Efficacy of dupilumab in real-life settings: a STROBE study.

BACKGROUND: Dupilumab, a monoclonal antibody targeting IL-4 and IL-13, has demonstrated its efficacy in several clinical trials. However, to date, real-life data remains limited. OBJECTIVE: The aim of our study was to assess the real-life impact of dupilumab on patients with severe and uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) quality of life. MATERIALS AND METHODS: This was a retrospective, monocentric, observational, real-life study, conducted in accordance with the STROBE guidelines. The following parameters were collected before treatment and at 1, 4, and 12 months: Sino-Nasal Outcome Test-22 (SNOT-22), nasal polyp score (NPS), Sniffin' Sticks-16 (SST-16), visual analog scale (VAS) for loss of smell, nasal congestion score (NCS), gustatory VAS, asthma control, oral corticosteroid usage, surgery rates, and occurrence of side effects. RESULTS: The study included 47 patients. SNOT-22 scores decreased from 52.4 ± 24.3 to 12.7 ± 10.5 at 12 months (p < 0.001). NPS decreased from 6.15 ± 1.71 to 1.57 ± 1.40 at 12 months (p < 0.001). SST-16 scores increased from 1.6 ± 2.83 to 9.1 ± 5.4 at 12 months (p < 0.001). NCS decreased from 2.45 ± 0.72 to 0.38 ± 0.63 at 12 months (p < 0.001). Prior to treatment, 72.3% were using oral corticosteroids, compared to 17.0% at 12 months (p < 0.01). Two patients required additional surgery, and 17% reported completely uncontrolled asthma, compared to 0% at 12 months (p < 0.01). CONCLUSION: Our real-life results confirm the efficacy of Dupilumab in the treatment of severe and uncontrolled CRSwNP.

Comparative Assessment of Contact Osteogenesis at the Titanium Implant-Bone Junction in Male Rabbits with Dissimilar Femoral Defects / Evaluación Comparativa de la Osteogénesis de Contacto en la Unión entre el Hueso y el Implante de Titanio en Conejos Macho con Defectos Femorales Diferentes

SUMMARY: Traumatized bone tissue has the capacity to repair itself so that it eventually regains its almost original form, even in the case of artificially inserted implants. The process that stays at the base of the regeneration is represented by osteogenesis or remote osteogenesis. The major difference between the two types of bone formation is the location of the cement line, which is located on the surface of the implant for contact osteogenesis and on the surface of the bone defect for remote osteogenesis. The aim of the present study was to assess the contact osteogenesis in the case of inserted titanium screws in holes with diameters of 1.8 mm and 1 mm respectively. The obtained results show, in the case of the groove with 1.8 mm that the newly proliferated bone represents 73.85 % of the total area, while in the case of the groove with 1 mm in diameter the value of the newly proliferated bone is 26.15 %. In conclusion, the insertion of titanium screws by self-tapping into the hole smaller than the core of the screw is accompanied by bone proliferation by contact osteogenesis much more modest than in the case of insertion into the hole larger than the core of the screw.

El tejido óseo traumatizado tiene la capacidad de reparar en forma espontánea, de modo que eventualmente recupera su forma casi original, incluso en el caso de implantes insertados artificialmente. El proceso que queda en la base de la regeneración está representado por la osteogénesis u osteogénesis a distancia. La principal diferencia entre los dos tipos de formación ósea es la ubicación de la línea de cemento, que se encuentra en la superficie del implante para la osteogénesis de contacto y en la superficie del defecto óseo para la osteogénesis remota. El objetivo del presente estudio fue evaluar la osteogénesis de contacto en el caso de tornillos de titanio insertados en forámenes con diámetros de 1,8 mm y 1 mm respectivamente. Los resultados obtenidos muestran, en el caso del surco de 1,8 mm que el hueso neoproliferado representa el 73,85 % del área total, mientras que en el caso del surco de 1 mm de diámetro el valor del hueso neoproliferado es del 26,15 %. En conclusión, la inserción de tornillos de titanio por autorroscantes en el foramen menor que el núcleo del tornillo se acompaña de una proliferación ósea por osteogénesis de contacto mucho más modesta que en el caso de la inserción en el foramen mayor que el núcleo del tornillo.

Squamous cell carcinoma of the anal sac in two cats.

