Hypogonadism induced by surgical stress and brain trauma is reversed by human chorionic gonadotropin in male rats: A potential therapy for surgical and TBI-induced hypogonadism?

Introduction: Hypogonadotropic hypogonadism (HH) is an almost universal, yet underappreciated, endocrinological complication of traumatic brain injury (TBI). The goal of this study was to determine whether the developmental hormone human chorionic gonadotropin (hCG) treatment could reverse HH induced by a TBI. Methods: Plasma samples were collected at post-surgery/post-injury (PSD/PID) days -10, 1, 11, 19 and 29 from male Sprague-Dawley rats (5- to 6-month-old) that had undergone a Sham surgery (craniectomy alone) or CCI injury (craniectomy + bilateral moderate-to-severe CCI injury) and treatment with saline or hCG (400 IU/kg; i.m.) every other day. Results: Both Sham and CCI injury significantly decreased circulating testosterone (T), 11-deoxycorticosterone (11-DOC) and corticosterone concentrations to a similar extent (79.1% vs. 80.0%; 46.6% vs. 48.4%; 56.2% vs. 32.5%; respectively) by PSD/PID 1. hCG treatment returned circulating T to baseline concentrations by PSD/PID 1 (8.9 ± 1.5 ng/ml and 8.3 ± 1.9 ng/ml; respectively) and was maintained through PSD/PID 29. hCG treatment significantly, but transiently, increased circulating progesterone (P4) ~3-fold (30.2 ± 10.5 ng/ml and 24.2 ± 5.8 ng/ml) above that of baseline concentrations on PSD 1 and PID 1, respectively. hCG treatment did not reverse hypoadrenalism following either procedure. Conclusions: Together, these data indicate that (1) craniectomy is sufficient to induce persistent hypogonadism and hypoadrenalism, (2) hCG can reverse hypogonadism induced by a craniectomy or craniectomy +CCI injury, suggesting that (3) craniectomy and CCI injury induce a persistent hypogonadism by decreasing hypothalamic and/or pituitary function rather than testicular function in male rats. The potential role of hCG as a cheap, safe and readily available treatment for reversing surgery or TBI-induced hypogonadism is discussed

Conjugated linoleic acid administration induces amnesia in male sprague dawley rats and exacerbates recovery from functional deficits induced by a controlled cortical impact injury

Long-chain polyunsaturated fatty acids like conjugated linoleic acids (CLA) are required for normal neural development and cognitive function and have been ascribed various beneficial functions. Recently, oral CLA also has been shown to increase testosterone (T) biosynthesis, which is known to diminish traumatic brain injury (TBI)-induced neuropathology and reduce deficits induced by stroke in adult rats. To test the impact of CLA on cognitive recovery following a TBI, 5–6 month old male Sprague Dawley rats received a focal injury (craniectomy + controlled cortical impact (CCI; n = 17)) or Sham injury (craniectomy alone; n = 12) and were injected with 25 mg/kg body weight of Clarinol® G-80 (80% CLA in safflower oil; n = 16) or saline (n = 13) every 48 h for 4 weeks. Sham surgery decreased baseline plasma progesterone (P4) by 64.2% (from 9.5 ± 3.4 ng/mL to 3.4 ± 0.5 ng/mL; p = 0.068), T by 74.6% (from 5.9 ± 1.2 ng/mL to 1.5 ± 0.3 ng/mL; p \u3c 0.05), 11-deoxycorticosterone (11-DOC) by 37.5% (from 289.3 ± 42.0 ng/mL to 180.7 ± 3.3 ng/mL), and corticosterone by 50.8% (from 195.1 ± 22.4 ng/mL to 95.9 ± 2.2 ng/mL), by post-surgery day 1. CCI injury induced similar declines in P4, T, 11-DOC and corticosterone (58.9%, 74.6%, 39.4% and 24.6%, respectively) by post-surgery day 1. These results suggest that both Sham surgery and CCI injury induce hypogonadism and hypoadrenalism in adult male rats. CLA treatment did not reverse hypogonadism in Sham (P4: 2.5 ± 1.0 ng/mL; T: 0.9 ± 0.2 ng/mL) or CCI-injured (P4: 2.2 ± 0.9 ng/mL; T: 1.0 ± 0.2 ng/mL, p \u3e 0.05) animals by post-injury day 29, but rapidly reversed by post-injury day 1 the hypoadrenalism in Sham (11-DOC: 372.6 ± 36.6 ng/mL; corticosterone: 202.6 ± 15.6 ng/mL) and CCI-injured (11-DOC: 384.2 ± 101.3 ng/mL; corticosterone: 234.6 ± 43.8 ng/mL) animals. In Sham surgery animals, CLA did not alter body weight, but did markedly increase latency to find the hidden Morris Water Maze platform (40.3 ± 13.0 s) compared to saline treated Sham animals (8.8 ± 1.7 s). In CCI injured animals, CLA did not alter CCI-induced body weight loss, CCI-induced cystic infarct size, or deficits in rotarod performance. However, like Sham animals, CLA injections exacerbated the latency of CCI-injured rats to find the hidden MWM platform (66.8 ± 10.6 s) compared to CCI-injured rats treated with saline (30.7 ± 5.5 s, p \u3c 0.05). These results indicate that chronic treatment of CLA at a dose of 25 mg/kg body weight in adult male rats over 1-month 1) does not reverse craniectomy- and craniectomy + CCI-induced hypogonadism, but does reverse craniectomy- and craniectomy + CCI-induced hypoadrenalism, 2) is detrimental to medium- and long-term spatial learning and memory in craniectomized uninjured rats, 3) limits cognitive recovery following a moderate-severe CCI injury, and 4) does not alter body weight

STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+T cell dysregulation and accumulation

The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co -exist-ing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8+ T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations. STAT3 GOF mutations drove the accumulation of effector CD8+ T cell clones highly expressing NKG2D, the receptor for stress-induced MHC-class-I-related molecules. This subset also expressed genes for granzymes, perforin, interferon-y, and Ccl5/Rantes and required NKG2D and the IL-15/IL-2 receptor IL2RB for maximal accumula-tion. Leukocyte-restricted STAT3 GOF was sufficient and CD8+ T cells were essential for lethal pathology in mice. These results demonstrate that STAT3 GOF mutations cause effector CD8+ T cell oligoclonal accumu-lation and that these rogue cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukemia/lymphoma driver genes contribute to autoimmune disease.Peer reviewe

Implementation and evaluation of an innovative leadership and teacher training program for non-physician emergency medicine practitioners in Uganda

Introduction: Leadership and teaching skills are essential, but not often emphasized, components of medical training. As emergency care develops as a specialty in Uganda, two cadres of providers are being trained: physicians and non-physician clinicians (NPCs). Building formal leadership and educator training into these curricula is essential. Methods: A week long continuing education (CE) course on leadership and teaching is described and evaluated for effectiveness using Kirkpatrick’s framework for learner-centred outcomes. The emergency care trained NPCs participated in a week-long course consisting of lectures, role-playing, and small group discussions, as well as a personality self-assessment. The evaluation process consisted of: 1) an immediate post-course survey to measure learner satisfaction, 2) a retrospective, pre/post self-assessment with a Likert-type scoring tool to measure knowledge gains, and 3) a three-month follow up survey and structured interviews to measure knowledge retention and behaviour change in practice. Results: All 15 NPCs participated in the evaluation process. Learner satisfaction was high with an average score of 9.3 (on a 1–10 scale) for course content, amount learned, and use of time. Participants reported gains in knowledge for each of the 24 competencies measured, with an average difference in pre- and post-course Likert scores of 1.11 (on a scale of 1–5). Lastly, all 15 participants shared detailed examples of using course content in practice three months after the course finished. The most frequently mentioned themes were “giving and receiving feedback,” “delegating and assigning tasks,” and “communication.” Conclusion: This course was a successful CE intervention in this setting as measured by Kirkpatrick’s framework. The most frequently mentioned concepts used in practice point to the NPCs ability to take on leadership roles in this setting. Further research and evaluation methods should focus on the influence of culture and personalities on leadership education and translation into practice in an EM setting. Keywords: Human capacity development, Training and education, Faculty development, Emergency medicine, Low-resource settings, Kirkpatric

Correction: Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury.

[This corrects the article DOI: 10.1371/journal.pone.0169494.]

Chronic CLA administration compromises short-medium term learning and memory in both uninjured and CCI-injured rats as assessed by latency to locate the Morris water maze (MWM) following novel platform placement.

<p>Second Run: Five minutes after Run 1 (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169494#pone.0169494.g004" target="_blank">Fig 4</a>), latency in seconds to reach the hidden platform at PID 6–10 (Acquisition Phase; platform in SE quadrant) and at PID’s 20–22 (Re-acquisition Phase; platform changed to NE quadrant, ‘Novel Platform Placement’) was tested. MWM Run 2 latency data (mean ± SEM) on PID’s 6–10 and 21–22 were analyzed from 29 rats as follows: Sham + saline (n = 5), Sham + CLA (n = 7), CCI + saline (n = 8) and CCI + CLA (n = 9). Data were analyzed using 2-way repeated measures ANOVA; post-hoc analyses were performed using the Tukey multiple comparison test (p < 0.05; a, b, c and d = differences between time and group, e = differences within groups between the acquisition (PID 10) and re-acquisition phases (PID 20)).</p

CCI, but not CLA, reduces body weight.

<p>Body weight (as a % of baseline weight) each day from PID -10 to PID 29 for Sham + saline (n = 5), Sham + CLA (n = 7), CCI + saline (n = 8) and CCI + CLA (n = 9) groups. Data were analyzed using 2-way repeated measures ANOVA; post-hoc analyses were performed using the Tukey multiple comparison test (p < 0.05; letters indicate differences between pre- and post-surgery body weights between groups across the experiment).</p