Quality of life after mandibulectomy: the impact of the resected subsite.

The purpose of this study was to identify the factors that impact the quality of life (QOL) scores of patients undergoing mandibulectomy. All patients with a diagnosis of an oral cavity neoplasm involving the mandible who underwent a mandibulectomy between January 1, 2000 and December 31, 2015 and completed a University of Washington QOL questionnaire (UW-QOL) were included in the study. Fifty-eight patients fulfilled all inclusion criteria and completed the UW-QOL questionnaire. Forty patients (69%) underwent a segmental mandibulectomy and 18 patients underwent a marginal mandibulectomy. Forty-eight patients (82.7%) had a free flap reconstruction. There was no significant difference in the QOL scores between patients who underwent a marginal or a segmental mandibulectomy. In contrast, patients who underwent symphysial resection reported significantly worse scores in various domains compared to patients with body or ramus segmental mandibulectomy. Patients who underwent a segmental mandibulectomy that included the symphysis had worse outcomes in chewing, recreation, health-related and social QOL domains compared to those whose mandibulectomy did not include the symphysis.

Comparison of the histopathological characteristics of osteomyelitis, medication-related osteonecrosis of the jaw, and osteoradionecrosis.

The purpose of this study was to compare the histopathological parameters of chronic/suppurative osteomyelitis, medication-related osteonecrosis of the jaw (MRONJ), and osteoradionecrosis (ORN), and to examine the hypothesis that distinct histological features can be related to a specific disease, allowing for diagnosis based on microscopic evaluation alone. One hundred and ten samples were reviewed by two examiners in a blinded fashion, and a semi-quantitative histomorphometric analysis was performed. The parameters evaluated included the presence or absence of necrotic bone, inflammation, reactive bone formation, bacteria, and osteoclasts. No statistically significant differences were found between groups for any parameter. Necrotic bone was common to all three diagnoses. Inflammation and reactive bone formation were present in all three diagnoses. The presence of bacteria was a prominent feature in all cases. Osteoclasts were scarce in MRONJ and osteomyelitis, and non-existent in ORN. The results of this study failed to identify distinctive microscopic characteristics in any of the three entities that could be used to differentiate between them. Therefore, it is impossible to reach a specific final diagnosis based on microscopic findings alone. The role of microscopic analysis is to serve as an aid to diagnosis that must be complemented by the patient's history and imaging.

[One stage combined endoscopic and per-oral buccal fat pad approach for large oro-antral-fistula closure with secondary chronic maxillary sinusitis].

There are numerous surgical approaches for oro-antral-fistula (OAF) closure. Secondary sinus disease is still considered by many experts a relative contra indication for primary closure. To describe a single-stage combined endoscopic sinus surgery and per-oral buccal fat pad (BFP) flap approach for large OAF causing chronic maxillary sinusitis. The records of all the patients with OAF and chronic manifestations of secondary rhinosinusitis that were treated between 2010 and 2013 in our tertiary care medical center were reviewed. The exclusion criteria were: OAF 5 mm, resolved sino-nasal disease, OAF secondary to malignancy, recurrent fistula, medical history that included radiotherapy to the maxillary bone and age <18 years. Each procedure was performed by a team consisting of a rhinologist and a maxillofacial surgeon. The surgical approach included an endoscopic middle antrostomy with maxillary sinus drainage, and a per-oral BFP regional flap for OAF closure. Total OAF closure, complications and need for revision surgeries. Forty-five patients that underwent OAF closure together with sinus surgery using a combined endoscopic sinus surgery (ESS) and BFP flap approach met the inclusion criteria. There were 28 males and 17 females with a mean ± SD age of 53.5 ± 14.9 years (range 22-80 years). The presenting signs and symptoms included purulent rhinorrhea (n = 22, 48.9%), foreign body in sinus (n = 10, 22.2%) nasal congestion (n = 7, 15.5%), halitosis (n = 6, 13.3%) and pain (n = 5, 12.2%). Surgical complications included local pain (n = 2, 4.4%), persistent rhinitis (n = 2, 4.4%) and synechia (n = 1, 2.2%). One patient required revision surgery due, to an unresolved OAF. The OAF of all the other 44 patients (97.8%) was closed after the first procedure and the paranasal sinuses on the treated side were completely recovered. The mean follow-up time for the group was 7.6 ± 4.3 months (7-21 months), and no untoward sequelae or recurrence were reported. Combined, one step, endoscopic Maxillary sinus drainage together with per-oral BFP flap approach is an efficacious surgical approach for safe closure of OAFs that are complicated with secondary chronic maxillary sinusitis.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012.