This report describes two cases of feline anal sac squamous cell carcinoma. Cat 1 was managed with a multimodal approach combining surgical resection, radiation therapy and systemic therapy (toceranib phosphate; Palladia™) until local recurrence was identified at 236 days postsurgery. At that time, the cat received carboplatin. With the tumour being progressive, the cat was euthanased 552 days post initial surgery. Cat 2 was managed palliatively with a non-steroidal anti-inflammatory (meloxicam) and supportive medications. Unfortunately, with further decline in quality of life following initial diagnosis, the cat was euthanased 28 days later. Squamous cell carcinoma should be considered as a possible differential diagnosis when a cat is presented for investigation of an anal sac mass.

Chemopreventive Effects of Propolis in the MNU-Induced Rat Mammary Tumor Model.

Currently, one of the central problems in cancer management is the relapse of disease following conventional treatments, yet few therapeutic agents targeting resistance and tolerance exist. Propolis is known as a healing agent since ancient times. Therefore, over time, its curative properties have kept the interest of scientists, thus leading permanently to investigations of its other possible undiscovered effects. In this context, current experiments were performed to establish the chemopreventive potential of propolis extract (PE) (1.05 mg/kg BW/day) in N-methyl-N-nitrosourea- (MNU-) induced rat mammary tumors. MNU-inoculated/PE-treated rats had tumors of different physical attributes compared with control rats MNU-inoculated. The number of developed tumors (mean 49% versus 100%), incidence (mean 49% versus 100%), multiplicity (1.8 versus 3.7 (p < 0.001)), tumor volume (mean 10 cm3 versus 16 cm3 (p < 0.001)), and weight of the tumor mass (mean 7.42 g versus 9.00 g (p < 0.05)) were noted. The numbers of grade I tumors recorded for MNU-inoculated rats were 24 (Group 1) and 7 (Group 2) for MNU-induced/PE-treated rats. In the serum of rats MNU-inoculated/PE-treated were found higher levels of antioxidative enzymes (SOD, CAT, and GPx) than in MNU-induced. Taken together, these data indicate that propolis could be a chemopreventive agent against MNU-induced mammary carcinogenesis.

The effect of the sodium-glucose cotransporter type-2 inhibitor dapagliflozin on glomerular filtration rate in healthy cats.

Sodium-glucose cotransporter type-2 inhibitors (SGLT2is) reduce glomerular hyperfiltration in diabetic people with early diabetic nephropathy. The objective of this report was to assess changes in glomerular filtration rate in healthy cats after treatment with a SGLT2i. Eight healthy research adult castrated male cats were used in a randomized, controlled, cross-over study design. We induced isolated renal tubular glucosuria by dosing cats with the SGLT2i dapagliflozin. The cats received by mouth 10 mg dapagliflozin or control every 24 h in each of the 4, 5-d trial periods that were separated by a 7-d washout period. We assessed glomerular filtration rate (iohexol clearance method), serum urea, creatinine, symmetric dimethylarginine, and 24-h sodium and chloride urinary excretion on the fifth day of each trial period. We analyzed the data with a mixed linear model that included the fixed effects of treatment (treated and control) and trial period, and the random effect of the cat. Compared with controls, cats treated with dapagliflozin had a significant increase in mean (±SE) glomerular filtration rate (3.1 ± 0.2 vs 2.5 ± 0.2 mL/kg/min; P = 0.01), whereas there were no significant differences in serum urea, creatinine and symmetric dimethylarginine, and 24-h urine sodium and chloride excretion. We propose that dapagliflozin-mediated delivery of sodium and glucose distal from the proximal convoluted tubule induced compensatory increased sodium absorption at the thick ascending loop of Henle that resulted in decreased sodium delivery to the distal tubule leading to tubuloglomerular feedback-mediated glomerular hyperfiltration. Future studies should determine if SGLT2is' renoprotective effect in people can be enhanced with the addition of a Na+-K+-Cl- diuretic and whether dapagliflozin will be useful in mitigating proteinuria and hypertension that follow glomerular hyperfiltration in diabetic companion animals in a similar mechanism as in people.

Xenotransfusion of canine blood to cats: a review of 49 cases and their outcome.

