Comparisons of the clinical outcomes of different postoperative radiation strategies for treatment of head and neck squamous cell carcinoma.

PURPOSE: We previously reported unfavorable locoregional control with limited field postoperative radiotherapy for head and neck squamous cell carcinoma patients and thus revised the strategy to cover the whole neck. Head and neck squamous cell carcinoma Patients' outcomes were retrospectively analyzed to compare the efficacy of two treatments. MATERIAL AND METHODS: Before 2010, the clinical target volume covered the tumor bed and/or involved the neck region. Since 2011, whole-neck irradiation was planned. Univariate analysis, multivariate analysis, and propensity score matching were performed. The study included 275 patients: 186 received limited field postoperative radiotherapy and 89 received whole-neck postoperative radiotherapy. The median follow-up time for the entire cohort was 40.8 months. RESULTS: In univariate analysis, the radiation strategy had no significant effect on overall survival and progression-free survival. In multivariate analysis, whole-neck postoperative radiotherapy was a favorable factor for overall survival, progression-free survival, and locoregional control. Propensity score matching resulted in a cohort comprising 118 well-matched patients evenly divided between the limited field postoperative radiotherapy and whole-neck postoperative radiotherapy groups. Whole-neck postoperative radiotherapy group achieved a significantly better 2-year overall survival (56.4% vs. 78.1%; P = 0.003), 2-year progression-free survival (34.7% vs. 59.8%; P = 0.009), and 2-year locoregional control (54.4% vs. 83.2%; P < 0.001). The limited field postoperative radiotherapy group developed significantly more locoregional recurrences both in-field (35.2% vs. 15.1%, P = 0.003) and out-of-field (25.0% vs. 0%, P < 0.001) in the matched-pair cohort. CONCLUSION: Whole-neck postoperative radiotherapy is a more appropriate choice than limited field postoperative radiotherapy to improve overall survival, progression-free survival and locoregional control.

Comparison between chemoselection and definitive radiotherapy in patients with cervical esophageal squamous cell carcinoma.

BACKGROUD: Laryngeal preservation is an important consideration when treating cervical esophageal cancers (CECs) such as laryngeal cancer. The standard treatment for CEC allowing laryngeal preservation is chemoradiotherapy. However, in cases of laryngeal cancer, chemoselection has also been applied as a treatment strategy that promotes larynx preservation. This strategy involves assigning the appropriate radical treatment according to the primary tumor's response to induction chemotherapy. Since there have been no studies of the application of chemoselection in CEC cases, the present study compared the results, including laryngeal preservation rates, obtained upon applying chemoselection and chemoradiotherapy to CEC. STUDY DESIGN: This was a retrospective cohort study of cervical esophageal squamous cell carcinoma patients treated using chemoselection or chemoradiotherapy at Aichi Cancer Center Hospital between January 2000 and March 2013. A total of 42 patients were enrolled. RESULTS: The 2-year overall survival and laryngeal preservation rates for the chemoselection group versus the primary radiotherapy group were 65.1 and 57.3 versus 40 and 83.3%, respectively (P = 0.017 and P = 0.122, respectively). The 2-year locoregional control rates for the chemoselection and primary radiotherapy groups were 68 and 25%, respectively (P = 0.045). CONCLUSION: The chemoselection group achieved favorable results. Therefore, chemoselection can be applied as a treatment strategy for CEC.

The Charlson comorbidity index is a prognostic factor in sinonasal tract squamous cell carcinoma.

OBJECTIVE: High Charlson comorbidity index values have been reported to be associated with shorter overall survival in various types of cancer. We investigated whether Charlson comorbidity index values were correlated with overall survival in patients with resectable sinonasal tract squamous cell carcinoma. METHODS: Seventy-nine patients with resectable sinonasal tract squamous cell carcinoma were treated with curative intent. The Charlson comorbidity index values were calculated by the summation of the weight scores of 19 medical conditions (other than sinonasal tract squamous cell carcinoma) before treatment. The survival rate was analyzed according to the Kaplan-Meier method. Univariate and multivariate survival analyses were performed using the Wilcoxon test and the Cox proportional hazards model, respectively. RESULTS: According to a univariate analysis, a Charlson comorbidity index value ≥6 was found to be significantly correlated with shorter overall survival (P < 0.02). In the multivariate survival analysis with adjustment for the clinical T and N classification, age, sex, anatomical location, treatment group (radiotherapy/surgery) and chemotherapy (presence/absence), a Charlson comorbidity index value ≥6 was found to be associated with the significantly shorter overall survival. CONCLUSIONS: These results suggest that the Charlson comorbidity index functions as a prognostic factor in cases of resectable sinonasal tract squamous cell carcinoma.