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.

The German national registry for primary immunodeficiencies (PID).

In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

Multiplexed assays by high-content imaging for assessment of GPCR activity.

G-protein-coupled receptors (GPCR) participate in many disease pathways and represent the largest family of therapeutic targets. Thus, great investments are made to discover drugs modulating GPCR-mediated events. Among functional assays for screening GPCRs, the Transfluor imaging assay is based on redistribution of cytosolic beta-arrestin to an activated GPCR and has become widely used in high-content screening. However, assessing Transfluor alone has limitations: relying on a single mechanistic step of beta-arrestin redistribution during GPCR activation, providing no information on the stimulated GPCR's intracellular fate, and using only a single fluorescent color (green fluorescent protein). Taking full advantage of high-content imaging to screen approximately 2000 compounds, the authors multiplexed the Transfluor assay with an immunofluorescence-based quantification of GPCR internalization. This approach identified and classified 377 compounds interfering with agonist-induced activation of the Transfluor assay, receptor internalization, or both. In addition, a subset of compounds was analyzed for their performance across imaging, cell-based calcium release (fluorometric imaging plate reader [FLIPR]), and biochemical receptor binding assays (scintillation proximity assay). This indicated that the imaging assays have even better predictive power for direct inhibition of receptor binding than the FLIPR assay. In conclusion, compounds inducing unique responses can suggest novel mechanisms of action and be used as tools to study GPCR activation and internalization.

Rck2, a member of the calmodulin-protein kinase family, links protein synthesis to high osmolarity MAP kinase signaling in budding yeast.

Rck2, a yeast Ser/Thr protein kinase homologous to mammalian calmodulin kinases, requires phosphorylation for activation. We provide evidence that in budding yeast, this step can be executed by the osmostress-activated mitogen-activated protein kinase Hog1. Rck2 phosphorylation was transiently increased during osmostress or in mutants with a hyperactive high osmolarity glycerol (HOG) pathway. This modification depended on catalytically active Hog1 kinase and two putative mitogen-activated protein kinase phosphorylation sites in Rck2. Immunokinase assays showed that Hog1 can directly phosphorylate Rck2 to stimulate its enzymatic activity toward translation elongation factor 2. We demonstrate that Hog1 and Rck2 are necessary for attenuation of protein synthesis in response to osmotic challenge and show that modification of elongation factor 2 induced by osmostress depends on Rck2 and Hog1 in vivo. Therefore, we propose that the transient down-regulation of protein synthesis after osmotic shock is a response not to damage but to an extracellular signal mediated by Hog1 and Rck2.

Stress-induced map kinase Hog1 is part of transcription activation complexes.

In response to hyperosmotic environments, most eukaryotic cells activate a specialized mitogen-activated protein (MAP) kinase pathway. In S. cerevisiae, the key protein kinase, Hog1, coordinates the transcriptional induction of a variety of genes devoted to osmoadaptation and general stress protection. Depending on the promoter context, Hog1 can function through a variety of structurally unrelated transcription factors. Using chromatin precipitation assays, we discovered that the kinase itself becomes intimately linked with promoter regions during stress responses. This interaction is dependent on the presence of stress-mediating transcriptional activators. In turn, Hog1 modulates promoter association of at least one of these factors. Additional findings highlight the possibility that Hog1 constitutes an integral part of the upstream activation complex, perhaps targeting not only the activator but also components of the general transcription machinery.

Polarized localization of yeast Pbs2 depends on osmostress, the membrane protein Sho1 and Cdc42.

In Saccharomyces cerevisiae cells, high external osmolarity leads to the activation of a p38-related mitogen-activated protein (MAP) kinase though Pbs2. Pbs2 tagged with green fluorescent protein (Pbs2-GFP) is evenly distributed in the cytoplasm but excluded from the nucleus before and after exposure to stress. Here we show that a catalytically inactive form of Pbs2 attains a highly polarised localization during osmostress. This phenomenon depends of the osmosensor Sho1 and on a functional Cdc42 GTPase. Cdc42, but not the actin cytoskeleton, influences Sho1-dependent activation of the MAP kinase. Sho1 itself accumulates at sites of polar growth, but independently of stress conditions and Cdc42. These observations allow us to define the sequence of events that occurs during propogation of osmostress signals.

