FIBCD1 ameliorates weight loss in chemotherapy-induced murine mucositis.

PURPOSE: Chemotherapy-induced gastrointestinal toxicity is a common adverse event during chemotherapeutic treatment. No uniformly applicable strategies exist to predict, prevent, or treat gastrointestinal toxicity. Thus, a goal of mucositis research is to identify targets for therapeutic interventions and individualized risk prediction. Fibrinogen C domain containing 1 (FIBCD1) is a transmembrane protein expressed in human intestinal epithelial cells with functions in the innate immune system. Previous observations have shown that FIBCD1 ameliorates dextran sulfate sodium (DSS)-induced intestinal inflammation in vivo. We evaluated the effect of FIBCD1 in a murine model of chemotherapy-induced gastrointestinal toxicity and inflammation. METHODS: Transgenic (Tg) mice overexpressing FIBCD1 in the intestinal epithelium (Fibcd1Tg) and wild-type (WT) littermates (C57BL/6N) were randomized to receive an intraperitoneal injection of doxorubicin 20 mg/kg or saline and were terminated 2 or 7 days after the injection. Gastrointestinal toxicity was evaluated by weight change, intestinal length, villus height/crypt depth, and histological mucositis score. Expression of inflammatory markers (IL-6, IL-1ß, and Tnfα) was measured by quantitative real-time PCR in intestinal tissue samples. RESULTS: Following doxorubicin treatment, WT mice exhibited an increased weight loss compared with Tg littermates (p < 0.001). No differences between genotypes were seen in mucositis score, intestinal length, villus height/crypt depth, or IL-6, IL-1ß, and Tnfα expression. CONCLUSION: Our findings suggest that FIBCD1 could ameliorate chemotherapy-induced gastrointestinal toxicity by reducing weight loss; however, the mechanism of this possible protective effect remains to be defined warranting additional investigations.

No time for change? Impact of contextual factors on the effect of training primary care healthcare workers in Kyrgyzstan and Vietnam on how to manage asthma in children - A FRESH AIR implementation study.

BACKGROUND: Training is a common and cost-effective way of trying to improve quality of care in low- and middle-income countries but studies of contextual factors for the successful translation of increased knowledge into clinical change are lacking, especially in primary care. The purpose of this study was to assess the impact of contextual factors on the effect of training rural healthcare workers in Kyrgyzstan and Vietnam on their knowledge and clinical performance in managing pediatric patients with respiratory symptoms. METHODS: Primary care health workers in Kyrgyzstan and Vietnam underwent a one-day training session on asthma in children under five. The effect of training was measured on knowledge and clinical performance using a validated questionnaire, and by direct clinical observations. RESULTS: Eighty-one healthcare workers participated in the training. Their knowledge increased by 1.1 Cohen's d (CI: 0.7 to 1.4) in Kyrgyzstan where baseline performance was lower and 1.5 Cohen's d (CI: 0.5 to 2.5) in Vietnam. Consultations were performed by different types of health care workers in Kyrgyzstan and there was a 79.1% (CI 73.9 to 84.3%) increase in consultations where at least one core symptom of respiratory illness was asked. Only medical doctors participated in Vietnam, where the increase was 25.0% (CI 15.1 to 34.9%). Clinical examination improved significantly after training in Kyrgyzstan. In Vietnam, the number of actions performed generally declined. The most pronounced difference in contextual factors was consultation time, which was median 15 min in Kyrgyzstan and 2 min in Vietnam. DISCUSSION AND CONCLUSION: The effects on knowledge of training primary care health workers in lower middle-income countries in diagnosis and management of asthma in children under five only translated into changes in clinical performance where consultation time allowed for changes to clinical practice, emphasizing the importance of considering contextual factors in order to succeed in behavioral change after training.

Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life: A randomized clinical trial.

BACKGROUND: Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. OBJECTIVE: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. METHODS: The Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age. RESULTS: By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. CONCLUSION: Neonatal BCG had no effect on the development of RW before 13 months of age.

Mothers' informational needs when deciding to have their newborn infant vaccinated with BCG. A Mixed-methods design.