OBJECTIVES: To describe the use of a xenotransfusion protocol, the outcome of xenotransfusion in recipient cats and to assess owner memory of the xenotransfusion. MATERIALS AND METHODS: Cats administered xenotransfusions in two hospitals between January 2016 and July 2018 were included. Adherence to xenotransfusion protocol, cause of anaemia, blood type, packed cell volume (PCV), transfusion volume, transfusion reactions, PCV 12 hours after transfusion and survival to discharge were recorded. Owners of surviving cats were questioned to assess if they remembered that a xenotransfusion had been performed. RESULTS: Forty-nine cats underwent the xenotransfusion protocol. The most common causes of anaemia were surgical blood loss (n = 17), immune-mediated haemolytic anaemia (n = 14) and neoplasia (n = 14). Median PCV before transfusion was 10%. Six cats (12%) had febrile non-haemolytic transfusion reactions. Median PCV 12 hours after transfusion was 25%. Ten cats (20%) died or were euthanased within 24 hours of xenotransfusion. A delayed haemolytic transfusion reaction occurred in 25 of 39 (64%) cats manifesting as icterus in 15 cats after a median of 1.9 days and haemolytic serum in 19 cats after a median of 2 days. Of the 18 cats alive at 1 week after discharge, 15 (83%) were still alive at a median of 173 days after xenotransfusion. All owners contacted remembered that their cats had received a xenotransfusion. CLINICAL SIGNIFICANCE: Xenotransfusion of canine packed red blood cells to cats is possible but haemolysis should be expected between 1 and 6 days after transfusion.

Effect of clinical signs, endocrinopathies, timing of surgery, hyperlipidemia, and hyperbilirubinemia on outcome in dogs with gallbladder mucocele.

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study. Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14-8.23; P<0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19-3.77; P=0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08-3.47; P=0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10-5.50; P=0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30-0.72; P=0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01-1.04; P<0.001) and age (OR, 1.17; 95% CI, 1.08-1.26; P<0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54-0.69) and a specificity of 0.63 (95% CI, 0.59-0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study.

Presumptive migrating gall bladder mucocoele in two dogs with gall bladder rupture.

A 10-year-old neutered female soft-coated wheaten terrier and a 10-year-old, entire female Pomeranian were presented for vomiting and anorexia. Using ultrasound, an oval structure with a stellate, kiwifruit-like appearance typical of a gall bladder mucocoele was observed in the caudal abdomen of the soft-coated wheaten terrier and adjacent to the liver in the Pomeranian. There was also a moderate volume of abdominal effusion in both dogs. Cytology of the peritoneal fluid indicated a sterile exudative process but varied between the two dogs, with an absence of bile pigment in the soft-coated wheaten terrier and marked bile peritonitis in the Pomeranian. An entire free-floating ectopic mucocoele was confirmed via exploratory laparotomy with concomitant gall bladder rupture and common bile duct obstruction. Both dogs recovered completely after surgery. This is the first report of cases of gall bladder rupture with entire free-floating gall bladder mucocoeles in dogs.

Kinetics of Plasma Cell-Free DNA and Creatine Kinase in a Canine Model of Tissue Injury.

BACKGROUND: Cell-free DNA (cfDNA) comprises short, double-stranded circulating DNA sequences released from damaged cells. In people, cfDNA concentrations correlate well with disease severity and tissue damage. No reports are available regarding cfDNA kinetics in dogs. OBJECTIVES/HYPOTHESIS: Cell-free DNA will have a short biological half-life and would be able to stratify mild, moderate, and severe tissue injury. Our study aims were to determine the kinetics and biological half-life of cfDNA and to contrast them with those of creatine kinase (CK). ANIMALS: Three groups of 10 dogs undergoing open ovariohysterectomy, surgery for cranial cruciate ligament rupture (CCLR), or hemilaminectomy. METHODS: Plasma for cfDNA and CK analysis was collected at admission, at induction of anesthesia, postsurgery (time 0) and at 6, 12, 24, 36, 48, 60, and 72 hours after surgery. RESULTS: The biological half-life of plasma cfDNA and CK were 5.64 hours (95% confidence interval [CI 95], 4.36-7.98 hours) and 28.7 hours (CI95, 25.3-33.3 hours), respectively. In the hemilaminectomy group, cfDNA concentrations differed significantly from admission at 6-12 hours after surgery. Creatine kinase activity differed among the surgical groups and reached a peak 6 hours after surgery. In the ovariohysterectomy and CCLR groups, plasma CK activity 72 hours after surgery did not differ from admission activity of the ovariohysterectomy group. In contrast, in the hemilaminectomy group, plasma CK activity after 72 hours did not return to the ovariohysterectomy group admission activity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma CK activity has a longer biological half-life than previously thought. In contrast to plasma CK activity, cfDNA has a short half-life and could be a useful marker for peracute severe tissue injury.

