MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses.

Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favours pro- or anti-inflammatory CD4+ T cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4+ T cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4+ T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4+ T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus-specific CD4+ T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen presenting cells and that IEC MHC II expression fine-tunes local effector CD4+ T cell responses during intestinal inflammation.

[A man with acute decline in vision and sleep apnoea]. / Een man met een acute visusdaling en slaapapneus.

BACKGROUND: Non-arteritic anterior ischaemic optic neuropathy (NAION) is the most common acute optic neuropathy in people older than 50 years. CASE DESCRIPTION: A 66-year-old man with hypertension consulted the ophthalmologist because of increasing visual-field loss in his right eye; 3 weeks previously he had noticed visual decline in the same eye when he woke up. The eye was not painful. Further questioning revealed that the patient also suffered from sleep apnoea. Following additional investigations we diagnosed NAION. CONCLUSION: There is no effective treatment for NAION. Risk factors such as high blood pressure and obstructive sleep apnoea syndrome can be addressed to reduce the risk of reoccurrence of NAION in the other eye.

Management and outcomes of intraductal papillary mucinous neoplasms.

Background: This study evaluated the outcome and survival of patients with radiologically suspected intraductal papillary mucinous neoplasms (IPMNs). Methods: IPMN management was reviewed according to Fukuoka risk factors and IPMN localization, differentiating main-duct (MD), mixed-type (MT) and branch-duct (BD) IPMNs. Perioperative results were compared with those of patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) over the same interval (2010-2014). Overall (OS) and disease-specific (DSS) survival rates were calculated and subgroups compared. Results: Of 142 patients with IPMNs, 26 had MD-IPMN, eight had MT-IPMN and 108 had BD-IPMN. Some 74 per cent of patients with MD- and MT-IPMN were managed by primary resection, whereas this was used in only 27·8 per cent of those with BD-IPMN. The risk of secondary resection and malignant transformation for BD-IPMNs smaller than 20 mm was 8 and 2 per cent respectively during follow-up. Pancreatic head resection of IPMNs was associated with an increased risk of postoperative pancreatic fistula grade B/C compared with resection of PDAC (12 of 33 (36 per cent) versus 41 of 221 (18·6 per cent) respectively; P = 0·010), and greater morbidity and mortality (Clavien-Dindo grade III: 15 of 33 (45 per cent) versus 56 of 221 (25·3 per cent) respectively; grade IV: 1 (3 per cent) versus 7 (3·2 per cent); grade V: 2 (6 per cent) versus 2 (0·9 per cent); P = 0·008). Five-year OS and DSS rates in patients with MD-IPMN were worse than those for MT- and BD-IPMN (OS: 44, 86 and 97·4 per cent respectively, P < 0·001; DSS: 60, 100 and 98·6 per cent; P < 0·001). Patients with invasive IPMN had worse OS and DSS rates than those with non-invasive dysplasia (OS: IPMN-carcinoma (10 patients) 33 per cent, high-grade dysplasia 100 per cent, intermediate-grade dysplasia 63 per cent, low grade-dysplasia 100 per cent, P < 0·001; DSS: IPMN-carcinoma 43 per cent, all grades of dysplasia 100 per cent, P < 0·001). Patients with high-risk stigmata had poorer survival than those without risk factors (OS: high-risk stigmata (35 patients) 55 per cent, worrisome features (31) 95 per cent, no risk factors (76) 100 per cent, P < 0·001; DSS: 71, 100 and 100 per cent respectively, P < 0·001). Conclusion: The risk of malignant transformation was very low for BD-IPMNs, but the development of high-risk stigmata was associated with disease-specific mortality. Patients with IPMN had greater morbidity after resection than those having resection of PDAC.

Functional outcomes of upper eyelid blepharoplasty: A systematic review.