OBJECTIVE: To explore the informational needs of mothers with different levels of education in order to improve counselling about vaccination. METHODS: In the setting of a large vaccination trial, mothers' assessments and yield of written information in combination with telephone consultations were evaluated in a survey. Furthermore, searching strategies for additional information were investigated. Mothers' perspectives on informational needs were explored in focus group discussions. RESULTS: Out of 2025 mothers, 95% felt well-informed. Of the 4% not feeling well-informed, there were significantly more mothers with basic schooling and nontheoretical education. There was no correlation between searching for additional information and feeling well-informed. The telephone consultation was found to be very supportive for the decision. CONCLUSION: The written information was digestible over time. The telephone consultation ensured the mothers' understanding by tailoring and deriving meaning from the information to her special needs. Moreover, it helped the mothers gain an overview of risks and benefits and inspired confidence. These findings indicate that the telephone consultation improved health literacy. PRACTICE IMPLICATIONS: Individual counselling about vaccines is required in addition to information about side effects and accurate instructions on how to react upon them.

Bacillus Calmette-Guérin vaccination, thymic size, and thymic output in healthy newborns.

BACKGROUND: The Bacillus Calmette-Guérin vaccine (BCG) has been associated with beneficial nonspecific effects on infant health. We aimed to examine the effect of BCG at birth on thymic size and the associations between thymic output, circulating lymphocytes, risk of infection, and thymic size. METHODS: In infants randomized to BCG or no BCG, thymic index (TI), and thymic/weight index (TWI) were measured by ultrasound at birth and at the age of 3 mo. T cell subpopulations including CD4+ T cells, CD8+ T cells, and recent thymic emigrants (RTEs) were assessed by flow cytometry. Infections up to age 3 mo were parent-reported. RESULTS: BCG vaccination did not affect thymic size at age 3 mo, measured as TI. At birth, the number of lymphocytes, CD4+ T cells, CD8+ T cells, and RTEs were positively associated with TI and TWI. Furthermore, a reduced risk of infections up to age 3 mo was associated with a large thymic size at birth. CONCLUSION: We found no effect of BCG vaccination on thymic size. The positive association between thymic output, lymphocytes, reduced risk of infections, and TI/TWI suggests that assessment of TI/TWI by ultrasound may be a predictor of the immunological capacity in the newborn.

Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13 months.

BACKGROUND: Vaccination with Bacillus Calmette-Guérin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. METHODS: The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency, or no Danish-speaking parent. Follow-up information was collected through telephone interviews at 3 and 13 months of age. Subgroups of participants were offered blood sampling at 13 months of age. RESULTS: By 13 months of age, the parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35 kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36]). CONCLUSION: In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age.

The association between Bacillus Calmette-Guérin vaccination (1331 SSI) skin reaction and subsequent scar development in infants.

BACKGROUND: The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis is administered intradermally, and vaccination is often followed by a scar at the injection site. Among BCG-vaccinated individuals, having a scar has been associated with lower mortality. We aimed to examine the impact of vaccination technique for scarring in a high income setting, by assessing the associations between the post injection reaction, the wheal size, and the probability of developing a scar, and scar size. METHODS: This study was nested within a clinical multicenter study randomizing 4262 infants to either BCG vaccination (BCG 1331 SSI) or no intervention. In this substudy, including 492 vaccinated infants, the immediate post BCG vaccination reaction was registered as either wheal (a raised, blanched papule at the injection site), bulge (a palpable element at the injection site), or no reaction. The presence or absence of a BCG scar and the size the scar was measured at 13 months of age. RESULTS: Of 492 infants included, 87% had a wheal after vaccination, 11% had a bulge, and 2% had no reaction. The mean wheal size was 3.8 mm (95% confidence interval 3.7-3.9). Overall, 95% (442/466, 26 lost to follow-up) of BCG-vaccinated infants had a scar at 13 months of age. In infants with a wheal, the probability of developing a scar was 96%, declining to 87% in the case of a bulge, and to 56% in the case of no reaction (p for same probability = 0.03). Wheal size was positively correlated with the probability of getting a scar and scar size. CONCLUSION: Scarring after BCG vaccination has been associated with lower infant mortality. In a high-income setting, we found that correct injection technique is highly important for the development of a BCG scar and that registration of the category of BCG skin reaction (as wheal, bulge, or no reaction) may be used to identify infants at risk of scar failure. Finally, the wheal size was positively associated with both the probability of getting a scar and scar size. TRIAL REGISTRATION: The study was registered at www.ClinicalTrials.gov with trial registration number NCT01694108 .

