cian played by Cary Grant, is followed everywhere by a large, silent man. The man is with him as he addresses an anatomy class, as he conducts the student orchestra, as he stands over a patient in the operating room. The man speaks only at rare moments, each crucial, coming to Noah's aid as the voice of wisdom, of conscience, or of the past. When Noah is finally challenged by a university tribunal to defend his relationship with the odd man he calls "my friend," the story comes out: the man is a convicted murderer, executed by hanging and sent 20 years earlier to Noah, a medical student who needed "a cadaver of my own." The "cadaver" awakened as soon as Noah stuck a gloved finger in his mouth, and has never since left his side. Early experiences in the anatomy laboratory underpin later practice in ways that are not easy to articulate. The knowledge gained there guides diagnosis, allows us to link phenomena that seem on the body's surface to be unrelated, and gives us fluency in a discourse that lets us to describe what is happening to our patients. Visualizing the structures hidden beneath the skin allows us to identify conditions otherwise beyond our grasp. Although the overwhelming bulk of the knowledge we use to care for patients is learned outside the lab, and the centrality of the experience wanes even by the end of first year, what we learn in anatomy lab is somehow, quietly, always there. In this issue of MSJAMA, literature professor John Bender recounts his season as an outsider in the lab and describes how the process serves as a ritual entry into the medical profession. Beyond the technical knowledge it affords, anatomy lab links us to the past and begins our socialization to future practice. We dissect knowing that we are making the same cuts and seeking the same structures as physicians centuries earlier. But today, we pride ourselves on taking more from the experience, on engaging with the gift that is the donation. Samantha Stewart and Rita Charon describe anatomy study as an initial confrontation with life and death that will follow us throughout our careers, and discuss a way these early lessons might be retrieved. S. Ryan Gregory and Thomas Cole describe the history of dissection across centuries, while Aaron Tward and Hugh Patterson account for the shift from grave robbing to cadaver donation in the United States. Finally, to launch our new creative writing section murmur, Matthew Ehrlich evaluates his cadaver's chief complaint. The first body in our care has neither the needs nor the agency of a patient, and yet for many of us, it is the body we will envision as we examine the intact surface of each patient who comes to us. Whether it is our initiation into "the professional tribe of physicians" (Bender), "the scientific method" (Gregory and Cole), or "the use of affective responses" (Stewart and Charon), anatomy lab is as much a part of how we see as what we know. "The trouble with you, Elwell," Noah's ally says to his accuser at the end, "is you've never had a cadaver of your own." ON THE COVER
Context Kisspeptin–neurokinin B (NKB)–dynorphin neurons are critical regulators of the hypothalamic–pituitary–gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear. Objective To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB. Design Case/control. Setting Academic medical center. Participants Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice. Interventions Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin. Main Outcome Measures LH pulse characteristics. Results Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin. Conclusion The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with b-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.
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