OBJECTIVE: Various functional outcomes after upper blepharoplasty are reported in the literature. We systematically reviewed the literature to assess the objective and subjective functional effects of upper blepharoplasty. METHODS: After a systematic search of four search engines (Pubmed, Embase, Cinahl and Cochraine), any study on objective and subjective (patient reported) functional outcome after upper blepharoplasty was subjected to a quality assessment for possible inclusion in the review. The intervention was defined as a solitary surgical upper blepharoplasty containing the removal of skin, with or without the removal of a strip of orbicularis oculi muscle and/or upper orbital fat. Eligible studies were randomized controlled trials, controlled trials, cohort studies and case series (n ≥ 10). RESULTS: A total of 3525 studies were assessed, of which 28 studies were included in this systematic review. Favorable outcomes after an upper blepharoplasty were reported and included enlarged visual field, enhanced quality of life related to fewer headaches and improved vision. Furthermore, sensitivity of the eyelids decreased, with differences in recovery. Outcomes for eyebrow height, astigmatism, contrast sensitivity and eyelid kinematics were not consistent between the studies. No meta-analysis could be performed due to the limited scope of included studies and the great variety in outcomes and blepharoplasty techniques. CONCLUSIONS: Upper blepharoplasty is accompanied by a great variety of beneficial functional outcomes including an increased visual field and improvement in headache- and vision-related quality of life. Further research is needed, especially where results are conflicting (effects on eye dryness and eyebrow height) and/or the data are limited (contrast sensitivity, astigmatism).

Identification of a haplotype associated with cholesterol deficiency and increased juvenile mortality in Holstein cattle.

Over the last decades, several genetic disorders have been discovered in cattle. However, the genetic background of disorders in calves is less reported. Recently, German cattle farmers reported on calves from specific matings with chronic diarrhea and retarded growth of unknown etiology. Affected calves did not respond to any medical treatment and died within the first months of life. These calves were underdeveloped in weight and showed progressive and severe emaciation despite of normal feed intake. Hallmark findings of the blood biochemical analysis were pronounced hypocholesterolemia and deficiency of fat-soluble vitamins. Results of the clinical and blood biochemical examination had striking similarities with findings reported in human hypobetalipoproteinemia. Postmortem examination revealed near-complete atrophy of the body fat reserves including the spinal canal and bone marrow. To identify the causal region, we performed a genome-wide association study with 9 affected and 21,077 control animals genotyped with the Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA), revealing a strong association signal on BTA 11. Subsequent autozygosity mapping identified a disease-associated haplotype encompassing 1.01 Mb. The segment of extended homozygosity contains 6 transcripts, among them the gene APOB, which is causal for cholesterol disorders in humans. However, results from multi-sample variant calling of 1 affected and 47 unaffected animals did not detect any putative causal mutation. The disease-associated haplotype has an important adverse effect on calf mortality in the homozygous state when comparing survival rates of risk matings vs. non-risk matings. Blood cholesterol values of animals are significantly associated with the carrier status indicating a codominant inheritance. The frequency of the haplotype in the current Holstein population was estimated to be 4.2%. This study describes the identification and phenotypic manifestation of a new Holstein haplotype characterized by pronounced hypocholesterolemia, chronic emaciation, growth retardation, and increased mortality in young cattle, denominated as cholesterol deficiency haplotype. Our genomic investigations and phenotypic examinations provide additional evidence for a mutation within the APOB gene causing cholesterol deficiency in Holstein cattle.

The prevalence of microcystic macular changes on optical coherence tomography of the macular region in optic nerve atrophy of non-neuritis origin: a prospective study.

BACKGROUND: Microcystic macular changes, also called microcystic macular oedema, have recently been reported in patients with multiple sclerosis, particularly after optic neuritis. But it has since emerged that the finding is not specific for optic neuritis. This study was designed to prospectively investigate the prevalence of microcystic perifoveal changes in patients with optic atrophy not due to optic neuritis. METHODS: A prospective, cross-sectional study including 54 patients with a history of optic atrophy and 54 healthy control subjects. Spectral domain optical coherence tomography (SD-OCT) was used to scan the macular area and to measure the peripapillar retinal nerve fibre layer thickness. Scanning laser ophthalmoscopy (SLO) was used for imaging of the macular area. RESULTS: Microcystic macular changes were present in 11/54 patients (20.4%), 17/90 eyes with optic atrophy (18.9%) and absent in the normal eyes of patients with monocular optic atrophy and all healthy control eyes. No correlations were found with the age, duration of optic atrophy or severity of optic atrophy. Besides the known perifoveal (semi) circular abnormal reflexes on SLO imaging, we also noticed a more patchy pattern of low SLO reflections in some patients with optic atrophy. CONCLUSIONS: Microcystic macular changes are a frequent observation in patients with optic atrophy of another cause than optic neuritis. The cause of these abnormalities remains a matter of debate. It is important for clinicians to recognise these macular changes and to realise that the cause may lie remotely away from the macula.

Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3⁺ Treg cell function in the intestine.

Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4(+) T cells are poorly understood. Here we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4(+) T cells in the intestinal lamina propria, with T helper type 17 (Th17) cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells constitutively secrete IL-18 that acts directly on IL-18R1-expressing CD4(+) T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1 signaling. In addition, although IL-18R1 is not required for colonic Foxp3(+) regulatory T (Treg) cell differentiation, we found that IL-18R1 signaling was critical for Foxp3(+) Treg cell-mediated control of intestinal inflammation, where it promoted the expression of key Treg effector molecules. Thus IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4(+) T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders.

The agreement between abnormal venous lactate and arterial lactate in the ED: a retrospective chart review.

INTRODUCTION: The evidence for prognostication using lactate is often based on arterial lactate (AL). Arterial sampling is painful and difficult, and carries risks. Studies comparing peripheral venous lactate (PVL) with AL showed little difference but predominantly included patients with normal lactate. The objective of this study was to measure agreement between PVL and AL in patients with elevated venous lactate. METHODS: This is a retrospective cross-sectional study. INCLUSION CRITERIA: ED patients age≥16, attending from October 2010 to June 2011 inclusive, with PVL≥2.0 mmol/L and AL taken within 1 hour. EXCLUSION CRITERIA: intravenous fluid prior to or between initial venous and arterial sampling. Primary endpoint: agreement between PVL and AL defined as mean difference±95% limits of agreement (LOA). The misclassification rate was assessed. RESULTS: N=232. VL median 3.50 mmol/L, range 2.00 to 15.00 mmol/L. AL median 2.45 mmol/L, range 1.0 to 13.2 mmol/L. The mean difference±SD between PVL and AL for all patients was 1.06±1.30 mmol/L (95%LOA -1.53 to 3.66 mmol/L). Using a cut-off of 2 mmol/L and 4 mmol/L, 36.2% and 17.9% of patients respectively were incorrectly classified as having elevated lactate. CONCLUSION: We report greater bias between VL and AL with broader LOA than previously documented. This may partly be due to the fact that we studied only patients with abnormal venous values, for whom close agreement would confer greatest clinical significance. The agreement between abnormal PVL and AL is poor and the high rate of misclassification may suggest that PVL is not a good substitute for AL if the venous lactate is abnormal.

NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen.

The inflammasomes have an important role in connecting the detection of endogenous and microbial danger signals to caspase-1 activation and induction of protective immune responses. NLRC4 is a cytosolic NOD (nucleotide binding and oligomerization domain)-like receptor (NLR) that can trigger inflammasome formation in response to bacterial flagellin, an immunodominant antigen in the intestine. To characterize the role of NLRC4 in bacterially triggered intestinal inflammation, we used the murine pathogen Citrobacter rodentium, an extracellular, attaching/effacing bacterium similar to enterohemorrhagic Escherichia coli and enteropathogenic E. coli. Following infection with C. rodentium, we found that Nlrc4(-/-) mice developed more severe weight loss, increased bacterial colonization levels, and exacerbated intestinal inflammation compared with wild-type counterparts. Nlrc4(-/-) mice mounted robust adaptive immune responses but were unable to control early colonization by C. rodentium, suggesting that a defect in innate immunity was responsible. Experiments using bone marrow (BM) chimeras revealed that the protective effects of NLRC4 were dependent on its expression in non-hematopoietic cells, and quantitative PCR (Q-PCR) analyses revealed that NLRC4 was highly expressed in epithelial crypts but not in intestinal stroma. Thus, early NLRC4 sensing in intestinal epithelial cells regulates colonization by an extracellular bacterial pathogen and limits subsequent intestinal damage.