Lymph node ratio predicts survival in hypopharyngeal cancer with positive lymph node metastasis.

The lymph node density (LND) has been reported to be a significant prognostic factor in various types of carcinoma. This study investigated whether the LND is associated with survival in patients with hypopharyngeal squamous cell carcinoma (HPSCC) who have positive lymph nodes without distant metastasis. Forty-six patients who were pathologically diagnosed with HPSCC with positive lymph nodes and without distant metastasis were enrolled in this study. The LND was defined as the ratio of positive lymph nodes to the total number of lymph nodes. An LND of ≥0.09 was found to be significantly correlated with a shorter overall (p = 0.044) and disease-specific (p = 0.019) survival according to a log-rank test. In a multivariate survival analysis using a Cox proportional hazards model adjusted for the pathological T category (pT3-4/pT1-2), pathological N category (pN2/pN1) and positive surgical margin and/or extracapsular spread (presence/absence), both an LND of ≥0.09 and pT3-4 category were associated with significantly shorter overall survival (p < 0.01) and disease-specific survival (p < 0.01). These results suggest that the LND functions as a prognostic factor for HPSCC patients with positive lymph nodes who do not have distant metastasis.

Near-infrared photoimmunotherapy for salivary duct carcinoma.

In Japan, near-infrared photoimmunotherapy (NIR-PIT) was introduced in 2021 as a treatment option for unresectable recurrent head and neck cancer. The treatment targets the epidermal growth factor receptor (EGFR), which is overexpressed in 80-90 % of head and neck squamous cell carcinoma (HNSCC). NIR-PIT should theoretically show therapeutic efficacy if EGFR is expressed, even in nonsquamous cell carcinomas (non-SCC). To the best of our knowledge, there are no case reports of NIR-PIT for non-SCC. We performed NIR-PIT in a patient with non-SCC of the head and neck region. After performing two NIR-PIT treatments, small free clusters of residual tumor cells were observed. Immunostaining in this specimen revealed EGFR expression in residual tumor cells. The residual tumor cells had been irradiated sufficiently to achieve necrosis. It is suggested that not only laser irradiation and expression of EGFR but also other factors are involved in the efficacy of this treatment. Further investigation for these other factors is warranted.

Factors associated with non-completion of palliative radiotherapy for spinal metastasis in patients with terminal cancer: a retrospective study.

BACKGROUND: Predictors of non-completion of radiotherapy (RT) should be identified to determine the optimal RT dose. Therefore, this study aimed to explore factors associated with non-completion of palliative RT in patients with terminal cancer. METHODS: In this retrospective study, patients with terminal cancer who received RT (not including single-fraction RT) for relief of pain caused by spinal metastasis were categorized into complete and incomplete groups. Baseline characteristics, hematologic test data [e.g., total lymphocyte count (TLC)], performance status, palliative performance scale (PPS) score, psoas muscle index (PMI), Charlson comorbidity index, and age-adjusted Charlson comorbidity index of the patients were compared between the two groups. RESULTS: The complete group comprised 58 patients (median age: 68 years; female/male: 17/41; number of irradiation fractions: ≥2 to <10, 20 patients; 10, 34 patients; and >10, 4 patients), and the incomplete group comprised 9 patients (median age: 68 years; female/male: 3/6; number of irradiation fractions: ≥2 to <10, 2 patients; 10, 7 patients; and >10, 0 patient). The proportion of patient death within 1 week or 1 month was higher in the incomplete group than in the complete group. Compared with that in the incomplete group, TLC measured 1 week before RT (pre-TLC) and PMI recorded before RT were significantly higher in the complete group (P=0.013 and P=0.012, respectively). In multivariable analyses, pre-TLC was significantly associated with the incomplete group (P=0.048). Compared with the complete group, the incomplete group included several patients whose PPS scores rapidly decreased. CONCLUSIONS: Pre-TLC can predict non-completion of palliative RT in patients with terminal cancer.

RNA interference of gonadotropin-inhibitory hormone gene induces aggressive and sexual behaviors in birds.

