A Review of Immunotherapy for Head and Neck Cancer.

The introduction of immune checkpoint inhibitors (ICIs) to oncological care has transformed the management of various malignancies, including head and neck squamous cell carcinoma (HNSCC), offering improved outcomes. The first-line treatment of recurrent and malignant HNSCC for many years was combined platinum, 5-fluorouracil, and cetuximab. Recently, the ICI pembrolizumab was approved as a first-line treatment, with or without chemotherapy, based on tumor and immune cell percentage of programmed-death ligand 1 (PD-L1). Multiple head and neck (HN) cancer trials have subsequently explored immunotherapies in combination with surgery, chemotherapy, and/or radiation. Immunotherapy regimens may be personalized by tumor biomarker, including PD-L1 content, tumor mutational burden, and microsatellite instability. However, further clinical trials are needed to refine biomarker-driven protocols and standardize pathological methods to guide combined regimen timing, sequencing, and deescalation. Gaps remain for protocols using immunotherapy to reverse oral premalignant lesions, particularly high-risk leukoplakias. A phase II nonrandomized controlled trial, using the ICI nivolumab, showed a 2-y cancer-free survival of 73%, although larger trials are needed. Guidelines are also needed to standardize the role of dental evaluation and care before, during, and after immunotherapy, specifically in regard to oral immune-related adverse events and their impact on cancer recurrence. Standardized diagnostic and oral care coordination strategies to close these gaps are needed to ensure continued success of HN cancer immunotherapy.

Reactive Chlorine Species Reversibly Inhibit DnaB Protein Splicing in Mycobacteria.

Intervening proteins, or inteins, are mobile genetic elements that are translated within host polypeptides and removed at the protein level by splicing. In protein splicing, a self-mediated reaction removes the intein, leaving a peptide bond in place. While protein splicing can proceed in the absence of external cofactors, several examples of conditional protein splicing (CPS) have emerged. In CPS, the rate and accuracy of splicing are highly dependent on environmental conditions. Because the activity of the intein-containing host protein is compromised prior to splicing and inteins are highly abundant in the microbial world, CPS represents an emerging form of posttranslational regulation that is potentially widespread in microbes. Reactive chlorine species (RCS) are highly potent oxidants encountered by bacteria in a variety of natural environments, including within cells of the mammalian innate immune system. Here, we demonstrate that two naturally occurring RCS, namely, hypochlorous acid (the active compound in bleach) and N-chlorotaurine, can reversibly block splicing of DnaB inteins from Mycobacterium leprae and Mycobacterium smegmatis in vitro. Further, using a reporter that monitors DnaB intein activity within M. smegmatis, we show that DnaB protein splicing is inhibited by RCS in the native host. DnaB, an essential replicative helicase, is the most common intein-housing protein in bacteria. These results add to the growing list of environmental conditions that are relevant to the survival of the intein-containing host and influence protein splicing, as well as suggesting a novel mycobacterial response to RCS. We propose a model in which DnaB splicing, and therefore replication, is paused when these mycobacteria encounter RCS. IMPORTANCE Inteins are both widespread and abundant in microbes, including within several bacterial and fungal pathogens. Inteins are domains translated within host proteins and removed at the protein level by splicing. Traditionally considered molecular parasites, some inteins have emerged in recent years as adaptive posttranslational regulatory elements. Several studies have demonstrated CPS, in which the rate and accuracy of protein splicing, and thus host protein functions, are responsive to environmental conditions relevant to the intein-containing organism. In this work, we demonstrate that two naturally occurring RCS, including the active compound in household bleach, reversibly inhibit protein splicing of Mycobacterium leprae and Mycobacterium smegmatis DnaB inteins. In addition to describing a new physiologically relevant condition that can temporarily inhibit protein splicing, this study suggests a novel stress response in Mycobacterium, a bacterial genus of tremendous importance to humans.

A comparison of clinical outcomes of acute testicular torsion between prepubertal and postpubertal males.