Canine intrathoracic sarcoma with ultrastructural characteristics of human synovial sarcoma - case report.

BACKGROUND: Canine joint sarcomas, designated synovial sarcomas, are uncommon malignant mesenchymal neoplasms that occur in the large joints of the extremities of middle-aged, large-breed dogs. We report the diagnosis of an intrathoracic sarcoma with ultrastructural characteristics reminiscent of human synovial sarcoma in a dog. CASE PRESENTATION: A 7-year-old female spayed Tibetan terrier crossbred dog was presented for acute severe labored breathing and diagnosed with an intrathoracic neoplastic mass. The neoplasm resulted in the accumulation of substantial amounts of viscous pleural fluid that led to dyspnea. The neoplastic mass consisted of interweaving bundles of large pleomorphic mesenchymal cells, supported by an alcian blue positive myxomatous matrix. The neoplastic cells were immunohistochemically negative for cytokeratin and CD18. Transmission electron microscopy indicated that the neoplastic cells had desmosome junctions, short microvilli-like structures and ample amounts of rough endoplasmic reticulum resembling type B-like synoviocytes and synovial sarcoma as reported in people. Despite complete surgical excision of the neoplastic mass, clinical signs recurred after a month and led to the euthanasia of the dog. CONCLUSION: Currently, there are no immunohistochemical markers specific for synovial sarcoma. Canine neoplasms with transmission electron microscopy characteristics resembling type B-like synoviocytes should be considered similar to the human sarcomas that carry the specific translocations between chromosomes X and 18.

Gene expression of estrogen and oxytocin receptors in the uterus of pregnant and parturient bitches

In the canine species, the precise mechanisms of pregnancy maintenance and the initiation of parturition are not completely understood. The expression of genes encoding the receptors for estrogen (ERα mRNA) and oxytocin (OTR mRNA) was studied in the endometrium and myometrium during pregnancy and parturition in dogs. Real-time PCR was performed to quantify the levels of ERα mRNA and OTR mRNA in the uterus of bitches during early (up to 20 days of gestation), mid (20 to 40 days) and late pregnancy (41 to 60 days), and parturition (first stage of labor). All tissues expressed ERα and OTR mRNA, and are thus possibly able to respond to eventual estrogen and oxytocin hormonal stimuli. No statistically significant differences in the expression of ERα mRNA were verified in the endometrium and myometrium throughout pregnancy and parturition, but expression of OTR mRNA increased at both parturition and late pregnancy. We concluded that the increase of endometrial and myometrial OTR mRNA expression in dogs is not an event dependent on estrogenic stimulation. Moreover, the contractility response of the canine uterus to oxytocin begins during pregnancy and maintains myometrial activity. The expression of OTR mRNA in canine uterine tissues varied over time, which supports an interpretation that the sensitivity and response to hormone therapy varies during the course of pregnancy and labor. Further studies are needed to elucidate the factors underlying the synthesis of uterine oxytocin receptors and the possible role of ERβ rather than ERα in the uterine tissues during pregnancy and parturition in dogs.

In vitro re-expression of the aryl hydrocarbon receptor (Ahr) in cultured Ahr-deficient mouse antral follicles partially restores the phenotype to that of cultured wild-type mouse follicles.

BACKGROUND: The aryl hydrocarbon receptor (AHR) mediates the toxic effects of various endocrine disrupting chemicals. In female mice, global deletion of the Ahr (AhrKO) results in slow growth of ovarian antral follicles. No studies, however, have examined whether injection of the Ahr restores the phenotypes of cultured AhrKO ovarian antral follicles to wild-type levels. METHODS: We developed a system to construct a recombinant adenovirus containing the Ahr to re-express the Ahr in AhrKO granulosa cells and whole antral follicles. We then compared follicle growth and levels of factors in the AHR signaling pathway (Ahr, Ahrr, Cyp1a1, and Cyp1b1) in wild-type, AhrKO, and Ahr re-expressed follicles. Further, we compared the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in wild-type, AhrKO, and Ahr re-expressed follicles. RESULTS: Ahr injection into AhrKO follicles partially restored their growth pattern to wild-type levels. Further, Ahr re-expressed follicles had significantly higher levels of Ahr, Ahrr, Cyp1a1, and Cyp1b1 compared to wild-type follicles. Upon TCDD treatment, only Cyp1a1 levels were significantly higher in Ahr re-expressed follicles compared to the levels in wild-type follicles. CONCLUSION: Our system of re-expression of the Ahr partially restores follicle growth and transcript levels of factors in the AHR signaling pathway to wild-type levels.