Gonadotropin-inhibitory hormone (GnIH) was originally identified in the Japanese quail as a hypothalamic neuropeptide inhibitor of pituitary gonadotropin synthesis and release. GnIH neuronal fibers not only terminate in the median eminence to control anterior pituitary function but also extend widely in the brain, suggesting multiple roles in the regulation of behavior. To identify the role of GnIH neurons in the regulation of behavior, we tested the effect of RNA interference (RNAi) of the GnIH gene on aggressive and sexual behaviors of white-crowned sparrows and Japanese quail. Administration of small interfering RNA against GnIH precursor mRNA (GnIH siRNA) into the third ventricle of white-crowned sparrows reduced resting time, spontaneous production of complex vocalizations, and stimulated brief agonistic vocalizations. These behaviors resembled those of breeding birds during territorial defense. Central administration of GnIH siRNA induced aggressive and sexual behaviors and GnIH administration suppressed GnIH RNAi induced aggressive and sexual behaviors in the male quail. In summary, GnIH may function as a central nervous system suppressor of social interaction, thus playing an important role in the control of reproductive behavior, general aggression and territorial defense.

Protease-Activated Receptor 1 (PAR1) Expression Contributes to HPV-Associated Oropharyngeal Cancer Prognosis.

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer occasionally has a poor prognosis, making prognostic risk stratification crucial. Protease-activated receptor-1 (PAR1) is involved in carcinogenesis, and its expression is regulated by alpha-arrestin domain-containing protein 3 (ARRDC3). It is also involved in the tumor microenvironment. We sought to evaluate the predictive ability of PAR1, ARRDC3, and tumor-infiltrating lymphocyte (TIL) scores in patients with oropharyngeal, hypopharyngeal, and uterine cervical cancers, serving as comparators for HPV-associated oropharyngeal cancer. METHODS: Immunohistochemical analysis of p16, ARRDC3, and PAR1 expression was performed on 79 oropharyngeal, 44 hypopharyngeal, and 42 uterine cervical cancer samples. The TIL scores were assessed and classified into the following groups based on invasion: low: 0-10%, medium: 20-40%, and high: > 50%. For prognostic analysis, the three groups were evaluated by dividing them into low, medium, and high categories, or alternatively into two groups using the median value as the cutoff. RESULTS: p16 was expressed in 44 (56%) oropharyngeal, 8 (18%) hypopharyngeal, and all uterine cervical cancer samples. ARRDC3 was detected in 39 (49%) oropharyngeal, 25 (57%) hypopharyngeal, and 23 (55%) uterine cervical cancer samples. PAR1 was expressed in 45 (57%) oropharyngeal, 22 (50%) hypopharyngeal, and 22 (50%) uterine cervical cancer samples. Patients diagnosed with p16-positive oropharyngeal cancer had a substantially improved prognosis compared to those diagnosed with p16-negative cancer. The PAR1-negative cases had a considerably improved prognosis compared to the positive cases (disease-specific survival [DSS] and -negative cases (disease-free survival [DFS]). Multivariate analysis revealed that ARRDC3-positive cases had an appreciably better DSS prognosis than patients with p16-negative oropharyngeal cancers. PAR1-positive patients among patients with p16-positive oropharyngeal cancer had a poor prognosis. With respect to DFS, patients with PAR1-positive and p16-negative oropharyngeal cancer had a 35-fold higher recurrence rate than those with PAR1-negative and p16-negative oropharyngeal cancer. CONCLUSION: Our results suggest that PAR1 expression affects the prognosis and recurrence rate of HPV-associated oropharyngeal cancer.

Predictive factors for dissection-free sentinel node micrometastases in early oral squamous cell carcinoma.