SHORT INTRODUCTION/BACKGROUND: Surgical intervention for acute testicular torsion can require either orchiopexy or orchiectomy. The decision of which surgery to perform is dependant on the amount of time that the testicle experienced ischemia and the viability of the testicle after reperfusion. OBJECTIVE: It is hypothesized that (1) there is a difference in orchiectomy and orchiopexy rates between prepubertal and postpubertal males with acute testicular torsion and (2) presenting symptoms may vary between the two age groups as prepubertal males may present with atypical symptoms, which could result in delayed presentation and diagnosis. STUDY DESIGN: A retrospective chart review was conducted on pediatric patients who were diagnosed with acute testicular torsion between June 2010 and August 2017. Demographic and clinical characteristics were extracted: age, ethnicity, referral pattern, primary insurance status, symptoms at presentation, prior history of ipsilateral testicular pain or intermittent torsion, recent trauma to genitalia, duration of symptoms (hours), gradual vs. acute onset of symptoms, time/weekday/season at presentation, and time interval from arrival at the study institution to surgical intervention (minutes). Patients were categorized into two groups: prepubertal group (age 1-12 years) and postpubertal group (age 13-18 years). Statistical analyses were performed using R, version 3.3.1. RESULTS: Ninety-one patients were included in the study. The overall orchiectomy rate was 30.8%. More prepubertal males underwent orchiectomy than postpubertal males (42.4% vs. 24.1%, respectively). Prepubertal males were more likely to present with abdominal pain than postpubertal males (27.3% vs. 10.3%, respectively). Those who underwent orchiectomy were more likely to present with longer duration of symptoms, testicular swelling, and abdominal pain than those who underwent orchiopexy. The risk of orchiectomy decreased by 14% per 1-year increase in age (odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.94-1.00, p = .009). A steady decline in the proportion of patients undergoing orchiectomy was seen from 1 to 12 years of age. DISCUSSION: This study found that prepubertal males are at higher risk for orchiectomy than postpubertal males. The risk of orchiectomy decreases by 14-16% per 1-year increase in age. Prepubertal males are more likely to present with atypical symptoms and delayed presentation and diagnosis, leading to delayed surgical intervention. It is important for providers to perform a genital examination in prepubertal males who present with abdominal pain to rule out acute testicular torsion. Patients presenting with longer duration of symptoms, testicular swelling, and abdominal pain are at higher risk for orchiectomy. No correlation was found between orchiectomy rate and ethnicity, referral status, primary insurance status, and time/weekday/season at presentation. CONCLUSION: Among patients presenting to a tertiary pediatric hospital with acute testicular torsion, prepubertal males (younger than 12 years) are at higher risk for orchiectomy than postpubertal males. Prepubertal males are more likely to present with atypical symptoms which results in delayed presentation and diagnosis, leading to delayed in surgical intervention.

Mechanics hands in patients with antisynthetase syndrome: 25 cases.

BACKGROUND: Antisynthetase antibodies (ASA) are directed against aminoacyl-tRNA-synthetases, ubiquitous enzymes of which eight types have hitherto been described. They are seen primarily in antisynthetase syndrome (ASS), in which diffuse interstitial lung disease is associated with inflammatory myopathy, joint involvement and cutaneous signs, in particular mechanic's hands. The aim of this study was to determine the prevalence and semiological characteristics of cutaneous involvement in patients presenting ASA. PATIENTS AND METHODS: We carried out a retrospective study of the medical files of patients with ASA diagnosed at the Strasbourg University Hospital between 1994 and 2009. RESULTS: We identified 22 women and 3 men presenting ASS (n=21), dermatomyositis (n=3) or sclerodermatomyositis (n=1). Mean age at the time of diagnosis was 56 years (12-79). The most commonly seen antibodies were anti-Jo1 (n=19), with the other cases of ASA involving anti-PL12 (n=3), anti-PL7 (n=2) and anti-EJ (n=1) antibodies. Five patients died from pulmonary complications. Mechanic's hands (characteristic plaques and papules along the edge of the first fingers on both hands) were found in 10 patients with ASS (7 cases) or dermatomyositis (3 cases), at the time of diagnosis in 7 cases and during a systemic episode in 3 cases. Muscular involvement was seen in all patients: 9 had diffuse interstitial lung disease and 8 had joint involvement. Cutaneous signs regressed totally or partially in all patients under treatment; in 6 patients, worsening was seen during systemic episodes of the disease. One of the 10 patients died through pulmonary complications. DISCUSSION: Mechanic's hands are a key indicator in cases of ASA and its outcome is intimately linked with underlying systemic involvement, particularly pulmonary. The characteristic semiology enables this disorder to be recognised and allows differentiation from psoriasis or irritant contact dermatitis of the hands, and it does not vary according to antibody. Whether or not the disease is life-threatening is unaffected by the presence of this sign.