Response of Saccharomyces cerevisiae to severe osmotic stress: evidence for a novel activation mechanism of the HOG MAP kinase pathway.

The HOG/p38 MAP kinase route is an important stress-activated signal transduction pathway that is well conserved among eukaryotes. Here, we describe a novel mechanism of activation of the HOG pathway in budding yeast. This mechanism operates upon severe osmostress conditions (1.4 M NaCl) and is independent of the Sln1p and Sho1p osmosensors. The alternative input feeds into the HOG pathway MAPKK Pbs2p and requires activation of Pbs2p by phosphorylation. We show that, upon severe osmotic shock, Hog1p nuclear accumulation and phosphorylation is delayed compared with mild stress. Moreover, both events lost their transient pattern, presumably because of the absence of negative feedback mediated by Ptp2p tyrosine phosphatase, which we found to be localized in the nucleus. Under severe osmotic stress conditions, the delayed nuclear accumulation correlates with a delay in stress-responsive gene expression. Severe osmoshock leads to a situation in which active and nuclear-localized Hog1p is transiently unable to induce transcription of osmotic stress-responsive genes. It also appeared from our studies that the Sho1p osmosensor is less active under severe osmotic stress conditions, whereas the Sln1p/Ypd1p/Ssk1p sensor and signal transducer functions normally under these circumstances.

Nucleocytoplasmic traffic of MAP kinases.

MAPK pathways represent a unique extracellular signal response system. An important feature of such a multicomponent system appears to be the spatial intracellular organization of individual components. Recent studies demonstrate that the MAP kinases of such pathways are the molecular link between the plasma membrane sensors and the nuclear transcription factors. Stimulation of several MAPK pathways induces rapid and transient nuclear accumulation of MAP kinases. Investigations on the mode of regulation of this process using higher eukaryotes Erk2 and lower eukaryotes Hog1 and Sty1/Spc1 have revealed that at least three events contribute to signal-induced nuclear localization of these MAP kinases: activation by phosphorylation, regulated nuclear import and export, and nuclear retention.

Osmotic stress-induced gene expression in Saccharomyces cerevisiae requires Msn1p and the novel nuclear factor Hot1p.

After a sudden shift to high osmolarity, Saccharomyces cerevisiae cells respond by transiently inducing the expression of stress-protective genes. Msn2p and Msn4p have been described as two transcription factors that determine the extent of this response. In msn2 msn4 mutants, however, many promoters still show a distinct rise in transcriptional activity upon osmotic stress. Here we describe two structurally related nuclear factors, Msn1p and a newly identified protein, Hot1p (for high-osmolarity-induced transcription), which are also involved in osmotic stress-induced transcription. hot1 single mutants are specifically compromised in the transient induction of GPD1 and GPP2, which encode enzymes involved in glycerol biosynthesis, and exhibit delayed glycerol accumulation after stress exposure. Similar to a gpd1 mutation, a hot1 defect can rescue cells from inappropriately high HOG pathway activity. In contrast, Hot1p has little influence on the osmotic stress induction of CTT1, where Msn1p appears to play a more prominent role. Cells lacking Msn1p, Msn2p, Msn4p, and Hot1p are almost devoid of the short-term transcriptional response of the genes GPD1, GPP2, CTT1, and HSP12 to osmotic stress. Such cells also show a distinct reduction in the nuclear residence of the mitogen-activated protein kinase Hog1p upon osmotic stress. Thus, Hot1p and Msn1p may define an additional tier of transcriptional regulators that control responses to high-osmolarity stress.

Kinase activity-dependent nuclear export opposes stress-induced nuclear accumulation and retention of Hog1 mitogen-activated protein kinase in the budding yeast Saccharomyces cerevisiae.

