The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity

NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an “alternative self” mechanism for MHC class I inhibition.     

Pre-term delivery and periodontal disease: a case-control study from Croatia

AIM: The aim of this report was to assess the strength and influence of periodontitis as a possible risk factor for pre-term birth (PTB) in a cohort of 81 primiparous Croatian mothers aged 18-39 years. METHODS: PTB cases (n = 17; mean age 25 +/- 2.9 years; age range 20-33 years) were defined as spontaneous delivery after less than 37 completed weeks of gestation that were followed by spontaneous labour or spontaneous rupture of membranes. Controls (full-time births) were normal births at or after 37 weeks of gestation (n = 64; mean age 25 +/- 2.9 years; age range 19-39 years). Information on known risk factors and obstetric factors included the current pregnancy history, maternal age at delivery, pre-natal care, nutritional status, tobacco use, alcohol use, genitourinary infections, vaginosis, gestational age, and birth weight. Full-mouth periodontal examination was performed on all mothers within 2 days of delivery. RESULTS: PTB cases had significantly worse periodontal status than controls (p = 0.008). Multivariate logistic regression model, after controlling for other risk factors, demonstrated that periodontal disease is a significant independent risk factor for PTB, with an adjusted odds ratio of 8.13 for the PTB group (95% confidence interval 2.73-45.9). CONCLUSION: Periodontal disease represents a strong, independent, and clinically significant risk factor for PTB in the studied cohort. There are strong indicators that periodontal therapy should form a part of preventive prenatal care in Croatia.     

Assessment of platelet function by whole blood impedance aggregometry in coronary artery bypass grafting patients on acetylsalicylic acid treatment may prompt a switch to dual antiplatelet therapy

Residual platelet reactivity (RPR) following coronary artery bypass grafting (CABG) might be related to thrombotic complications and major ischemic cardiac events. The aim of this study was to evaluate the changes in platelet reactivity monitored pre- and postoperatively using multiple-electrode aggregometry (MEA) and to propose an alternative therapeutic approach in a subgroup of patients with postoperative RPR. Ninety-nine patients undergoing elective CABG were enrolled in the study, of whom 41 (41.4%) were diabetic. Preoperatively, all patients received 100 mg acetylsalicylic acid (ASA), with 47 of 99 (47.4%) patients receiving an additional 75 mg clopidogrel (CLO). The blood samples were drawn the day before surgery, and on the first and 4th postoperative day. Platelet count and fibrinogen level were documented, as well as type and daily dose of antiplatelet therapy (APT) received pre- and postoperatively. Multiple-electrode aggregometry using tests based on arachidonic acid (ASPI test) and adenosine diphosphate (ADP test) was performed on the day before and 4 days after surgery. Preoperatively, we detected 31 of 99 (31.3%) patients with RPR (ASPI > 30 AUC). Platelet count correlated with both the ASPI (P = 0.03) and ADP (0.002) tests. Fibrinogen correlated with ADP test values (P < 0.001) and was found to have a higher level in the diabetic subgroup (P = 0.01). In comparison with preoperative results, we detected higher values of ASPI test postoperatively (P = 0.04), with 46 of 99 (46.5%) patients having RPR despite a higher dose of 300 mg ASA being administered. Postoperatively, diabetic patients had higher ASPI test values (P = 0.01), and a higher proportion of patients with RPR compared with the nondiabetic subgroup (58.5 vs 38%, P = 0.04). The subgroup of patients with detected ASPI >30 AUC at the 4th postoperative day consequently received as a part of our clinical routine an additional 75 mg CLO per day, in terms of platelet inhibition optimization. Multiple-electrode aggregometry can recognize patients with RPR during both the pre- and post-CABG period. Postoperatively administered ASA (300 mg) did not sufficiently inhibit platelet aggregation in 46.5% of post-CABG patients. In this group of patients a switch to dual APT should be considered.     

Both TLR2 and TLR4 are required for the effective immune response in Staphylococcus aureus-induced experimental murine brain abscess

Toll-like receptors (TLRs) play central roles in the innate reaction to bacterial products and transmit specific immune responses against these pathogens. TLRs are expressed on numerous cell types, including innate immune cells, and on astrocytes, neurons, and microglial cells of the central nervous system (CNS). Lipoproteins and lipopolysaccharides are specifically recognized by TLR2 and TLR4, respectively. We examined the in vivo role of TLR2 and TLR4 in Staphylococcus aureus-induced brain abscess. Phenotypically, 87% of TLR2(-/-) mice and 43% of TLR4(-/-) mice died whereas all wild-type (WT) mice recovered. Clearance of bacteria from the CNS was significantly delayed in TLR2(-/-) mice compared with TLR4(-/-) and WT animals. Recruitment of granulocytes and macrophages to the CNS, as well as microglial activation and expansion, was up-regulated in TLR2(-/-) mice. Although inflammation persisted especially in the CNS of TLR2(-/-) mice, but also of TLR4(-/-) mice, WT mice terminated the infection more effectively. Collectively, these data show that the immune response to experimental S. aureus-induced brain abscess depends crucially on the recognition of S. aureus by TLR2 but that TLR4 is also required for an optimal intracerebral immune response in this disorder.     

