 yr old the vessels of the buttock skin were normal. In 4 individuals 80-93 yr old, the vessels were abnormally thin (0.5-1.0 micrometer). The veil cells were either absent or decreased in number in these specimens. We propose that (1) the veil cell is responsible for the synthesis and maintenance of the peripheral portion of the vascular wall of the dermal microcirculatory vessels; (2) the veil cell is stimulated to produce excessive basement membrane-like material in response to UV light, factors associated with diabetes mellitus, and possibly to factors associated with the early phase of chronological aging; and (3) with progressive aging there is a decrease in the number and synthetic activity of veil cells which correlates with the appearance of abnormally thin walled vessels.

Demonstration of immune complexes in spontaneous and histamine-induced lesions and in normal skin of patients with leukocytoclastic angitis.

Clinical and laboratory observations have strongly suggested that leukocytoclastic angitis is an immune complex disease. Since immune complexes can be visualized as electron-dense deposits by electron microscopy (EM), this method was used in conjunction with direct immunofluorescence (IF) to determine whether complexes could be demonstrated in spontaneous lesions, and in uninvolved skin in which the vessels were made permeable by the local injection of histamine. Histamine-induced wheals were produced in the uninvolved skin of patients with active angitis. In the resulting wheal, EM studies revealed electron-dense deposits characteristic of immune complexes in postcapillary venules and direct IF studies demonstrated complement and immunoglobulins in the vessel walls. Neutrophils in varying stages of disintegration were present thereby reproducing the histopathologic changes of spontaneous lesions. EM and IF studies of nonmanipulated uninvolved skin also revealed electron-dense deposits and immune reactants in the vessel walls. Neutrophils were not present, however. This observation indicates that immune complexes are deposited in vessels before tissue damage ensues. Study of spontaneous lesions older than 24 hr revealed only fibrin by EM and no immune reactants by direct IF. In spontaneous lesions less than 24 hr old, electron-dense deposits and fibrin were seen by EM, and complement and immunoglobulins by IF. Histamine-induced wheals should be a useful device to investigate patients with disorders that have an immune complex pathogenesis.

Ultrastructural abnormalities of the microvasculature and elastic fibers in the skin of juvenile diabetics.

We examined by electron microscopy the calf and buttock skin of 15 juvenile diabetics, 9-36 years old, to determine whether microangiopathy was present. We found in 14 of 15 buttock specimens, and in all 15 calf skin specimens, that the vascular walls were thickened by the peripheral deposition of a belt of basement membrane-like material admixed with variable amounts of collagen (reticulin) fibrils. In addition there appeared to be an increased amount of unidentified material, most likely basement membrane, deposited within the vascular wall itself. We also found age-related elastic fiber abnormalities in the dermis and in the arterioles which were identical to those observed in normal, nondiabetic aged individuals 50-93 years old. We suggest that the vascular and elastic fiber abnormalities in diabetic skin may represent a manifestation of accelerated aging rather than being related to the various underlying metabolic derangements in diabetes.

Role of the microcirculation in the treatment and pathogenesis of psoriasis.

Controversy exists whether the initiating events in psoriasis are primarily epidermal or dermal (vascular). To study this point, serial biopsies from 6 patients were taken from the periphery of individual plaques before, and at 1 to 3 day intervals during, Goeckerman and PUVA treatments. Part of the biopsy was studied by electron microscopy to determine the fine structure of the capillary loops and part was incubated with tritiated thymidine to determine the labeling index (LI) of the basal cells. Normal appearing buttock skin of the 11 other psoriatic patients not under treatment was studied by identical methods. In 4 of the 6 treated patients, the capillary loops began to return toward normal 3 to 8 days before the LI began to decrease. Two patients did not show a return toward normal of either capillaries or LI during the period of the experiment. The LI was elevated in the normal appearing buttock skin of 6 of 11 untreated psoriatics. In 4 of the 6, the loops were normal arterial capillaries. We did not observe abnormal (venous) capillaries associated with a normal LI in the other 5 untreated patients. These data support the concept that the initiating factors in psoriasis are in the epidermis, but epidermal hyperplasia cannot occur without vascular proliferation. Understanding the factors responsible for shortening the capillary loops during epidermal normalization and for inhibition of capillary growth in the presence of an increased LI could lead to other ways of controlling psoriasis.

Ultrastructure of the human dermal microcirculation. III. The vessels in the mid- and lower dermis and subcutaneous fat.

This paper describes the ultrastructure of the microcirculatory vessels in the mid- and lower dermis and subcutaneous fat. Reconstruction of vessel walls, tracing out the courses of individual vessels, and survey examination of vessels were carried out by various combinations of routine and serial, ultrathin, and 1-micron sections. Intracellular myofilamentous bundles associated with extracellular filaments were a characteristic feature of the endothelial cells in arterioles possessing an internal elastic lamina, but were only rarely seen in endothelial cells of venules. The ultrastructural features of these bundles and filaments suggested both contractile and anchoring functions. The elastic lamina of the arterioles was shown to be composed of individual elastic fibers oriented in the long axis of the blood vessel under the endothelium, rather than being a continuous sheet as in larger arteries and arterioles. The capillaries in the fat had walls of normal thickness (0.1-0.3 micron) similar to capillaries in other organs, in contrast to the dermal capillaries whose walls are 2-3 micron thick. The arterioles, capillaries, and venules in the fat were frequently devoid of veil cells in contrast to those in the dermis. Venous capillaries with bridged fenestrations were found in close proximity to eccrine sweat glands and hair bulbs in the forearm, trunk, and buttock skin.