Atmospheric emission characterization of Marcellus shale natural gas development sites.

Limited direct measurements of criteria pollutants emissions and precursors, as well as natural gas constituents, from Marcellus shale gas development activities contribute to uncertainty about their atmospheric impact. Real-time measurements were made with the Aerodyne Research Inc. Mobile Laboratory to characterize emission rates of atmospheric pollutants. Sites investigated include production well pads, a well pad with a drill rig, a well completion, and compressor stations. Tracer release ratio methods were used to estimate emission rates. A first-order correction factor was developed to account for errors introduced by fenceline tracer release. In contrast to observations from other shale plays, elevated volatile organic compounds, other than CH4 and C2H6, were generally not observed at the investigated sites. Elevated submicrometer particle mass concentrations were also generally not observed. Emission rates from compressor stations ranged from 0.006 to 0.162 tons per day (tpd) for NOx, 0.029 to 0.426 tpd for CO, and 67.9 to 371 tpd for CO2. CH4 and C2H6 emission rates from compressor stations ranged from 0.411 to 4.936 tpd and 0.023 to 0.062 tpd, respectively. Although limited in sample size, this study provides emission rate estimates for some processes in a newly developed natural gas resource and contributes valuable comparisons to other shale gas studies.

Note: Effect of photodiode aluminum cathode frame on spectral sensitivity in the soft x-ray energy band.

Silicon photodiodes used for soft x-ray detection typically have a thin metal electrode partially covering the active area of the photodiode, which subtly alters the spectral sensitivity of the photodiode. As a specific example, AXUV4BST photodiodes from International Radiation Detectors have a 1.0 µm thick aluminum frame covering 19% of the active area of the photodiode, which attenuates the measured x-ray signal below ~6 keV. This effect has a small systematic impact on the electron temperature calculated from measurements of soft x-ray bremsstrahlung emission from a high-temperature plasma. Although the systematic error introduced by the aluminum frame is only a few percent in typical experimental conditions on the Madison Symmetric Torus, it may be more significant for other instruments that use similar detectors.

Density of tobacco retailers and its association with sociodemographic characteristics of communities across New York.

OBJECTIVE: To examine the association of community median income, race/ethnicity and age with the availability of tobacco products in New York State and six subareas. STUDY DESIGN: Spatial regression analysis applied to licensed tobacco retailer and sociodemographic data in 2009 in New York. METHODS: This study assessed the association between tobacco retailer density and four demographic correlates (percentage African American, percentage Hispanic, percentage aged <18 years and median household income) at the census tract level in New York in 2009. Associations were modelled for New York State and six subareas: Greater New York City/Long Island, New York minus Greater New York City/Long Island (rest of State), the Capital region (containing the city of Albany and surrounding areas), Erie County (containing the city of Buffalo), Monroe County (containing the city of Rochester) and Onondaga County (containing the city of Syracuse). In total, 19,420 licensed tobacco retailers were linked to 4795 residential census tracts. RESULTS: In New York State, residential census tracts with higher proportions of African Americans and Hispanics generally had a significantly higher density of tobacco retailers. Census tracts with a higher percentage of residents aged <18 years and higher median household income generally had a significantly lower density of tobacco retailers. However, these associations were not statistically significant in all areas studied. CONCLUSIONS: Tobacco retailers tend to be more densely distributed in areas characterized by high minority or low-income populations, but these associations were not found in all areas. This may suggest that policy measures to reduce the density of tobacco retailers may be more effective at reducing disparities in tobacco availability and exposure to point-of-sale advertising in some areas than in others.

[Persisting pain after open articulosynovectomy--gossypiboma]. / Persistierende Schmerzen nach offener Artikulosynovektomie am Kniegelenk--die vergessene Kompresse.

We report about a 44-year-old woman who presented at our Orthopaedic Department suffering from persisting pain and a tumor of the right knee after open articulosynovectomy. MRI did not clarify the entity at all. The X-ray examination could identify an inlying compress after a synovectomy in 1999. The intra-articular foreign body could be removed by open revision surgery.

