Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Group III and IV muscle afferents differentially affect the motor cortex and motoneurones in humans

The influence of group III and IV muscle afferents on human motor pathways is poorly understood. We used experimental muscle pain to investigate their effects at cortical and spinal levels. In two studies, electromyographic (EMG) responses in elbow flexors and extensors to stimulation of the motor cortex (MEPs) and corticospinal tract (CMEPs) were evoked before, during, and after infusion of hypertonic saline into biceps brachii to evoke deep pain. In study 1, MEPs and CMEPs were evoked in relaxed muscles and during contractions to a constant elbow flexion force . In study 2, responses were evoked during elbow flexion and extension to a constant level of biceps or triceps brachii EMG , respectively. During pain, the size of CMEPs in relaxed biceps and triceps increased (by ∼47% and ∼56%, respectively; P < 0.05). MEPs did not change with pain, but relative to CMEPs, they decreased in biceps (by ∼34%) and triceps (by ∼43%; P < 0.05). During flexion with constant force, ongoing background EMG and MEPs decreased for biceps during pain (by ∼14% and 15%; P < 0.05). During flexion with a constant EMG level, CMEPs in biceps and triceps increased during pain (by ∼30% and ∼26%, respectively; P < 0.05) and relative to CMEPs, MEPs decreased for both muscles (by ∼20% and ∼17%; P < 0.05). For extension, CMEPs in triceps increased during pain (by ∼22%) whereas MEPs decreased (by ∼15%; P < 0.05). Activity in group III and IV muscle afferents produced by hypertonic saline facilitates motoneurones innervating elbow flexor and extensor muscles but depresses motor cortical cells projecting to these muscles.