Ultrastructural and three-dimensional analysis of the contractile cells of the cutaneous microvasculature.

The three-dimensional relationships between smooth muscle cells and endothelial cells and between pericytes and endothelial cells in four segments of the microcirculation were analyzed by computer reconstructions from serial electron micrographs. In elastic-containing arterioles, the smooth muscle cells formed an inner longitudinal layer above and parallel to the elastica and an outer spiral layer. In the terminal arterioles the two layers of smooth muscle cells and elastica were replaced by a single smooth muscle cell that completely encircled the endothelial cell tube. The pericytes in the post-capillary venules completely encircled and gripped the endothelium through multiple contact points from their lateral processes. In the large venules the pericytes only partially encircled the endothelial cell tube and were more randomly placed.

Contour mapping of the cutaneous microvasculature by computerized laser Doppler velocimetry.

A probe holder for laser Doppler velocimetry was designed to allow a narrow (1.24-mm) probe to be moved in increments of 1.04 mm, approximately the width of the probe window itself, so that four contiguous 1-mm2 spots in a 2.29 x 2.29 mm area could be sampled. An area as large as 2.48 x 2.48 cm can be measured with this device. The flux was fed into a computer by an analog/digital board, for visualization as a wave-form on the monitor, and for analysis by fast Fourier transforms and power spectrum analysis. Each spot sampled was given a unique x,y coordinate and the mean amplitude of the flux was designated as the z coordinate. With the aid of software, the values of these three coordinates were mathematically processed to produce contour graphs with shading that represented a map of the arteriolar circulation in the skin. This methodology allows for accurate movement and placement of the probe on the skin and the ability to relocate a spot within 1 mm of its original location after intervals of hours to days. Video images of the superficial plexus at the sites where the maps were made confirm the topographic appearance of these maps. Data generated by these maps raise the intriguing possibility that microcirculatory vessels may be engaged in a division of labor--some involved primarily with tissue perfusion, others with thermoregulation.

Ultrastructure of the human dermal microcirculation: the horizontal plexus of the papillary dermis.

Electron microscopy was used to define the ultrastructure of the various segments of the human cutaneous microcirculation in normal forearem skin. The organization of the vessels in the horizontal plexus of the papillary dermis was reconstructed from 1-mum plasticembedded sections. Ultrathin sections were taken at 10- to 20-mum intervals over a distance of 450 mum. Arterioles were followed through the capillary bed to their venous connections. Terminal arterioles, arterial and venous capillaries, and postcapillary venules were identified on the basis of size, cellular composition of their walls, and their relationship to the other segments of the microvascular bed. The arterial segments were characterized by a homogeneous basement membrane and the venous segments by a multilaminated basement membrane. The elastic lamina in the arterioles was a discontinuous layer which gradually disappeared from the arteriolar wall to form an external sheath just before the arteriole connected with the arterial capillary segment. The vascular walls varied from 1 to 5 mum in all of the segments of the microvascular bed. Criteria are proposed for identifying the various segments of the microcirculation so that their roles in dermatoses and vascular malformations can be evaluated.

Ultrastructure of the human dermal microcirculation. II. The capillary loops of the dermal papillae.

Electron microscopy was used to define the ultrastructure of the capillary loops in the dermal papillae of normal, eczematous, and psoriatic skin. Capillary loops were reconstructed from 1-mum plastic-embedded sections. Ultrathin sections were taken at 4- to 6-mum intervals for correlation with the thick sections. The capillary loops of normal forearm and elbow skin could be divided into two segments: an intrapapillary and extrapapillary portion. The intrapapillary portion had the ultrastructural characteristics of an arterial capillary--homogeneous-appearing basement membrane without bridged fenestrations. The ascending limb in the extrapapillary portion was also an arterial capillary and the descending limb in the same portion had venous characteristics--multilayered basement membrane. The intrapapillary arterial loop developed venous characteristics abruptly after the vessel left the dermal papilla proper. The capillary loops in acute nummular eczema were identical in ultrastructure to those of normal skin. Bridged fenestrations were found in one capillary loop in eczema but not in normal skin. By contrast, the intrapapillary capillary loops in psoriasis were venous capillaries which were characterized by bridge fenestrations and multilayered basement membrane. The ultrastructural features of the capillary loops and those of the microcirculatory segments in the horizontal dermal plexus should provide sufficient criteria for one to evaluate the nature of vascular abnormalities that occur in the upper dermis.

Ultrastructure of the capillary loops in the dermal papillae of psoriasis.

Electron microscopy was used to define the ultrastructure of the capillary loops in the dermal papillae of psoriatic lesions. Pustular psoriasis of von Zumbusch and psoriasis vulgaris were studied before and after treatment with the Goeckerman regimen. Capillary loops were reconstructed from 1-mum plastic-embedded sections. Ultrathin sections were taken at intervals for correlation with the 1-mum sections. There were no ultrastructural differences between the capillary loops in psoriasis vulgaris and pustular psoriasis. The intrapapillary portion of the loop was predominantly a venous capillary. Four basic ultrastructural loop patterns were recognized which can serve as markers in studying the responses of psoriatic loops in various experimental situations. Following 3 weeks of Goeckerman therapy, the morphology of psoriatic capillary loops changed from venous capillaries to arterial capillaries which are found in the papillae of normal skin. This transformation was observed to begin 48 to 72 hr after the initiation of therapy.