Attention deficit and hyperactivity disorder symptoms respond to gluten-free diet in patients with coeliac disease

Introduction: Patients with coeliac disease commonly report symptoms of ‘brain fog’. The aim of this study was to assess self-reported symptoms of impaired concentration in coeliac disease before and after treatment with gluten-free diet, compared with healthy controls and patient controls.

Methods: Patients with newly diagnosed coeliac disease were included consecutively from two out-patient clinics. The patients completed the questionnaires Adult ADHD Self-Report Scale v1.1 Symptoms Checklist (ASRS), Hospital Anxiety and Depression Scale (HADS) and Gastrointestinal Symptom Rating Scale (GSRS) prior to start of a gluten-free diet and after at least 12 months on the diet. Patients with an established diagnosis of inflammatory bowel disease served as patient controls (n?=?36). Health care personnel at Oslo University Hospital served as healthy controls (n?=?60) and filled out ASRS and HADS.

Results: A total of 31 newly diagnosed coeliac patients were included in the study. Of these, 26 patients met for follow-up and repeated the questionnaires. Prior to treatment, patients with coeliac disease had significantly higher scores than healthy controls on both the ASRS (p?=?.0014) and HADS (p=.0004). After a gluten-free diet, their scores improved and were not significantly different from healthy controls. There were no significant differences between patients with coeliac disease prior to treatment and patient controls with inflammatory bowel disease.

Conclusion: Prior to treatment, coeliac disease patients reported significantly more symptoms than healthy controls on ASRS and HADS. The differences disappeared after a minimum of 12 months on a gluten-free diet.     

Human-relevant near-organ neuromodulation of the immune system via the splenic nerve

Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve–induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.

The inflammatory status of the body is monitored and regulated through the neuroimmune axis, connecting the brain to the immune system via both humoral and neural pathways (1–3). In particular, the inflammatory reflex (3) controls systemic immune responses; detection of inflammatory stimuli in the periphery is communicated to the brain that activates outflow of neural signals to promote peripheral immune responses proportional to the threat. Studies in rodent models have identified the cholinergic anti-inflammatory pathway (CAIP) as the brain’s efferent response to infection and inflammation through peripheral neurotransmitters released in lymphoid organs, mainly the spleen (4, 5). Within this pathway, the peripheral connection between the vagus nerve (VN), the splenic nerve (SpN), and its terminal release of noradrenaline (NA) into the spleen have been identified as crucial components of this neural circuit (6–8) (SI Appendix, Fig. S1A).Importantly, the CAIP can be harnessed to promote immune control. Activation of the cervical VN by electrical stimulation (vagus nerve stimulation—VNS; SI Appendix, Fig. S1A) has been shown to be effective in reducing lipopolysaccharide (LPS)-induced levels of tumor necrosis factor alpha (TNF-α) (4, 6, 7) and in preclinical rodent models of chronic inflammatory diseases (9, 10). Murine models have generally been used to demonstrate biological proof of concepts of novel neuromodulation therapies in this and other contexts. However, the development of clinical bioelectronic medicines requires the accurate estimation and validation of stimulation parameters in a histologically, surgically, and anatomically relevant model to define device and therapy requirements. The translation of stimulation parameters from rodent to human is hampered by anatomical (e.g., size of nerves), histological (e.g., number of axons, connective tissue thickness, proportion of adipose tissue), and physiological (e.g., immunological) differences. Therefore, it is suggested that the use of large animal models, human tissues, and in silico modeling are more appropriate for the optimization and scaling of human-relevant parameters (11, 12).Although early clinical feasibility studies have provided preliminary evidence of immunomodulatory effects of VNS in patients (13, 14), clear demonstration of the translation of the splenic anti-inflammatory pathway in clinically relevant species is currently lacking in the literature. The VN has a functionally and anatomically complex composition. In animals and humans, the VN contains both afferent and efferent axons of varying size (large, medium, and small) and degree of myelination (heavily myelinated, lightly myelinated, and unmyelinated axons) innervating multiple organs and muscles (15). As a consequence, currently used VNS results in activation of off-target circuits (SI Appendix, Fig. S1A) that can cause dysphonia, coughing, hoarseness, pain, and dyspnea (16–18); in some patients, these can be managed and can also improve over time (18). Further, it remains unclear which axons (efferent versus afferent, myelinated versus unmyelinated) within the VN relay immunomodulatory signals to peripheral organs (19, 20). As a result, it is difficult to optimize the stimulation parameters necessary to activate axons within the VN which carry signals to the spleen. Typically, clinical parameters are selected based on the individual patient’s tolerance of off-target effects (13, 21) without direct evidence of activation of the anti-inflammatory pathway because of a lack of an organ-specific biomarker. Since the SpN directly transmits neural signals to the spleen and is the fundamental nodal circuit in mediating the anti-inflammatory response (22), SpN stimulation (SpNS) may represent an alternative modality providing the opportunity for near-organ modulation of the immune system (SI Appendix, Fig. S1 B and C). Proof of concept experiments in rodents have shown that immune responses can indeed be modulated by stimulation of the SpN with comparable cytokine suppressive effects to VNS (7, 8, 23).Here, we anatomically, histologically, and functionally compared the mouse, rat, pig, and human SpN, demonstrating the superiority of the pig as a translational model of the human SpN. We then performed functional in vivo pig electrophysiological studies to identify organ-specific physiological biomarkers that can be used to assess nerve engagement and to refine stimulation parameters. Finally, we assessed the large animal translation of the spleen-dependent anti-inflammatory pathway in the pig using in vitro splenocyte preparations together with two in vivo models of acute inflammation.     