Cyclic esotropia and the treatment of over-elevation in adduction and V-pattern.

AIM: To describe the development and treatment of V-pattern and bilateral over-elevation in adduction in patients with cyclic esotropia. METHODS: Three patients with cyclic esotropia are described in retrospect. All patients underwent bilateral medial recession, while one patient additionally had a weakening procedure of both inferior oblique muscles. RESULTS: All patients developed a V-pattern and bilateral over-elevation in adduction. After strabismus surgery, normal eye alignment with some signs of binocularity was reached in all three patients. Moreover, the over-elevation in adduction and V-pattern completely resolved. CONCLUSIONS: V-pattern and bilateral over-elevation in adduction was seen in all patients with cyclic esotropia in the stage that fusion was disrupted. Possible explanations for the origin of these patterns are discussed. Strabismus surgery aimed to correct the horizontal esotropic angle restored fusion and eliminated the vertical incommitancies in lateral gaze, and the V-pattern.

Chiasmal coefficient of flash and pattern visual evoked potentials for detection of chiasmal misrouting in albinism.

The diagnosis of albinism can be confirmed by electrophysiological examination, when chiasmal misrouting can be demonstrated. The present study describes a quantitative analysis method for this purpose. A chiasmal coefficient (CC) was calculated by correlating the differential potential over left and right hemisphere, when stimulating left versus right eye. This CC will be negative in albinism and positive in normal individuals. VEPs were recorded in 20 control subjects, four children with congenital motor nystagmus and six children with albinism. In up to 25% of the controls the CC was negative, when using flash VEP. However, with pattern VEP all had a positive CC. All children with albinism had a negative CC. Three of the four patients with congenital motor nystagmus had a positive CC, and one child had a small negative value with flash stimulation. In conclusion, determination of CC is a valuable and objective analysis method for electrophysiological determination of chiasmal misrouting. The method is relatively simple and only needs two electrode tracings. One should be aware of false-positive results when using flash stimulation. Whenever possible pattern stimulation should be used.

A girl without a chiasm: electrophysiologic and MRI evidence for the absence of crossing optic nerve fibers in a girl with a congenital nystagmus.

An otherwise healthy 15-year-old girl with a congenital nystagmus was evaluated at our department using visual evoked potential recording and magnetic resonance imaging. She appears to have the unique isolated inborn absence of the optic chiasm, described only once before in two unrelated girls. Unlike these previously described cases, our patient does not seem to display a see-saw nystagmus.

Infantile esotropia in very low birth weight (VLBW) children.

VLBW children are known to have a high frequency of early onset strabismus, which is related to the high prevalence of pre- and perinatal cerebral disturbances reported in these children. It is unknown if the early onset strabismus in VLBW children has the characteristics of infantile esotropia. If so, then (acquired) cerebral damage may play an important role in the origin of this type of strabismus. For this reason, the charts of 265 VLBW children were retrospectively reviewed. Strabismus was present in 55 (20.7%) children. Mean follow-up was 75 weeks, with 29.8% of the children having a follow-up of less then 6 months. Only 5 children (1.9%) with characteristics of infantile esotropia could be identified. Another 8 children (3.0%) possibly had infantile esotropia, but follow-up had been too infrequent during the first year of life to determine the time of onset of strabismus precisely. The other 42 children with strabismus all had ophthalmological disorders (i.e. ROP, optic nerve atrophy, cortical blindness) explaining early disruption of binocular visual development. Therefore, VLBW children are at risk for early onset strabismus. However, infantile esotropia is not typical for VLBW children and may be an indication that early acquired cerebral damage does not play an important role in the pathogenesis of infantile esotropia.

Effect of Mg2+ on stress, myosin phosphorylation, and ATPase activity in detergent-skinned swine carotid media.