Histopathological features of canine spontaneous non-neoplastic gastric polyps - a retrospective study of 15 cases.

Fifteen cases of canine gastric polyps, collected over a 4-year period, were investigated using gross inspection, histological procedures and immunohistochemical techniques for Helicobacter infection. No breed or sex predisposition was found for gastric polyps, although they occurred mainly in elderly animals. There were 9 pedunculated and 6 sessile polypoid growths, between 5 to 30 mm in diameter developed mainly in the pyloric region of the stomach. The most common type of gastric polyps was the hyperplastic one. The inflammatory type was identified in three cases. Foci of AB/PAS Goblet positive cells resembling intestinal metaplasia, mild dysplasia of gastric epithelium, well delimited calcified areas, islands of osteoid matrix and nematodes were present in some of these lesions. Histological examination of the adjacent gastric polyp (surrounding gastric mucosa) revealed a severe chronic inflammation in 13 cases and a high grade of Helicobacter species colonization in all cases, but Kendall test analysis showed no correlation between Helicobacter spp. colonization degree and gastritis scores (τ = 0289; p = 0.204). A significant correlation was found between Helicobacter spp. location and gastritis scores (τ = 0.497; p = 0.035). Immunohistochemistry performed with a polyclonal antibody confirmed Helicobacter spp. infection in all cases. Based on their morphology, Helicobacter pylori - like organisms were described in 3 of 15 cases. No high degree of dysplasia nor neoplasia were identified in these lesions. The etiology and pathogenesis of gastric polyps in dogs are still unknown, although a severe chronic antral gastritis may be a predisposing condition for development of gastric polyps in dogs.

Littoral cell angiosarcoma in a dog.

This report describes the microscopical and immunohistochemical characteristics of littoral cell angiosarcoma in a 12-year-old, neutered female, beagle dog. The dog succumbed to metastatic disease 3 months after diagnosis of a mid-splenic mass. The tumour was characterized by two histological patterns: anastomosing microvascular channels and microvascular papillary fronds. The neoplastic cells expressed both endothelial and histiocytic markers and were erythrophagocytic. Immunohistochemical findings consistent with malignancy were CD34 expression and high Ki67 nuclear immunoreactivity.

Cumulative exposure to CD8+ granzyme Bhi T cells is associated with reduced lung function early after lung transplantation.

Outcomes following lung transplant remain suboptimal. This is attributable to variable posttransplant recovery of lung function, and inconsistent degrees of lung function loss after peak function is reached. Granzyme B is elevated in the blood and bronchoalveolar lavage (BAL) in acute rejection. We hypothesized that persistent exposure to T cells high in granzyme B would negatively correlate with lung function. We investigated cumulative exposure measured as the area-under-the-curve (AUC) of CD8+ T cell granzyme Bhi cells in the first year posttransplant in both BAL and blood in 24 transplant recipients. We assessed the correlation between cumulative 1-year exposure and FEV1 slope. There was a negative correlation between 1-year exposure and FEV1 slope within the first year (r=-0.63; P=.001). This relationship persisted even when adjusted for transplant type, gender, age, rejection, and indication for transplantation. In contrast, no relationship was seen with the 1-year AUC and lung function after 1 year posttransplant. In contrast to the BAL granzyme Bhi levels, granzyme Bhi levels from the blood showed no relationship with lung function. These findings suggest that CD8+ T-cell-driven factors are responsible for early improvements in lung function after transplantation.

Chemopreventive effects of Calluna vulgaris and Vitis vinifera extracts on UVB-induced skin damage in SKH-1 hairless mice.