Serum amyloid A protein forms a complex with a fragment of apolipoprotein A-I in the domestic blue fox: a protective mechanism against AA amyloidosis?

The spontaneous occurrence of protein AA-type of amyloidosis varies among animal species. As reactive AA-type of amyloidosis has never been detected in the blue fox, we obtained acute phase sera to search for amyloid-protective elements. The purified SAA fraction was characterized by mass and sequence analyses to disclose any unique domains in the amino acid sequence. The data revealed an SAA protein with heterogeneities in several positions, and showed the typical insertion between positions 69 and 70. By comparing the amino acid sequence with that from other mammals, no unique sequence could be observed. However, a C-terminal fragment of apolipoprotein A-I (ApoA-I) was found attached to the SAA. The amino acid sequence of the ApoA-I fragment revealed a partially blocked and ragged N-terminus. A comparison of the amino acid sequence of ApoA-I with that from the dog showed that the ApoA-I fragment started about position 190, had an intact C-terminus, and showed an identical sequence in all positions, except one. Based on the data, we suggest an interaction of the C-terminal fragment of ApoA-I with the SAA protein that inhibits the AA fibrillogenesis in the blue fox.     

Increased angiogenesis is associated with a 32-gene expression signature and 6p21 amplification in aggressive endometrial cancer

Background

Angiogenesis is a hallmark of cancer. The aim of this study was to explore whether microvessel proliferation is associated with gene expression profiles or copy number alterations in endometrial cancer.

Methods

A prospective series of endometrial carcinomas was studied for angiogenesis markers, gene expression profiles, and gene copy number data. For validation, an independent series of endometrial carcinomas as well as an external cohort of endometrial cancer patients were examined by gene expression microarrays.

Results

Increased microvessel proliferation (MVP) was associated with aggressive tumor features and reduced survival, and a 32-gene expression signature was found to separate tumors with high versus low MVP. An increased 32-gene signature score was confirmed to associate with high-grade tumor features and reduced survival by independent cohorts. Copy number studies revealed that amplification of the 6p21 region was significantly associated with MVP, a high 32-gene score, as well as reduced survival.

Conclusion

Increased MVP was significantly associated with aggressive endometrial cancer and reduced survival. Integrated analyses demonstrated significant associations between increased vascular proliferation, amplification of the 6p21 region, VEGF-A mRNA expression, and the 32-gene angiogenesis signature. Our findings indicate amplification of 6p21 as a possible driver of tumor vascular proliferation in endometrial cancer.     

Use of silver diamine fluoride for the maintenance of dental prostheses in a high caries-risk patient: A medical management approach

A technique for using silver diamine fluoride (SDF) as part of a regimen to help maintain dental prostheses in a patient with scleroderma and at high risk of caries is presented. Medically compromised, xerostomic, or elderly patients generally face greater risk of caries and specifically with prosthetic retainer teeth. SDF is a minimally invasive solution to this problem. A technique is described for using SDF to arrest and prevent new caries with the goal of maintaining fixed and removable prostheses and supporting teeth in a cost-effective manner.     

Diagnostic value of B-Type natriuretic peptide and chest radiographic findings in patients with acute dyspnea