Adaptive Immunity against Streptococcus pyogenes in Adults Involves Increased IFN-γ and IgG3 Responses Compared with Children.

Each year, millions of people are infected with Streptococcus pyogenes, leading to an estimated 500,000 annual deaths worldwide. For unknown reasons, school-aged children have substantially higher infection rates than adults. The goal for this study was to provide, to our knowledge, the first detailed characterization of the human adaptive immune response against S. pyogenes in both children and adults. We report that all adults in our study, as well as most children, showed immunity against the two conserved group A streptococci (GAS) Ags, streptococcal C5a peptidase and immunogenic secreted protein. The response primarily consisted of three subsets of Th1 T cells, in which the TNF-α(+) and IL-2(+)TNF-α(+) subsets were most frequent. Humoral immunity was dominated by IgG1 and IgG3, whereas the Th2-associated IgG4 isotype was only detected at very low amounts. IgG3 levels correlated significantly with IFN-γ, but not with IL-5, IL-13, IL-17, or TNF-α. Interestingly, children showed a similar pattern of Ag-specific cytokine release, but displayed significantly lower levels of IgG3 and IFN-γ compared with adults. Thus, human immune responses against S. pyogenes consist of a robust Th1 cellular memory response in combination with IgG1/IgG3-dominated humoral immunity that increase with age. The significance of these data regarding both the increased GAS infection rate in children and the development of protective GAS vaccines is discussed.

Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial.

BACKGROUND: Childhood infections are common and Bacillus Calmette-Guérin (BCG) vaccination at birth may prevent these via nonspecific effects. METHODS: A randomized, clinical multicenter trial. All women planning to give birth (n = 16,521) at the three study sites were invited during the recruitment period. Participating children were randomized to receive BCG within 7 d of birth or to a no intervention control group. Parent-reported infections (events) were collected using telephone interviews at 3 and 13 mo. Data collectors were blinded to allocation. RESULTS: The analyses included 4,224/4,262 (99%) and 4,192/4,262 (98%) children at 3 and 13 mo. From 0 to 3 mo, there were 291 events in the BCG group vs. 336 events in the control group, incidence rate ratio (IRR) = 0.87 (95% confidence interval (CI): 0.72 to 1.05). In this age group, the IRR was 0.62 (95% CI: 0.39 to 0.98) if the mother was BCG vaccinated. From 3 to 13 mo, there were 7,028 vs. 6,791 events, IRR = 1.02 (95% CI: 0.97 to 1.07). CONCLUSION: This study did not find a nonspecific public health benefit of BCG on parent-reported infections. BCG may have reduced the incidence of infections in children of BCG-vaccinated mothers during the first 3 mo.

Translational aspects of rectal evoked potentials: a comparative study in rats and humans.

Inconsistencies between species has stunted the progress of developing new analgesics. To increase the success of translating results between species, improved comparable models are required. Twelve rats received rectal balloon distensions on 2 different days separated by 24.3 (SD 24.6) days. Rectal balloon distensions were also performed in 18 humans (mean age: 34 yr; range: 21-56 yr; 12 men) on two separate occasions, separated by 9.3 (SD 5.5) days. In rats, cerebral evoked potentials (CEPs) were recorded by use of implanted skull-electrodes to distension pressure of 80 mmHg. In humans surface electrodes and individualized pressure, corresponding to pain detection threshold, were used. Comparison of morphology was assessed by wavelet analysis. Within- and between-day reproducibility was assessed in terms of latencies, amplitudes, and frequency content. In rats CEPs showed triphasic morphology. No differences in latencies, amplitudes, and power distribution were seen within or between days (all P ≥ 0.5). Peak-to-peak amplitude between the first positive and negative potential were the most reproducible characteristic within and between days (evaluated by intraclass correlation coefficients, ICC) (ICC = 0.99 and ICC = 9.98, respectively). In humans CEPs showed a triphasic morphology. No differences in latencies, amplitudes, or power distribution were seen within or between days (all P ≥ 0.2). Latency to the second negative potential (ICC = 0.98) and the second positive potential (ICC = 0.95) was the most reproducible characteristic within and between days. A unique and reliable translational platform was established assessing visceral sensitivity in rats and humans, which may improve the translational process of developing new drugs targeting visceral pain.