Frequency of loss of heterozygosity of the NF2 gene in schwannomas from Croatian patients

Aim. To identify gross deletions in the NF2 gene in a panel of schwannomas from Croatian patients in order to establish their frequencies in Croatian population. Methods. Changes of the NF2 gene were tested by polymerase chain reaction/loss of heterozygosity (LOH) using two microsatellite markers, D22S444 and D22S929. Results. The analysis with both markers demonstrated that 43.75% of schwannomas exhibited LOH of the NF2 gene. The D22S444 region exhibited 45.5% of LOHs and the D22S929 region exhibited 14.3% of LOHs. Four LOHs were found in Antoni B, 2 in Antoni A, and 1 in Antoni A and B type tumors. Conclusion. The frequency of changes observed in Croatian patients is broadly similar to that reported in other populations and thus confirms the existing hypothesis regarding the tumorigenesis of schwannomas and contributes to schwannoma genetic profile helping us to better understand its etiology and treatment.     

A cold shock response triggering acute myocardial infarction

Acute risk factors are activities and events that suddenly and transiently increase the risk of acute cardiac events, as reported recently in International Journal of Cardiology. It has already been reported that sudden submersion in cold water may provoke myocardial infarction in both subjects with atherosclerotic coronary disease and young people with angiographically normal coronary arteries.We report a case of an acute myocardial infarction triggered by sudden exposure to cold air temperature extreme in a young person with acutely occluded proximal part of the left anterior descending coronary artery and normal other coronary arteries who had extreme obesity and cigarette smoking as cardiovascular risk factors.Our report indicates that the sudden cold exposure and the resulting cold shock response may provoke acute myocardial infarction in young susceptible patients.     

Eye Histology and Ganglion Cell Topography of Northern Elephant Seals (Mirounga angustirostris)

Northern elephant seals are one of the deepest diving marine mammals. As northern elephant seals often reach the bathypelagic zone, it is usually assumed that their eyes possess evolutionary adaptations that provide better ability to see in dim or scotopic environments. The purpose of this study was to carefully describe anatomical and histological traits of the eye that may improve light sensitivity. Northern elephant seals have large, somewhat elliptical eyes, with equatorial and anteroposterior diameters of 5.03 and 4.4 cm, respectively. The cornea is large in diameter and the lens is completely spherical. The iris has pronounced constrictor and dilator muscles, whereas the ciliary muscle is notably less developed. The tapetum lucidum is more prominent than in other pinnipeds, making up about 63% of retinal thickness in the posterior aspect of the globe. Within the retina, the pigmented epithelium lacks pigment except for the region close to the ora serrata. Parts of the photoreceptor and outer nuclear layers are folded. Although the photoreceptor layer is composed predominantly of rods, cone photoreceptors were also observed. Cells within the retinal ganglion cell layer are arranged in a single level. Ganglion cells reach their maximum density (～1,300 cells per mm²) dorsal to the optic disc, whereas the periphery of the retina is sparsely populated (<100 cells per mm²). All above mentioned features are consistent with the predicted evolutionary adaptations to the photic environment of the bathypelagic zone. Anat Rec, 299:798–805, 2016. © 2016 Wiley Periodicals, Inc.     

Fully Automated Detection and Quantification of Macular Fluid in OCT Using Deep Learning

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Increased plasma N-glycome complexity is associated with higher risk of type 2 diabetes

Aims/hypothesis

Better understanding of type 2 diabetes and its prevention is a pressing need. Changes in human plasma N-glycome are associated with many diseases and represent promising diagnostic and prognostic biomarkers. Variations in glucose metabolism directly affect glycosylation through the hexosamine pathway but studies of plasma glycome in type 2 diabetes are scarce. The aim of this study was to determine whether plasma protein N-glycome is changed in individuals who are at greater risk of developing type 2 diabetes.

Methods

Using a chromatographic approach, we analysed N-linked glycans from plasma proteins in two populations comprising individuals with registered hyperglycaemia during critical illness (increased risk for development of type 2 diabetes) and individuals who stayed normoglycaemic during the same condition: AcuteInflammation (59 cases vs 49 controls) and AcuteInflammation Replication (52 cases vs 14 controls) populations. N-glycome was also studied in individuals from FinRisk (37 incident cases of type 2 diabetes collected at baseline vs 37 controls), Orkney Complex Disease Study (ORCADES; 94 individuals with HbA_1c > 6.5% [47.5 mmol/mol] vs 658 controls) and Southall and Brent Revisited (SABRE) cohort studies (307 individuals with HbA_1c > 6.5% [47.5 mmol/mol] vs 307 controls).

Results

Individuals with increased risk for diabetes type 2 development (AcuteInflammation and AcuteInflammation Replication populations), incident cases of type 2 diabetes collected at baseline (FinRisk population) and individuals with elevated HbA_1c (ORCADES and SABRE populations) all presented with increased branching, galactosylation and sialylation of plasma protein N-glycans and these changes were of similar magnitude.

Conclusions/interpretation

Increased complexity of plasma N-glycan structures is associated with higher risk of developing type 2 diabetes and poorer regulation of blood glucose levels. Although further research is needed, this finding could offer a potential new approach for improvement in prevention of diabetes and its complications.