Topically applied camphor elicits a sensation of cool, but nothing is known about how it affects cold temperature sensing. We found that camphor sensitizes a subpopulation of menthol-sensitive native cutaneous nociceptors in the mouse to cold, but desensitizes and partially blocks heterologously expressed TRPM8 (transient receptor potential cation channel subfamily M member 8). In contrast, camphor reduces potassium outward currents in cultured sensory neurons and, in cold nociceptors, the cold-sensitizing effects of camphor and menthol are additive. Using a membrane potential dye-based screening assay and heterologously expressed potassium channels, we found that the effects of camphor are mediated by inhibition of K_v7.2/3 channels subtypes that generate the M-current in neurons. In line with this finding, the specific M-current blocker XE991 reproduced the cold-sensitizing effect of camphor in nociceptors. However, the M-channel blocking effects of XE991 and camphor are not sufficient to initiate cold transduction but require a cold-activated inward current generated by TRPM8. The cold-sensitizing effects of XE991 and camphor are largest in high-threshold cold nociceptors. Low-threshold corneal cold thermoreceptors that express high levels of TRPM8 and lack potassium channels are not affected by camphor. We also found that menthol—like camphor—potently inhibits K_v7.2/3 channels. The apparent functional synergism arising from TRPM8 activation and M-current block can improve the effectiveness of topical coolants and cooling lotions, and may also enhance TRPM8-mediated analgesia.

The β-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1^−/−mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1-deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a β-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain.

To date, no parameter with satisfactory accuracy exists for the diagnosis of appendicitis. This retrospective study describes the discriminatory value of preoperative hematologic factors associated with complicated and non-complicated pediatric appendicitis. Clinical and laboratory data were obtained from 294 children diagnosed with appendicitis on admission and treated at our tertiary-level pediatric hospital from 2015 to 2017; they were divided into three groups: control group (n = 118), histologically proven complicated (n = 120), and non-complicated (n = 56) appendicitis. Complicated appendicitis was associated with male preponderance and elevated neutrophil and monocyte levels (all p < 0.001). Non-complicated appendicitis was associated with elevated eosinophil levels (p = 0.023), and unaltered lymphocyte levels (p = 0.30). Compared to non-complicated disease, the lymphocyte-to-monocyte ratio (LMR) was decreased in complicated appendicitis (p = 0.003) but unaltered in the control group (p = 0.38). In the discrimination analysis, LMR had high accuracy (AUC 0.73 ± 0.05; p < 0.001; odds ratio (OR) (95% confidence interval (CI)) 6.0 (2.4-15.3)) and was the only parameter independently associated with complicated appendicitis on regression analysis (OR (95% CI), 0.544 (0.359-0.825); p = 0.004). We identified LMR as a novel potential marker for the differentiation of complicated from non-complicated pediatric appendicitis. This has implications on the treatment approach, either surgical in complicated disease or conservative in non-complicated disease.

Vitelline duct anomalies (VDA, including Meckel’s diverticulum (MD)) result from failed embryologic obliteration. This study aimed for characteristics in symptomatic versus asymptomatic VDA, analyzing clinico-laboratory data from 73 children, aged 1 day to 17 years, treated at a tertiary Pediatric Surgery Institution from 2002–2017. A male preponderance was obtained (ratio 3.6:1). MD accounted for 85% of VDA. Incidence of symptomatic VDA decreased with older age. Leading symptoms were intestinal obstruction and hemorrhage. Mucosal heterotopia (present in 39% of symptomatic MD) was associated with anemia and lowered CRP-levels. On ROC-analysis, hemoglobin < 8.6 g/dL, CRP < 0.6 mg/dL and MD distance to ileocecal valve >40 cm were predictors of ectopic tissue in symptomatic MD. Our data confirmed known characteristics as male preponderance, declined incidence of symptomatic cases with age and predominance of gastric ectopia in symptomatic MD. Moreover, anemia and prolonged distance of MD to ileocecal valve were predictors of ectopic mucosa in symptomatic MD.