Solar ultraviolet radiation (UV) is a major cause of non-melanoma skin cancer in humans. Photochemoprevention with natural products represents a simple but very effective strategy in the management of cutaneous neoplasia. The study investigated the protective activity of Calluna vulgaris (Cv) and red grape seeds (Vitis vinifera L, Burgund Mare variety) (BM) extracts in vivo on UVB-induced deleterious effects in SKH-1 mice skin. Forty SKH-1 mice were randomly divided into 4 groups (n=10): control, UVB irradiated, Cv + UVB irradiated, BM+UVB irradiated. Both extracts were applied topically on the skin in a dose of 4 mg/40 µl/cm(2) before UVB exposure - single dose. The effects were evaluated in skin 24 hours after irradiation through the presence of cyclobutane pyrimidine dimers (CPDs) and sunburn cells, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 levels. The antioxidant activity of BM extract was higher than those of Cv extract as determined using stable free radical DPPH assay and ABTS test. One single dose of UVB generated formation of CPDs (p<0.0001) and sunburn cells (p<0.0002) and increased the cytokine levels in skin (p<0.0001). Twenty hours following irradiation BM extract inhibited UVB-induced sunburn cells (p<0.02) and CPDs formation (p<0.0001). Pretreatment with Cv and BM extracts resulted in significantly reduced levels of IL-6 and TNF-α compared with UVB alone (p<0.0001). Our results suggest that BM extracts might be a potential candidate in preventing the damages induced by UV in skin.

Single, high-dose 17ß-estradiol therapy has anti-apoptotic effect and induces cerebral plasticity following transient forebrain ischemia in gerbils (Short communication).

Although much is known about the protective effect of acute estrogen therapy in cerebral ischemia, relatively little is known about the importance of apoptosis and cerebral plasticity in this mechanism. In this work 10 min global cerebral ischemia was produced by transient bilateral carotid occlusion in 4-month-old ovariectomized female gerbils. In every of our experimental group (sham for ischemia group, ischemia group and ischemia + a high, single dose 17ß-estradiol pre-treatment group) apoptotic (bcl-Xl, bax) and cerebral plasticity (GAP-43, synapsin-I, nestin) hippocampal genes' expression was measured four days after surgery. Expression of the anti-apoptotic bcl-Xl (p<0.01) and the cerebral plasticity marker synapsin-I and nestin (p<0.01) increased with acute estrogen pretreatment in ischemic animals. No change, however, in bax or GAP-43 expression was detected in estrogen treated animals compared to ischemic gerbils. These results suggest that acute estrogen therapy has anti-apoptotic effect and increases cerebral plasticity, which play an important role in cytoprotection or cerebroprotection.

Receptor for advanced glycation end products in donor lungs is associated with primary graft dysfunction after lung transplantation.

Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation. We hypothesized that Receptor for Advanced Glycation End-products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation. We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (transbronchial biopsy) from recipients with and without PGD. RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD versus transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/mL increase in donor RAGE level). In addition, RAGE levels remained high for 14 days in those recipients that developed severe graft dysfunction. Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD posttransplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD.

Association of a variant in the muscarinic acetylcholine receptor 2 gene (CHRM2) with nicotine addiction.

Genetic factors contribute to the overall risk of developing nicotine addiction, which is the major cause of preventable deaths in western countries. However, knowledge regarding specific polymorphisms influencing smoking phenotypes remains scarce. In the present study we provide evidence that a common single nucleotide polymorphism (SNP) in the 5' untranslated region of CHRM2, the gene coding for the muscarinic acetylcholine receptor 2 is associated with nicotine addiction. CHRM2 was defined as a candidate gene for nicotine addiction based on previous evidence that linked variations in CHRM2 to alcohol and drug dependence. A total of more than 5,500 subjects representative of the German population were genotyped and assessed regarding their smoking habits. The impact of three SNPs in CHRM2 on smoking behavior/nicotine addiction was investigated using logistic regression models or a quasi-Poisson regression model, respectively. We found the T allele of SNP rs324650 to be associated with an increased risk of smoking/nicotine dependence according to three different models, the recessive models of regular or heavy smokers vs. never-smokers (odds ratio 1.17 in both analyses) and according to the Fagerström index of nicotine addiction. In the analysis stratified by gender this association was only found in females. Our data provide further evidence that variations in CHRM2 may be associated with the genetic risk of addiction in general or with certain personality traits that predispose to the development of addiction. Alternatively, variations in CHRM2 could modulate presynaptic auto-regulation in cholinergic systems and may thereby affect an individual's response to nicotine more specifically.