Budding yeast adjusts to increases in external osmolarity via a specific mitogen-activated protein kinase signal pathway, the high-osmolarity glycerol response (HOG) pathway. Studies with a functional Hog1-green fluorescent protein (GFP) fusion reveal that even under nonstress conditions the mitogen-activated protein kinase Hog1 cycles between cytoplasmic and nuclear compartments. The basal distribution of the protein seems independent of its activator, Pbs2, and independent of its phosphorylation status. Upon osmotic challenge, the Hog1-GFP fusion becomes rapidly concentrated in the nucleus from which it is reexported after return to an iso-osmotic environment or after adaptation to high osmolarity. The preconditions and kinetics of increased nuclear localization correlate with those found for the dual phosphorylation of Hog1-GFP. The duration of Hog1 nuclear residence is modulated by the presence of the general stress activators Msn2 and Msn4. Reexport of Hog1 to the cytoplasm does not require de novo protein synthesis but depends on Hog1 kinase activity. Thus, at least three different mechanisms contribute to the intracellular distribution pattern of Hog1: phosphorylation-dependent nuclear accumulation, retention by nuclear targets, and a kinase-induced export.

Purification and characterization of the cell-wall-associated and extracellular alpha-glucosidases from Saccharomycopsis fibuligera.

Cell-wall-associated and extracellular alpha-glucosidases were purified to homogeneity from Saccharomycopsis fibuligera KZ growing on a medium containing cellobiose as the sole source of carbon; this substrate has the greatest inducing effect on the production of both forms of the enzyme. Depending on the source of carbon, 75-90% of the enzyme is associated with cell wall, from which it can be completely released by 1% Triton X-100 at 25 degrees C in 2 h. Both enzymes are glycoproteins in monomeric form with an apparent molecular mass of 132 kDa estimated by SDS/PAGE and 135 kDa estimated by gel filtration. N-linked carbohydrate accounts for 12% of the total mass. Both forms exhibited optimum activity at pH 5.5 and seem to be stable in the pH range 4.0-8.0 on incubation at 4 degrees C for 24 h. The cell-wall-associated form had an optimum activity at 42.5 degrees C and was stable in the absence of substrate up to 30 degrees C, while the extracellular form had optimal activity at 52.5 degrees C and was stable up to 40 degrees C. Both forms are unable to renature after thermal inactivation. The cell-wall-associated and extracellular alpha-glucosidases cleaved the same kind of substrates, from maltose to maltoheptaose, isomaltase and panose, although showing different rates of hydrolysis, and had little or no activity with polysaccharides. The extracellular form cross-reacts with antibody raised against the cell-wall-associated form, and both forms show the same peptide pattern after cleavage with chymotrypsin. The amino acid sequences of six peptides from both forms show marked similarity to those of Schwanniomyces occidentalis glucoamylase.

[Value of biological tests in the early diagnosis of acute steatosis in pregnancy]. / Intérêt des examens biologiques pour le diagnostic précoce d'une stéatose hépatique aiguë gravidique.

Four cases of acute fatty liver of pregnancy occurring over a ten year period are reported. All four patients had a caesarean section and one died postoperatively. The seven children (three twin pregnancies) were all alive. The early clinical signs were unspecific. Jaundice was the only one occurring in all patients. Routine biological tests before the jaundice develops may be of help for a diagnosis early enough to start the treatment in patients with unspecific gastrointestinal or hepatic manifestations, especially the liver function and blood coagulation tests. These latter allow to discord the diagnosis of viral hepatitis and the "Haemolysis-Elevated Liver enzyme concentrations-Low Platelets" (HELLP syndrome) respectively. Indeed, only a liver biopsy can ascertain the diagnosis.

[Imaging of the Achilles tendon on the computed tomogram. Normal findings and pathological changes]. / Die Darstellung der Achillessehne im Computertomogramm. Normalbefunde und pathologische Veränderungen.

Ligaments and tendons, including the Achilles tendon, show the highest density among normal soft tissue structures in the body. Traumatic and degenerative changes of the Achilles tendon are often associated with marked thickening and reduction in density associated with increased opacity of the space in front of the Achilles tendon. These changes are easily demonstrated by CT, whereas conventional radiological techniques only show non-specific changes. Twenty-five patients were examined, including nine with pain, seven following rupture of the Achilles tendon and nine post-operative controls; it was found that CT can add information important for the diagnosis and treatment planning of abnormalities of the Achilles tendon.