Epidemiological Study of Malignant Paediatric Liver Tumours in Denmark 1985-2020.

BACKGROUND: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events. METHODS: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome. RESULTS: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children. CONCLUSIONS: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.

Mitochondrial DNA Variation Contributes to the Aptitude for Dressage and Show Jumping Ability in the Holstein Horse Breed.

Maternal lineages are considered an important factor in breeding. Mitochondrial DNA (mtDNA) is maternally inherited and plays an important role in energy metabolism. It has already been associated with energy consumption and performances, e.g., stamina in humans and racehorses. For now, corresponding studies are lacking for sport performance of warmblood breeds. MtDNA sequences were available for 271 Holstein mares from 75 maternal lineages. As all mares within a lineage showed identical haplotypes regarding the non-synonymous variants, we expanded our data set by also including non-sequenced mares and assigning them to the lineage-specific haplotype. This sample consisting of 6334 to 16,447 mares was used to perform mitochondrial association analyses using breeding values (EBVs) estimated on behalf of the Fédération Équestre Nationale (FN) and on behalf of the Holstein Breeding Association (HOL). The association analyses revealed 20 mitochondrial SNPs (mtSNPs) significantly associated with FN-EBVs and partly overlapping 20 mtSNPs associated with HOL-EBVs. The results indicated that mtDNA contributes to performance differences between maternal lineages. Certain mitochondrial haplogroups were associated with special talents for dressage or show jumping. The findings encourage to set up innovative genetic evaluation models that also consider information on maternal lineages.

Exploring the Origin and Relatedness of Maternal Lineages Through Analysis of Mitochondrial DNA in the Holstein Horse.

Maternal lineages are important for the breeding decision in the Holstein horse breed. To investigate the genetic diversity of the maternal lineages and the relationships between founder mares, the maternal inherited mitochondrial genome (except the repetitive part of the non-coding region) of 271 mares representing 75 lineages was sequenced. The sequencing predominantly revealed complete homology in the nucleotide sequences between mares from one lineage with exceptions in 13 lineages, where differences in one to three positions are probably caused by de novo mutations or alternate fixation of heteroplasmy. We found 78 distinct haplotypes that have not yet been described in other breeds. Six of these occurred in two or three different lineages indicating a common ancestry. Haplotypes can be divided into eight clusters with all mares from one lineage belonging to the same cluster. Within a cluster, the average number of pairwise differences ranged from zero to 16.49 suggesting close maternal relationships between these mares. The results showed that the current breeding population originated from at least eight ancestral founder mares.

The effects of tapentadol and oxycodone on central processing of tonic pain.

OBJECTIVE: The present study investigated differences between opioids to experimental tonic pain in healthy men. METHODS: Twenty-one males participated in this cross-over-trial. Interventions twice daily were oxycodone (10 mg), tapentadol (50 mg) and placebo for 14 days. Tonic pain was induced on day 1, 4 and 14 by immersing the hand in 2 °C water for 120 s. Electroencephalography was recorded during test pain at baseline and after 14 days. Spectral analysis and source localization were investigated in predefined frequency bands. RESULTS: A decreased perception of pain on day 4 persisted throughout the 14 days compared to baseline (p < 0.006). Oxycodone decreased the electroencephalography spectral power in the delta and theta bands and increased power in the alpha1, alpha2 and beta1 bands (p < 0.03). Tapentadol increased spectral power in the alpha1 band (p < 0.001). Source localization revealed that oxycodone decreased activity of the temporal and limbic region in the delta band, and frontal lobe in the alpha2 and beta1 bands, whereas tapentadol decreased alpha1 band activity in the temporal lobe compared to placebo. CONCLUSION: Oxycodone and tapentadol reduced pain perception and changed the central processing of tonic pain. SIGNIFICANCE: Different mechanisms of action were involved, where oxycodone affected cortical structures more than tapentadol.

Tapentadol results in less deterioration of gastrointestinal function and symptoms than standard opioid therapy in healthy male volunteers.