Update on Anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: results of a multicenter study.

AIM: Anti-Saccharomyces cerevisiae antibodies (ASCA), anti-nuclear associated anti-neutrophil antibodies (NANA) and antibodies to exocrine pancreas (PAB), are serological tools for discriminating Crohn's disease (CrD) and ulcerative colitis (UC). Like CrD, coeliac disease (CoD) is an inflammatory bowel disease (IBD) associated with (auto) antibodies. Performing a multicenter study we primarily aimed to determine the performance of ASCA, NANA and PAB tests for IBD diagnosis in children and adults, and secondarily to evaluate the prevalence of these markers in CoD. METHODS: Sera of 109 patients with CrD, 78 with UC, 45 with CoD and 50 healthy blood donors were retrospectively included. ASCA, NANA and PAB were detected by indirect immunofluorescence (IIF). RESULTS: ASCA+/NANA- profile displayed a positive predictive value of 94.2% for CrD. Detection of ASCA was correlated with a more severe clinical profile of CrD and treatment of the disease did not influence their serum levels. ASCA positivity was found in 37.9% of active CoD. PAB were found in 36.7% CrD and 13.3% CoD patients and were not correlated with clinical features of CrD, except with an early onset of the disease. Fifteen CrD patients were ASCA negative and PAB positive. CONCLUSION: ASCA and PAB detected by IIF are specific markers for CrD although their presence does not rule out a possible active CoD. The combination of ASCA, NANA and PAB tests improves the sensitivity of immunological markers for CrD. Repeating ASCA, NANA, and PAB testing during the course of CrD has no clinical value.

Frequent requirement of hedgehog signaling in non-small cell lung carcinoma.

Although it had previously been suggested that the hedgehog (HH) pathway might be activated in some lung tumors, the dependence of non-small cell lung carcinomas (NSCLC) for HH activity had not been comprehensively studied. During a screen of a panel of 60 human tumor cell lines with an HH antagonist, we observed that the proliferation of a subset of NSCLC cell lines was inhibited. These NSCLC cell lines express HH, as well as key HH target genes, consistent with them being activated through an autocrine mechanism. Interestingly, we also identified a number of NSCLC cell lines that express high levels of the downstream transcription factor GLI1 and harbor enhanced levels of HH activity, but appear insensitive to known HH antagonists. We hypothesized that the high levels of GLI1 in these cells would function downstream of the HH antagonist target, allowing them to bypass the antagonist-mediated block in proliferation. Consistent with this hypothesis, when the levels of GLI1 are knocked down in such cells, they become sensitive to these inhibitors. We go on to show that a large percentage of primary NSCLC samples express GLI1, consistent with constitutive activation of the HH pathway in these samples. Taken together, these results establish the involvement of the HH signaling pathway in a subset of NSCLCs.

Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren's syndrome.

BACKGROUND: B cell activation may result in an increased secretion of immunoglobulin free light chains (FLCs) in autoimmune diseases. OBJECTIVE: To analyse serum FLC levels in patients with rheumatoid arthritis and in those with primary Sjögren's syndrome (pSS). PATIENTS AND METHODS: Blood samples were collected from 80 healthy blood donors, 50 patients with rheumatoid arthritis and 139 patients with pSS. Serum FLC level was measured using a new quantitative immunoassay. RESULTS: Mean (standard error (SE)) serum kappa and lambda FLC levels were significantly higher in patients with rheumatoid arthritis and in those with pSS than in controls (kappa : 18.9 (1.1) and 16.3 (1.4) v 10.5 (0.4) mg/l, p<0.001 and p = 0.001, respectively; lambda: 16.7 (1.2) and 19.3 (1.5) v 11.6 (0.6) mg/l, p<0.001 for both). 18 (36%) patients with rheumatoid arthritis and 31 (22.3%) patients with pSS had abnormal serum FLC levels (increased kappa or lambda levels and abnormal ratio of kappa:lambda). Serum kappa and lambda levels were correlated with other B cell activation markers in both diseases. FLC levels increased with disease activity, because, unlike total gammaglobulin and immunoglobulin G levels, they were significantly correlated with Disease Activity Score 28 in patients with rheumatoid arthritis (p = 0.004 for kappa, p = 0.05 for lambda) and with extraglandular involvement in pSS (p = 0.01 for kappa, p = 0.04 for lambda). CONCLUSION: FLC levels are increased and correlate with disease activity in patients with rheumatoid arthritis and in those with pSS, two diseases in which increased risk of lymphoma could result from persistent B cell activation and disease activity. Further studies are required to determine whether FLC assessment could represent a relevant biomarker for response to treatment (especially B cell depletion) and for the risk of lymphoma in autoimmune diseases.

