Anteriorer Durchbruch nach Eviszeration

Background

To evaluate the frequency of anterior surface breakdown for three techniques of evisceration with primary implant placement: the “classic” technique, the “scleral modification” technique, and the novel “scleral patch” technique.

Methods

Retrospective comparative case series with 73 consecutive eviscerations with primary implants that were performed in the Eye Clinic Rotterdam between January 2003 and January 2007.

Results

The operations involved the classic technique for 55% of the patients, scleral modification for 29%, and the novel scleral patch technique for 16%. In all, 9.6% of the patients had conjunctival breakdown: six in the classic group and one in the patch group. Although the frequency of this complication was higher in the classic group, the difference was not significant (P>0.05, chi-square test). Anterior surface breakdown was not related to implant size or prior eye surgery.

Conclusion

Compared with the scleral modification and scleral patch techniques, conjunctival breakdown and implant extrusion were seen more frequently after classic evisceration with implant placement. Implant size or indication for surgery were not related to the frequency of these complications.     

Application of optical coherence tomography for monitoring changes in cervicovaginal epithelial morphology in macaques: potential for assessment of microbicide safety

OBJECTIVES: Safety is a primary concern in the development of topical microbicides. Optical coherence tomography (OCT), a high-resolution, in-depth cross-sectional imaging modality, was utilized in conjunction with colposcopy to assess induced cervicovaginal epithelial changes that may predict product safety. STUDY DESIGN: OCT and colposcopic images of macaque vaginal and cervical tissues were obtained in excised tissue and in vivo under various conditions, including mechanical injury and nonoxynol-9 treatment. RESULTS: A scoring system was developed to categorize and quantify the OCT images based on morphologic features that indicate the presence or absence of an intact epithelial layer and inflammation. Using 3 categories (normal, mild to moderately abnormal, and severely abnormal), differences between healthy and injured tissue were apparent on OCT images. Normal images (category 1) had a bilayered structure representative of the epithelium and submucosa. Mild to moderately abnormal images (category 2) had areas of normal and abnormal epithelium. Severely abnormal images (category 3) had complete loss of the epithelium and/or inflammation, with loss of the bilayered structure on OCT. CONCLUSIONS: OCT is a noninvasive imaging modality complementary to colposcopy. It distinguished between normal and abnormal (or injured) tissue and thus holds promise for safety evaluations of candidate microbicides and other vaginal products.     

A systematic review of oral fungal infections in patients receiving cancer therapy

Purpose

The aims of this systematic review were to determine, in patients receiving cancer therapy, the prevalence of clinical oral fungal infection and fungal colonization, to determine the impact on quality of life and cost of care, and to review current management strategies for oral fungal infections.

Methods

Thirty-nine articles that met the inclusion/exclusion criteria were independently reviewed by two calibrated reviewers, each using a standard form. Information was extracted on a number of variables, including study design, study population, sample size, interventions, blinding, outcome measures, methods, results, and conclusions for each article. Areas of discrepancy between the two reviews were resolved by consensus. Studies were weighted as to the quality of the study design, and recommendations were based on the relative strength of each paper. Statistical analyses were performed to determine the weighted prevalence of clinical oral fungal infection and fungal colonization.

Results

For all cancer treatments, the weighted prevalence of clinical oral fungal infection was found to be 7.5% pre-treatment, 39.1% during treatment, and 32.6% after the end of cancer therapy. Head and neck radiotherapy and chemotherapy were each independently associated with a significantly increased risk for oral fungal infection. For all cancer treatments, the prevalence of oral colonization with fungal organisms was 48.2% before treatment, 72.2% during treatment, and 70.1% after treatment. The prophylactic use of fluconazole during cancer therapy resulted in a prevalence of clinical fungal infection of 1.9%. No information specific to oral fungal infections was found on quality of life or cost of care.

Conclusions

There is an increased risk of clinically significant oral fungal infection during cancer therapy. Systemic antifungals are effective in the prevention of clinical oral fungal infection in patients receiving cancer therapy. Currently available topical antifungal agents are less efficacious, suggesting a need for better topical agents.     