PURPOSE: To compare chest radiographic findings and circulating B-type natriuretic peptide (BNP) levels as an adjunct to clinical findings in the diagnosis of heart failure in patients presenting with acute dyspnea. METHODS: The diagnostic performance of radiographic evidence of cardiomegaly/redistribution and BNP levels > or =100 pg/mL as indicators of heart failure were assessed in 880 patients presenting with acute dyspnea to the emergency departments of five U.S. and two European teaching hospitals. BNP levels were determined by a rapid, point-of-care device. Two blinded cardiologists reviewed all clinical data and categorized patients as to whether they had acute heart failure (n = 447) or not (n = 433). RESULTS: Three-factor analyses showed that BNP levels > or =100 pg/mL contributed significantly to the prediction of heart failure over each of the radiographic indicators. In a multivariate logistic regression analysis, both BNP levels > or =100 pg/mL (odds ratio [OR] = 12.3; 95% confidence interval [CI]: 7.4 to 20.4) and radiographic findings of cardiomegaly (OR = 2.3; 95% CI: 1.4 to 3.7), cephalization (OR = 6.4; 95% CI: 3.3 to 12.5), and interstitial edema (OR = 7.0; 95% CI: 2.9 to 17.0) added significant, predictive information above historical and clinical predictors of heart failure. CONCLUSION: In patients presenting to the emergency department with acute dyspnea, BNP levels and chest radiographs provide complementary diagnostic information that may be useful in the early evaluation of heart failure.     

STEMI and NSTEMI: are they so different? 1 year outcomes in acute myocardial infarction as defined by the ESC/ACC definition (the OPERA registry).

AIMS: The ESC/ACC redefined myocardial infarction as any amount of necrosis caused by ischaemia. The aim of this study was to describe the management and outcomes using 'real-world' data taking the new definition of acute myocardial infarction into account. METHODS AND RESULTS: A total of 2,151 consecutive patients (76.0% men) with a myocardial infarction were enrolled at 56 centres in France. The median delay to presentation was shorter in patients with ST-segment elevation myocardial infarction (STEMI) vs. non-STEMI (NSTEMI) (4 vs. 7 h, P < 0.0001). STEMI patients were more likely to receive fibrinolysis (28.9 vs. 0.7%, P < 0.0001) or undergo PCI (71.0 vs. 51.6%, P < 0.0001) but less likely to have bypass surgery (3.1 vs. 4.9%, P < 0.05). At discharge, patients with STEMI received more aggressive secondary prevention therapies than those with NSTEMI, which was not supported by differences in disease severity. A total of 1878 patients were followed-up for 1 year: 36.7% of STEMI and 41.5% of NSTEMI patients were rehospitalized (P = 0.05); 16% in both groups were revascularized. In-hospital mortality was similar (4.6 vs. 4.3%), and 1-year mortality was 9.0% in STEMI patients and 11.6% in NSTEMI patients (Log-Rank P = 0.09). Independent correlates of in-hospital mortality were untreated dyslipidaemia, advanced age, diabetes, and low blood pressure. The strongest predictors of 1-year mortality were heart failure and age. Similar predictors were found in STEMI and NSTEMI subgroups. CONCLUSIONS: Despite different management, patients with STEMI and NSTEMI have similar prognoses and independent correlates of outcome. These findings support the new definition of myocardial infarction.     

Digital dermoscopy in clinical practise: a three-centre analysis

BACKGROUND: Early detection of cutaneous melanoma is the most important step to improve prognosis. In recent years objective techniques have been developed to improve diagnostics of pigmented lesions superior to the naked eye. Digital dermoscopy offers several advantages such as independence from the investigator, format ready for teledermatology and image storage, and comparability. SETTING: In a routine setting including three centres in Europe, i.e. Lugano and Locarno in Switzerland, and Dresden in Germany, the usefulness of digital dermoscopy in daily routine has been evaluated. PATIENTS AND METHODS: Digital dermoscopy was performed with the DB-MIPS system in 1308 patients, and 3544 pigmented lesions were evaluated. A total of 466 pigmented lesions were surgically removed and classified by histopathology. Among those 52 melanomas and 299 dysplastic, naevi could be identified. DB-MIPS system evaluated 35 variables of geometrics, colour, colour distribution and texture. Lesion identification is realized by clustering. Another important part of the analysis was to study the decision making, i.e. removal or follow-up of lesions. The tendency to follow-up was defined as the ratio of (number of suspicious lesions-removed lesions)/suspicious lesions. The interventism is defined as the ratio of the number of removed lesions to the number of suspicious lesions. RESULTS: The DB-MIPS system was robust and easy in handling in daily routine. The data analysis and digital imaging were realized in real time. Fifty-two melanomas could be identified including eight in situ melanomas and 33 T1a melanomas (thinner than 1 mm). Sensitivity of digital dermoscopy varied between 90% and 95% between the three centres. Specificity varied between 79.6% and 93.3%. The centres differed in the patient population, the mean diameter of pigmented lesions and decisions. Interventism varied between 36.3% and 76.0%, follow-up varied from 24% to 63%. Higher levels of clinician's false positive were associated with a higher percentage of interventism. CONCLUSIONS: Digital dermoscopy offers advantages for daily routine in detection of early melanoma. Sensitivity and specificity for early melanomas is high and thereby, the experienced dermatologist can be easily supported in daily routine of a pigment lesion clinic to improve diagnostics and hopefully prognosis in cutaneous melanoma.