Anti-pm/scl antibodies in connective tissue disease: Clinical and biological assessment of 14 patients.

INTRODUCTION: Anti-PM/Scl antibodies (Anti-PM/Scl) represent a rarely encountered type of antinuclear antibodies. They have mainly been reported in association with idiopathic inflammatory myositis - systemic sclerosis overlap syndromes (also called scleromyositis or sclerodermatomyositis) but also with polymyositis, dermatomyositis and systemic sclerosis without features of overlap syndromes. Studies concerning characteristics of patients with anti-PM/SCl are rare and include small numbers of patients. PATIENTS AND METHODS: Retrospective review of clinical and biological characteristics of 14 patients with anti-PM/Scl in two University Hospitals: one in Belgium (Erasme Hospital, Bruxelles) and one in France (Hautepierre Hospital, Strasbourg). RESULTS: Seven patients were identified in Erasme and 7 in Strasbourg: 5 with systemic sclerosis-(dermato)myositis overlap syndromes, 4 with dermatomyositis, 1 with polymyositis, 3 with systemic sclerosis, 1 with primary Sjögren's syndrome. The most frequently observed clinical characteristics (85% of patients) were: pulmonary interstitial disease and arthralgia or arthritis. No patient of our series died or developed cancer (mean follow-up:6.1 years). CONCLUSIONS: Our study failed to identify an homogeneous clinical pattern in patients with anti-PM/Scl, except for 2 characteristics shared by 85% of the patients. This lack of homogeneity is in agreement with preceding literature. We confirm the favourable prognosis associated with the presence of anti-PM/Scl, despite the high incidence of interstitial pulmonary disease. The absence of cancer associated with presence of anti-PM/Scl represents a partial explanation. Finally, we report herein the second case of primary Sjögren's syndrome associated with anti-PM/Scl.

Precision of computer-assisted core decompression drilling of the femoral head.

INTRODUCTION: Osteonecrosis of the femoral head is a local destructive disease with progression into devastating stages. Left untreated it mostly leads to severe secondary osteoarthrosis and early endoprosthetic joint replacement. Core decompression by exact drilling into the ischemic areas can be performed in early stages according to Ficat or ARCO. Computer-aided surgery might enhance the precision of the drilling and lower the radiation exposure time of both staff and patients. The aim of this study was to evaluate the precision of the fluoroscopically based VectorVision navigation system in an in vitro model. MATERIALS AND METHODS: Thirty sawbones were prepared with a defect filled up with a radiopaque gypsum sphere mimicking the osteonecrosis. Twenty sawbones were drilled by guidance of an intraoperative navigation system VectorVision (BrainLAB, Munich, Germany) and 10 sawbones by fluoroscopic control only. RESULTS: No gypsum sphere was missed. There was a statistically significant difference regarding the three-dimensional deviation (Euclidian norm) as well as maximum deviation in x-, y- or z-direction (maximum norm) to the desired mid-point of the lesion, with a mean of 0.51 and 0.4 mm in the navigated group and 1.1 and 0.88 mm in the control group, respectively. Furthermore, significant difference was found in the number of drilling corrections as well as the radiation time needed: no second drilling or correction of drilling direction was necessary in the navigated group compared to 1.4 in the control group. The radiation time needed was less than 1 s compared to 3.1 s, respectively. CONCLUSION: The fluoroscopy-based VectorVision navigation system shows a high feasibility of computer-guided drilling with a clear reduction of radiation exposure time and can therefore be integrated into clinical routine. The additional time needed is acceptable regarding the simultaneous reduction of radiation time.

Precision of computer-assisted core decompression drilling of the knee.