Tg-SwDI transgenic mice exhibit novel alterations in AbetaPP processing, Abeta degradation, and resilient amyloid angiopathy

Alzheimer's disease (AD) is characterized by the accumulation of extracellular insoluble amyloid, primarily derived from polymerized amyloid-beta (Abeta) peptides. We characterized the chemical composition of the Abeta peptides deposited in the brain parenchyma and cerebrovascular walls of triple transgenic Tg-SwDI mice that produce a rapid and profuse Abeta accumulation. The processing of the N- and C-terminal regions of mutant AbetaPP differs substantially from humans because the brain parenchyma accumulates numerous, diffuse, nonfibrillar plaques, whereas the thalamic microvessels harbor overwhelming amounts of compact, fibrillar, thioflavine-S- and apolipoprotein E-positive amyloid deposits. The abundant accretion of vascular amyloid, despite low AbetaPP transgene expression levels, suggests that inefficient Abeta proteolysis because of conformational changes and dimerization may be key pathogenic factors in this animal model. The disruption of amyloid plaque cores by immunotherapy is accompanied by increased perivascular deposition in both humans and transgenic mice. This analogous susceptibility and response to the disruption of amyloid deposits suggests that Tg-SwDI mice provide an excellent model in which to study the functional aftermath of immunotherapeutic interventions. These mice might also reveal new avenues to promote amyloidogenic AbetaPP processing and fundamental insights into the faulty degradation and clearance of Abeta in AD, pivotal issues in understanding AD pathophysiology and the assessment of new therapeutic agents.     

Neurocognitive sequelae of a giant arachnoid cyst: case study

We conducted a comprehensive neuropsychological evaluation of a normally functioning man with a giant arachnoid cyst encompassing much of the space normally occupied by the left hemisphere. Although of solidly average intellectual ability, the patient demonstrated neurocognitive deficits only revealed upon neuropsychological assessment. Despite the remarkable left hemisphere lesion, the pattern of cognitive dysfunction suggested right hemisphere pathology. We review the arachnoid cyst literature and discuss the possibility of a crowding phenomenon by which language function relocates to the more viable hemisphere. This case illustrates striking preservation of higher cognition in the presence of substantial structural abnormality.     

Primary extra-cranial meningioma following total hip replacement

A 61-year-old man presented with pain at the left hip and decreased mobility 10 years after total hip replacement. Imaging demonstrated a large destructive expansile mass adjacent to the prosthesis. Histological analysis confirmed the presence of an extra-cranial meningioma. Primary tumours after total hip replacement are rare and include soft tissue sarcomas, bone sarcomas and lymphomas. To our knowledge, no previous cases of primary extracranial meningioma have been identified. The imaging features, histology, pathogenesis and differential diagnosis are discussed.     

Identification of PSF, the polypyrimidine tract-binding protein-associated splicing factor, as a developmentally regulated neuronal protein.

The polypyrimidine tract-binding protein-associated splicing factor (PSF), which plays an essential role in mammalian spliceosomes, has been found to be expressed by differentiating neurons in developing mouse brain. The sequence of a fragment of mouse PSF was found to be remarkably similar to that of human PSF. Both the expression of PSF mRNA in cortex and cerebellum and PSF immunoreactivity in all brain areas were high during embryonic and early postnatal life and almost disappeared in adult tissue, except in the hippocampus and olfactory bulb where various neuronal populations remained PSF-immunopositive. Double-labeling experiments with anti-PSF antibody and anti-neurofilaments or anti-glial fibrillary acidic protein antibodies on sections of cortex, hippocampus, and cerebellum indicate that PSF is expressed by differentiating neurons but not by astrocytic cells. In vitro, mouse PSF was found to be expressed by differentiating cortical and cerebellar neurons. Radial glia or astrocyte nuclei were not immunopositive; however, oligodendrocytes differentiating in vitro were found to express PSF. The restricted expression of PSF suggests that this splicing factor could be involved in the control of neuronal-specific splicing events occurring at particular stages of neuronal differentiation and maturation.     

Anterior mediastinal abscess after closed sternal fracture.

BACKGROUND: Although sternal fractures after blunt chest trauma are markers for significant impact, the fracture itself is generally not associated with any specific wound complications. Mediastinal abscess and sternal osteomyelitis rarely occur after blunt trauma or cardiopulmonary resuscitation. Management of such complications is difficult, and requires a spectrum of operative procedures that range from simple closure to muscle flap reconstruction. METHODS: The trauma registry of a Level I trauma center was used to identify patients suffering a sternal fracture between January of 1994 and August of 1997. Records were reviewed for the mechanism of injury, length of hospital stay, and posttraumatic mediastinal abscess. RESULTS: Twenty-six patients were identified with sternal fracture. No clinically significant cardiac or aortic complications were noted. Three patients, all with a history of intravenous drug abuse and requiring central venous access in the emergency room, developed methicillin resistant Staphylococcus aureus mediastinitis. Sternal re-wiring and placement of an irrigation system successfully treated all three patients. CONCLUSION: Posttraumatic mediastinal abscess is an uncommon complication of blunt trauma in general and sternal fracture in particular. It can be recognized by the development of sternal instability. Risk factors include the presence of hematoma, intravenous drug abuse, and source of staphylococcal infection. Treatment with early debridement and irrigation can avoid the need for muscle flap closure.     

Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides

Vascular tone is dependent on smooth muscle K_ATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú syndrome. Unique among K_ATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined cryogenic electron microscopy structures of vascular K_ATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic K_ATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational “propeller” and “quatrefoil” geometries surrounding their Kir6.1 core. The glutamate/aspartate-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. Molecular dynamics simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B, and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated, and MgADP-bound activated conformations wherein the glutamate/aspartate-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward K_ATP channel activation.

Dynamic regulation of K⁺ channel gating is a primary point of control for processes governed by electrical excitability. ATP-sensitive potassium (K_ATP) channels, regulated by intracellular ATP to ADP ratios, transduce metabolic changes into electrical signals to govern many physiological processes (1). They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx, nontransporting members of the ABCC subfamily of ABC transporters (2). Various Kir6.x/SURx combinations generate channel isoforms with distinct tissue distribution and function (3, 4). Kir6.2/SUR1 channels are expressed in pancreatic β cells and control glucose-stimulated insulin secretion. Kir6.2/SUR2A channels are the predominant isoform in myocardium, while Kir6.1/SUR2B channels are the major isoform found in vascular smooth muscle. SUR2A and 2B are two splice variants of ABCC9 that differ in their C-terminal 42 amino acids (aa). In vascular smooth muscle, K_ATP activation leads to membrane hyperpolarization and vasodilation (5), while inhibition or deletion causes membrane depolarization, vasoconstriction, and hypertension (5–8). Mutations in the vascular K_ATP channel genes (KCNJ8 and ABCC9) cause Cantú syndrome (9–11), a severe pleiotropic systemic hypotension disorder including hypertrichosis, osteochondrodysplasia, and cardiomegaly (12).K_ATP channel gating by intracellular ATP and ADP involves allosteric sites on both subunits. ATP binding to Kir6.x inhibits the channel. SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel (1, 4, 13). Like all Kir channels, opening further requires PIP₂ bound to Kir6.x (14–16). Despite these commonalities, vascular Kir6.1/SUR2B K_ATP channels have distinct biophysical properties, nucleotide sensitivities, and pharmacology that differentiate them from other isoforms (17–19). First, vascular K_ATP channel unitary conductance is half that of Kir6.2-containing channels. Second, vascular channels lack spontaneous activity, only opening in the presence of NBD-dimerizing Mg-dinucleotides/trinucleotides; in contrast, pancreatic or cardiac channels containing Kir6.2 open spontaneously in the absence of ATP. Third, once activated, vascular K_ATP channels are relatively insensitive to ATP inhibition, requiring mM concentrations to observe an effect, while their pancreatic or cardiac counterparts are blocked by ATP at μM concentrations. Lastly, the antidiabetic sulfonylurea drug glibenclamide (Glib), which inhibits SUR1-containing pancreatic channels with high affinity, is ∼10-fold less potent toward the vascular and cardiac channels containing SUR2. Glib has been shown to reverse defects from gain-of-function Cantú mutations in mice (20). However, clinical application in Cantú patients is hindered by hypoglycemia from inhibition of pancreatic channels (21). Structural mechanisms underlying unique biophysical, physiological, and pharmacological properties among K_ATP channels are unknown.Here, we report cryogenic electron microscopy (cryoEM) structures for the vascular K_ATP channel, Kir6.1/SUR2B, in the presence of ATP and Glib. The structures show conformations not previously seen in pancreatic K_ATP channels prepared under the same condition (22–24). First, unlike in Kir6.2, Kir6.1 cytoplasmic domains (CDs) were displaced from the membrane too far to interact with PIP₂ for channel opening. Second, unlike pancreatic channels, which have a predominant propeller-shaped conformation when bound to ATP and Glib (22, 24), vascular K_ATP channels held four distinct conformations, two resembling propellers and two quatrefoils, marked by varying degrees of rotation of SUR2B toward the core Kir6.1 tetramer. Importantly, a long segment of SUR not previously resolved in any K_ATP structures, linking NBD1 and transmembrane domain 2 (TMD2), was revealed within vascular K_ATP structures to mediate the cytosolic interface between SUR2B and Kir6.1. In particular, the linker’s unique 15 glutamate/aspartate residues termed the ED-domain (25) established a nexus of interactions engaging SUR2B-NBD2 with Kir6.1 C-terminal domain (CTD). Molecular dynamics (MD) simulations showed MgADP binding to NBD2 was accompanied by substantial reconfiguration at this nexus, revealing the ED-domain provides a mobile autoinhibitory interaction that guards the transition of SUR2B from MgADP-free inactivated state to MgADP-bound activated state. Together, our findings point to a structural pathway through which SUR regulates Kir6 channel gating.