This sentinel node (SN) biopsy trial aimed to assess its effectiveness in identifying predictive factors of micrometastases and to determine whether elective neck dissection is necessary in oral squamous cell carcinoma. This retrospective study included 55 patients from three previous trials, with positive SNs. The relationship between the sizes of the metastatic focus and metastasis in non-sentinel node (NSN) was investigated. Four of the 55 largest metastatic focus were isolated tumor cells, and the remaining 51 were ranged from 0.2 to 15 mm, with a median of 2.6 mm. The difference of prevalence between 46 negative- and 9 positive-NSN was statistically significant with regard to age, long diameter of primary site and number of cases with regional recurrence. In comparing the size of largest metastatic focus dividing the number of positive SN, with metastaic focus range of < 3.0 mm in one-positive SN group, there were 18 (33%) negative-NSN and no positive-NSN. Regarding prognosis, 3-year overall survival rate of this group (n = 18) and other (n = 37) were 94% and 73% (p = 0.04), and 3-year recurrence free survival rate of this group and other were 94% and 51% (p = 0.03), respectively. Absolutely a further prospective clinical trial would be needed, micrometastases may be defined as solitary SN metastasis with < 3.0 mm of metastatic focus, and approximately 33% of neck dissections could be avoided using these criteria.

How to avoid development of AV block during RF ablation: anatomical and electrophysiological analyses at the time of AV node ablation.

BACKGROUND: With an aim to identify risk factors that can serve for prevention of atrioventricular (AV) block (AVB) during radiofrequency (RF) ablation, we conducted anatomical and electrophysiological investigations at the time of AV node ablation (AVNA). METHODS AND RESULTS: Ten patients who underwent AVNA were enrolled. RF energy was delivered from posterior region of septal annulus of the tricuspid valve to the His bundle potential (HBP) recording site using a stepwise approach. In each delivery, atrial/ventricle potential amplitude ratio (A/V ratio), HBP, and juctional ectopy (JE) that appeared during RF delivery were evaluated. Furthermore, fluoroscopic distance between ablation site and HBP recording site (anatomical H-ABL distance) and electrophysiological H-ABL interval were measured. HBP was recorded in 25 of total 70 RF deliveries. When HBP was recorded, the A/V ratio was significantly greater in the group with AVB than without AVB (1.6 ± 2.3 mV vs 0.1 ± 0.2 mV, P = 0.02). The minimum cycle length (CL) of JE was significantly shorter in the group with AVB than without AVB (438 ± 112 ms vs 557 ± 178, ms, P = 0.04). AVB developed frequently when H-ABL distance was less than 15 mm from right anterior oblique view 30° and 12 mm from left anterior oblique view 45° and when H-ABL interval was less than 10 ms. AVB did not develop over the above values. CONCLUSIONS: HBP with high A/V ratio, JE with short CL, short H-ABL distance, and short H-ABL interval of less than 10 ms should be avoided to prevent AVB during RF ablation at the near site of AV node.

Long-term results of the maze procedure on left ventricular function for persistent atrial fibrillation associated with mitral valve disease.

Although the maze procedure is often performed as a surgical treatment for atrial fibrillation (AF) combined with mitral valve surgery, the long-term efficacy of the maze procedure concerning cardiac function has not been determined. The aim of this study was to assess long-term results of the maze procedure for left ventricular function in patients with persistent AF associated with mitral valve disease. We analyzed 38 patients who underwent the maze procedure for persistent AF and mitral valve surgery. The cardiothoracic ratio on chest X-ray and the left atrial dimension, left ventricular end-diastolic dimension, left ventricular end-systolic dimension and left ventricular ejection fraction on transthoracic echocardiography were evaluated before and 6 years after the maze procedure. Twenty-two patients maintained sinus rhythm (SR group) and 16 patients had recurrence of permanent AF (AF group) after the maze procedure. Preoperative cardiac function and the methods of mitral surgery were similar between the two groups. At the latest follow-up, left ventricular function tended to be better in the SR group than in the AF group. Cardiovascular events occurred more often in the AF group during follow-up (50 vs. 18%, p < 0.05). This retrospective study revealed that maintaining the sinus rhythm after the maze procedure for patients who underwent mitral valve surgery might be important for preserving better long-term left ventricular function and result in fewer cardiovascular events.

Atrioventricular nodal ablation versus antiarrhythmic drugs after permanent pacemaker implantation for bradycardia-tachycardia syndrome.