INTRODUCTION: Core decompression by exact drilling into the ischemic areas is the treatment of choice in early stages of osteonecrosis of the femoral condyle. Computer-aided surgery might enhance the precision of the drilling and lower the radiation exposure time of both staff and patients. The aim of this study was to evaluate the precision of the fluoroscopically based VectorVision-navigation system in an in vitro model. MATERIALS AND METHODS: Thirty sawbones were prepared with a defect filled up with a radiopaque gypsum sphere mimicking the osteonecrosis. 20 sawbones were drilled by guidance of an intraoperative navigation system VectorVision (BrainLAB, Munich, Germany). Ten sawbones were drilled by fluoroscopic control only. RESULTS: A statistically significant difference with a mean distance of 0.58 mm in the navigated group and 0.98 mm in the control group regarding the distance to the desired mid-point of the lesion could be stated. Significant difference was further found in the number of drilling corrections as well as radiation time needed. CONCLUSION: The fluoroscopic-based VectorVision-navigation system shows a high feasibility and precision of computer-guided drilling with simultaneously reduction of radiation time and therefore could be integrated into clinical routine.

Diagnostic value of anti-F-actin antibodies in a French multicenter study.

According to international criteria, autoimmune hepatitis (AIH) type 1 is characterized by the presence of antinuclear or anti-smooth muscle antibodies (SMA) with F-actin specificity. SMA have been found in 85% of AIH patients, but are not specific to this disease, and anti-F-actin specificity is not always verified when SMA are detected. The objective of this study was to determine the diagnostic value of anti-F-actin antibodies in a large population. A multicenter study involving 12 clinical centers was performed. Patients were selected on the basis of the presence of F-actin SMA detected by indirect immunofluorescence (IIF) on rat liver-kidney-stomach sections and was confirmed by IIF on Hep2 cells treated with colchicine, or F-actin dot-blot. The clinical status of patients was determined from their medical records. One hundred sixty-eight patients were included: 76% women, 24% men; mean age of 45 years (range, 2-88 years), with a bimodal age distribution. Sixty percent had AIH type 1, and 40% had another disease. In the group of women younger than 25 years, 90% had AIH type 1. Other pathologies associated with antiactin were other liver diseases (19%), including viral hepatitis C (7%), and non-liver diseases (21%), including connective tissue diseases (12%). Antibody titers were higher in AIH than in other diseases. Antiactin antibodies are of major diagnostic value in AIH, especially in young women; they may be found in other disease settings, but mostly at low levels.

Evaluation of anti-citrullinated filaggrin antibodies as hallmarks for the diagnosis of rheumatic diseases.

BACKGROUND: Anti-filaggrin antibodies (AFA) are among the most specific antibodies for rheumatoid arthritis, so procedures for their detection should be included in early biological diagnoses. AFA can be detected by indirect immunofluorescence (anti-keratin antibodies, AKA) or by new enzyme immunoassays (EIA). Their comparative performance needs to be established. OBJECTIVE: To compare these technical procedures to optimise the serological diagnosis of rheumatoid arthritis. METHODS: Results obtained using AKA and EIA were compared in 271 sera from 140 patients with rheumatoid arthritis at various stages, 98 patients with other autoimmune diseases, and 33 healthy subjects. EIA were successively undertaken with citrullinated linear filaggrin peptide (home made EIA) or cyclic citrullinated peptide (CCP2, commercial kits). Rheumatoid factor (RF) was assessed by EIA in all patients. RESULTS: Anti-CCP2 kits showed the best sensitivity and specificity (65% and 96%, respectively). Among the 140 patients with rheumatoid arthritis, those with very recent disease (less than six months' duration, n = 21) were studied as a separate group. In this group, the sensitivity of anti-CCP2 kits decreased to approximately 50%. Nevertheless this assay remained the most accurate when compared with AKA or home made EIA using linear filaggrin peptides. The combination of anti-CCP2 and RF only slightly increased the sensitivity of the diagnosis of very early rheumatoid arthritis. CONCLUSIONS: Kits using citrullinated cyclic peptides (CCP2) were more suitable than either AKA or EIA using linear filaggrin peptides for the diagnosis of early rheumatoid disease.

Primary Sjögren's syndrome associated agranulocytosis: a benign disorder?