Smooth muscle contraction has a relatively high requirement for free magnesium (Mg2+). In this study we examined the effect of Mg2+ concentration ([Mg2+]) on Ca2+-dependent stress development and stress maintenance, myosin ATPase activity, and myosin light chain (MLC) phosphorylation levels in Triton X-100 detergent-skinned fibers of the swine carotid media. Increasing [Mg2+] in a stepwise fashion from 0.1 to 6 mM 1) decreased the magnitude and Ca2+ sensitivity of stress development but augmented the amount of stress maintained without proportional MLC phosphorylation, 2) produced a greater decrease in the Ca2+ sensitivity of MLC phosphorylation than that of stress development, and 3) decreased myosin ATPase activity. These findings demonstrate that Mg2+ differentially modulates the MLC phosphorylation-dependent development of stress and the MLC phosphorylation-independent maintenance of stress. We suggest that increases in [Mg2+] enhance stress maintenance by increasing [MgADP], thus increasing the number of cross bridges in a force-generating state, and by a direct effect on the pathway responsible for Ca2+-dependent, MLC phosphorylation-independent contractions.

Screening for suppression in young children: the polaroid suppression test.

BACKGROUND: Assessment of monocular visual impairment during screening of young children is often hampered by lack of cooperation. Because strabismus, amblyopia, or anisometropia may lead to monocular suppression during binocular viewing conditions, a test was developed to screen for suppression in young children. METHODS: Children were invited to look through two polaroid filters of different polarization direction at two pictures covered with polaroid filters of opposite polarization direction. In this way, each eye could only see one of the two pictures. In cases of suppression, only one picture would be visible. Acuity measurements in 201 5-year-old children were compared with the Polaroid Suppresion test (PST) results. RESULTS: The PST had a high success rate (99.5%) and testing time was under 1 minute. Specificity of the PST for acuity impairments was 91%. The low sensitivity of 60% was caused mainly by the fact that some children with binocular acuity impairments were not detected with the PST. However, the PST was highly sensitive for significant interocular acuity differences. CONCLUSION: The PST has been found to be a useful screening method for amblyogenic factors in young children. The test can be carried out without occlusion of one eye. The apparatus is portable, the test duration is short, and the costs are low. The results indicate that the PST is a very promising tool to use in clinical conditions and for screening large numbers of young children.

[Study of the elimination of residues and local tissue injury following intramuscular injection of a solution of the combination trimethoprim/sulfatroxazole in pigs]. / Onderzoek naar de eliminatie van residuen en lokale weefselbeschadiging na intramusculaire injectie van een oplossing van de combinatie van trimethoprim/sulfatroxazol bij varkens.

Two different studies are described. The first study deals with the elimination of residues of trimethoprim (TMP), sulfatroxazole (STX) and its main metabolite N4-acetyl-sulfatroxazole (N4-acetyl-STX) in pigs. Thirty -six pigs were treated with trimethoprim/sulfatroxazole IM in the nec k at a dosage of 16 mg/kg body weight for five days. Groups of four pig s were slaughtered at different time intervals. The study showed that concentration of STX, N4-acetyl-STX and TMP in edible tissues and at the injection sites were below 0.1 ppm on day nine after the last injection. S TX was eliminated the slowest, and STX can therefore be selected as a marker for residues of the trimethoprim/sulfatroxazole formulation in the tissues. The second study deals with irritation aspects of this trimethoprim /sulfatroxazole formulation. Four pigs of 32-35 kg were treated IM w with trimethoprim/sulfatroxazole and benzylpenicillin sodium. Each pig received the same injection volume, namely four trimethoprim/sulfatroxazole injections (16 mg/kg body weight per injection site), two in the back and two in the neck muscle, and two benzylpenicillin sodium injections (20,000 I.U./kg body weight per injection site), in the back muscle. All pigs were slaughtered 14 days after treatment and the extent of the irritation was compared. There were no differences between trimethoprim/sulfatroxazole and benzylpenicillin sodium with regard to irritation at the injection site in the back muscle. The irritation in the neck site was statistically less prominent than that in the back muscle and was considered not to affect the quality of the meat.