BACKGROUND: Tapentadol is a combined opioid agonist and norepinephrine reuptake inhibitor with fewer gastrointestinal side effects at equianalgesic doses compared with classical strong opioids. Previous studies on tapentadol have included multi-morbid patients in whom confounders exclude detailed assessment of the mechanistic effects and strict comparison with other opioids or placebo. This study aimed at investigating the effects of tapentadol and oxycodone on gastrointestinal motility and gastrointestinal side effects. METHODS: 21 healthy males participated in a randomized, double-blind, placebo-controlled, crossover study. Tapentadol (50 mg twice daily), oxycodone (10 mg twice daily), or placebo tablets were administered for 14 days. Segmental gastrointestinal transit times and colonic motility parameters were measured with electromagnetic capsules. Gastrointestinal side effects were assessed using questionnaires. KEY RESULTS: During dosing with tapentadol, gastrointestinal side effects and motility parameters were on placebo level. Compared with tapentadol, oxycodone increased whole gut transit time by 17.9 hours (p = .015) and rectosigmoid transit time by 6.5 hours (p = .005). Compared with tapentadol, oxycodone also reduced long, fast antegrade colonic movements (p = .001). In comparison with placebo, oxycodone prolonged whole gut transit time by 31.6 hours, (p < .001). Moreover, less long, fast antegrade colonic movements (p = .002) were observed during oxycodone. For oxycodone only, slow colonic movements were associated with gastrointestinal side effects. CONCLUSIONS & INFERENCES: In this mechanistic study, tapentadol caused significantly less colonic dysmotility and gastrointestinal side effects as compared with oxycodone in equianalgesic doses.

Determinants of Bacille Calmette-Guérin scarification in Danish children.

BACKGROUND: Studies in low-income countries have shown that among Bacille Calmette-Guérin (BCG) vaccinated children, those who develop a BCG-scar have significantly better survival than those who do not develop a scar. In a Danish multicenter randomized clinical trial we assessed determinants for developing a BCG-scar and for BCG scar size following neonatal BCG vaccination. METHODS: At three Danish hospitals, newborns were randomized 1:1 to BCG vaccination or no BCG vaccination. The infants were invited for a clinical examination at the ages of 3 and 13 months. At 13 months, the scar site was inspected and scar size measured. We investigated three groups of determinants; external, parental, and individual-level determinants on relative scar prevalence and differences in median scar sizes. RESULTS: Among 2118 BCG vaccinated infants, 2039 (96 %) were examined at 13 months; 1857 of these (91 %) had developed a BCG-scar. Compared with Copenhagen University Hospital, Hvidovre (85 %), Copenhagen University Hospital, Rigshospitalet had a scar prevalence of 95 % (adjusted Prevalence ratio (aPR) = 1.24 [CI 95 %: 1.18 to 1.30]); it was 93 % at Kolding Hospital (aPR 1.27 [CI 95 %: 1.19 to 1.35]). Increasing vaccine experience was positively associated with developing a scar and with scar size. CONCLUSION: Across multiple potential determinants of BCG scaring and size, logistical factors dominated. The results support that injection technique is an important determinant of developing a scar. Given the strong link between having a BCG scar and subsequent health, improved BCG vaccination technique could play a major role for child health.

Diabetic Neuropathy Influences Control of Spinal Mechanisms.

PURPOSE: Comprehensive evaluation of the upstream sensory processing in diabetic symmetrical polyneuropathy (DSPN) is sparse. The authors investigated the spinal nociceptive withdrawal reflex and the related elicited somatosensory evoked cortical potentials. They hypothesized that DSPN induces alterations in spinal and supraspinal sensory-motor processing compared with age- and gender-matched healthy controls. METHODS: In this study, 48 patients with type 1 diabetes and DSPN were compared with 21 healthy controls. Perception and reflex thresholds were determined and subjects received electrical stimulations on the plantar site of the foot at three stimulation intensities to evoke a nociceptive withdrawal reflex. Electromyogram and EEG were recorded for analysis. RESULTS: Patients with DSPN had higher perception (P < 0.001) and reflex (P = 0.012) thresholds. Fewer patients completed the recording session compared with healthy controls (34/48 vs. 21/21; P = 0.004). Diabetic symmetrical polyneuropathy reduced the odds ratio of a successful elicited nociceptive withdrawal reflex (odds ratio = 0.045; P = 0.014). Diabetic symmetrical polyneuropathy changed the evoked potentials (F = 2.86; P = 0.025), and post hoc test revealed reduction of amplitude (-3.72 mV; P = 0.021) and prolonged latencies (15.1 ms; P = 0.013) of the N1 peak. CONCLUSIONS: The study revealed that patients with type 1 diabetes and DSPN have significantly changed spinal and supraspinal processing of the somatosensory input. This implies that DSPN induces widespread differences in the central nervous system processing of afferent A-δ and A-ß fiber input. These differences in processing may potentially lead to identification of subgroups with different stages of small fiber neuropathy and ultimately differentiated treatments.