OBJECTIVE: To report on an uncommon association of agranulocytosis in primary Sjögren's syndrome (SS). METHODS: The clinical, haematological, and immunological features of seven patients with primary SS associated with a chronic (>6 months) agranulocytosis, and the outcome of the patients, were analysed. RESULTS: Patients were white women with an unexplained agranulocytosis. They all had non-erosive arthritis and three had a thrombocytopenia or Evan's syndrome. In three patients, transient or durable expansion of T lymphocytes was present in the peripheral blood or in the bone marrow, but evolved independently from neutrophil counts. There was no paroxysmal nocturnal haemoglobinuria clone or antibodies to neutrophil surface antigens. In vitro bone marrow culture was normal (four patients) or showed a decrease in colony forming unit-granulocyte monocyte (CFU-GM) and colony forming unit-erythroblast (CFU-E) (one patient). Serum levels of soluble Fas ligand (sFasL) were normal, and granulocyte-colony stimulating factor (G-CSF) concentrations were either normal or raised. One patient was treated with steroids associated with intravenous immunoglobulins and achieved a lasting response. Two other patients were treated with steroids and methotrexate, with poor efficacy. Short courses of subcutaneous G-CSF produced a transient and mild response in all three patients. Complete recovery of the neutrophils occurred temporarily during pregnancy in two patients. After a mean follow up of 34.8 months (range 6-139) all patients were alive and none developed serious infections. CONCLUSION: A subset of patients with primary SS and non-destructive arthritis may develop a chronic but well tolerated agranulocytosis that is usually poorly responsive to steroids and oral methotrexate.

Production of ochratoxin A by Aspergillus carbonarius on coffee cherries.

Robusta coffee cherries collected before and during sun drying from two coffee farms in Thailand were examined for moulds producing ochratoxin A (OA). Aspergillus ochraceus was only detected in one sample, whereas Aspergillus carbonarius was isolated from 7 out of 14 samples. On gamma-irradiated coffee cherries, each of the six tested A. carbonarius strains produced OA. More than 4800 microg kg(-1) of toxin were detected under optimal conditions (25 degrees C, a(w) 0.99). OA production was strongly reduced (230 microg kg(-1)) at an a(w) of 0.94.

In vivo association of ATFa with JNK/SAP kinase activities.

The human ATFa proteins belong to the CREB/ATF family of transcription factors. We have previously shown that the ATFa proteins may contribute to the modulation of the transcriptional activity of the Jun/Fos complexes (Chatton et al. (1994). Oncogene, 9, 375-385). We now show that a protein kinase activity is strongly associated with ATFa in vivo, as revealed by coimmunoprecipitation of ATFa/kinase complexes from whole cell extracts, with antibodies against ATFa. Two independent regions were found to be implicated in kinase binding: a major interaction site is located within the N-terminal 82 residues comprising an important metal-chelating element; a weaker binding site corresponds to the basic sequence element preceding the C-terminal leucine-zipper of ATFa. Induction experiments suggest that each of these ATFa domains may interact with different kinases. The major activity is associated with the ATFa N-terminal domain. Based on its response to various inducers, on both in vitro and in vivo binding assays, and on its immunological properties, this activity most likely corresponds to the 54/55 kDa JNK2 protein. Taken together, these observations suggest that the ATFa proteins, among other CREB/ATF proteins, may be important effectors of cell signalling pathways.

[Diplopia as a complication after surgery for strabismus in adolescents and adults]. / Dwojenie jako powiklanie po operacji zeza u mlodziezy i doroslych.

Diplopia may occur following surgery for the correction of constant manifest strabismus. Young children rarely complain of diplopia because of the plasticity of their visual system and the rapid development of suppression. However, in older children and adults post-operative diplopia may occur either as a transient well-tolerated phenomenon or occasionally as an intractable problem. It is a standard practice to carry out tests prior to surgery to try and predict the risk of post-operative diplopia, although the value of these tests and the incidence and severity of diplopia following squint surgery is not well documented. We reviewed the records of these 22 out of all our patients operated for squint who had diplopia (aged 13-45). 13 subjects presented diplopia only for 1 or 2 days after surgery 8 had intermittent one with good tolerance and 1 acquired constant diplopia (she was operated). Pre- and post-operative agents which could have had an impact on diplopia occurrence were evaluated. Diplopia was found in 48% patients who had positive test predicting the risk of post-operative diplopia. The test thus seems to be quite limited in its reliability and prior to surgery the patients should be thoroughly informed about a possibility of diplopia occurring as a surgery complication.