Effects of Vortioxetine and Escitalopram on Electroencephalographic Recordings - A Randomized, Crossover Trial in Healthy Males.

The antidepressant drug vortioxetine has a multimodal action modulating neurotransmission through inhibition of the serotonin transporter and modulation of serotonin receptors. Vortioxetine has also been shown to alleviate cognitive symptoms in preclinical studies and in patients with depression. However, it is largely unclear how vortioxetine affects the brain processing in humans. The present study was conducted in 32 healthy males in a randomized, double-blinded, placebo-controlled, active comparator, four-way crossover design. Treatments were 10 and 20 mg/day vortioxetine, 15 mg/day escitalopram, and placebo, administered orally once daily for three days. Results were compared to placebo. Treatment effect was assessed by recording spontaneous electroencephalography (EEG) and 40 Hz auditory steady state responses. For the spontaneous EEG, both vortioxetine and escitalopram decreased the frequency content in the theta band (4-8 Hz) and increased power in the beta (12-32 Hz) and gamma (32-45 Hz) bands. Vortioxetine and escitalopram decreased connectivity during rest in the theta band and increased connectivity in the gamma bands. Finally, both treatments caused decreased power in the evoked gamma band in response to 40 Hz auditory stimulation. Although the global EEG changes were comparable between vortioxetine and escitalopram, subtle differences between treatment effects on the EEG in terms of effect size and regional distribution of the EEG changes were apparent. To our knowledge, the current results are the first data on how vortioxetine affects EEG in humans. The present study calls for further investigations addressing the possible electrophysiological and cognitive effects of vortioxetine.

Peripheral, synaptic and central neuronal transmission is affected in type 1 diabetes.

AIMS: We hypothesized that adults with type 1 diabetes and severe polyneuropathy have alterations in neuronal transmission at different anatomical levels. The aims were to investigate upstream sensory neuronal activation in terms of peripheral, spinal, precortical, and cortical transmission. METHODS: 48 participants with type-1 diabetes and polyneuropathy, and 21 age-matched healthy participants were included. Electrophysiological median nerve recordings were used to analyze peripheral transmission at Erb's point (P9-N11); spinal evoked potentials at Cv7 (P11-N14); subcortical evoked potentials at Oz (N14-P18); early cortical evoked potentials at CP5 (N20-P22); late cortical evoked potentials at C1 (N60-P80) and estimated cortical inter-peak latencies as measures of central conduction time. RESULTS: In comparison to healthy, the presence of diabetes prolonged peripheral transmission at P9 and N11 (+0.49 ms, p = .000; +0.47 ms, p = .04, respectively), early cortical evoked potentials at CP5: N20 (+2.41 ms, p = .003) and P22 (+5.88 ms, p = .001) and cortical potentials at C1: N60 (+39.08 ms, p = .001) and P80 (+54.55 ms, p = .000) and central conduction time. Decreased amplitudes were shown peripherally (-2.13 µV, p = .000), spinally (-0.57 µV, p = .005) and pre-cortically (-0.22 µV, p = .004). In both healthy and people with diabetes increased central conduction time were associated with decreased parasympathetic tone (ρ = -0.52, p = .027; ρ = -0.35, p = .047, respectively). CONCLUSION: Neuronal afferent transmission and brain responses were significantly impaired in diabetes and the presence of prolonged central conduction time is indicative of severe extensive neuronal damage. Trial registry number: EUDRA CT: 2013-004375-12; clinicaltrials.gov: NCT02138045.