Patients often require antiarrhythmic drugs to control tachycardia after permanent pacemaker implantation (PMI) for bradycardia-tachycardia syndrome. We compared atrioventricular nodal ablation (AVNA) to antiarrhythmic drugs after PMI for bradycardia-tachycardia syndrome. Twenty-eight symptomatic patients with bradycardia-tachycardia syndrome, all of which had a long pause after termination of paroxysmal atrial fibrillation, underwent PMI with RV lead placement at the mid-septum site. Among these patients, 14 underwent PMI and AVNA (AVNA group). The remaining 14 patients underwent PMI only, and continued to take anti-arrhythmic drugs (drug group). We compared cardiac function (cardio-thoracic ratio on chest X-ray, left atrial diameter, left ventricular end-diastolic dimension, and left ventricular-ejection fraction by echocardiography), exercise tolerance (6-min walking distance), symptoms, and the number of antiarrhythmic drugs just before and 6 months after PMI. Baseline characteristics were similar between the two groups, except for the number of antiarrhythmic drugs. Six months after PMI, cardiac function, exercise tolerance, and symptoms did not differ significantly between the two groups. Compared to the drug group (p < 0.01), the number of antiarrhythmic drugs was significantly smaller in the AVNA group 6 months after PMI. Patients who underwent AVNA concurrently with PMI with RV lead placement at the mid-septum site for bradycardia-tachycardia syndrome were able to reduce the intake of drugs and improve their tachycardia-related symptoms while maintaining cardiac function and exercise tolerance.

Chronic cardiac resynchronization therapy reverses cardiac remodelling and improves invasive haemodynamics of patients with severe heart failure on optimal medical treatment.

AIMS: The aim of this study was to assess chronic invasive haemodynamic effects of cardiac resynchronization therapy (CRT) in patients with severe heart failure. METHODS AND RESULTS: Seventeen patients with New York Heart Association (NYHA) class III or IV and QRS duration >120 ms on optimal treatments underwent CRT. Haemodynamic data were obtained by cardiac catheterization before and 1 month after CRT. Clinical parameters and exercise tolerance were also evaluated. Chronic CRT improved haemodynamics significantly; mean pulmonary capillary wedge pressure decreased from 15.9 +/- 6.1 to 10.2 +/- 5.3 mmHg (P < 0.05), systolic pulmonary artery pressure decreased from 36.5 +/- 13.2 to 26.7 +/- 11.9 mmHg (P < 0.05), left ventricular end-diastolic pressure decreased from 15.6 +/- 7.2 to 10.5 +/- 7.3 mmHg (P < 0.05), end-diastolic volume decreased from 358.8 +/- 84.6 to 322.9 +/- 99.0 mL (P < 0.05), end-systolic volume decreased from 264.1 +/- 67.6 to 219.2 +/- 74.3 mL (P < 0.05), left ventricular ejection fraction increased from 25.4 +/- 6.2 to 33.1 +/- 4.9% (P < 0.05), and cardiac index increased from 1.9 +/- 0.4 to 2.2 +/- 0.5 L/min/m(2) (P < 0.05). Chronic CRT significantly improved functional capacity such as NYHA classification, 6 min walk distance, and peak oxygen uptake. CONCLUSION: Chronic CRT improved not only symptoms and exercise tolerance but also invasive haemodynamics associated with reversed cardiac remodelling.

The high-sensitivity modified Glasgow prognostic score is superior to the modified Glasgow prognostic score as a prognostic predictor for head and neck cancer.

BACKGROUND: There is increasing evidence that the inflammatory indices of modified Glasgow prognostic score (mGPS) and high-sensitivity mGPS (HS-mGPS) play important roles in predicting the survival in many cancer; however, evidence supporting such an association in head and neck cancer (HNC) is scarce. MATERIALS AND METHODS: We evaluated the impact of the mGPS and HS-mGPS on the overall survival (OS) in 129 patients with HNC treated at Aichi Cancer Center Central Hospital from 2012-2013. The mGPS was calculated as follows: mGPS of 0, C-reactive protein (CRP) ≤1.0 mg/dl; 1, CRP >1.0 mg/dl; 2, CRP>1.0 mg/dl and albumin <3.5 mg/dl. Regarding the HS-mGPS, the CRP threshold level was set as 0.3 mg/dl. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox proportional hazard models after adjusting for potential confounders. RESULTS: The prognosis of HNC worsened significantly as both the mGPS and HS-mGPS increased in a univariate analysis. After adjusting for covariates, the HS-mGPS was significantly associated with the OS (adjusted HR for HS-mGPS of 2 compared to an HS-mGPS of 0 [HRscore2-0] 3.14 [95% CI: 1.23-8.07], Ptrend < 0.001), while the mGPS was suggested to be associated with the survival (HRscore2-0 2.37 [95% CI:0.89-6.33], Ptrend = 0.145). Even after stratification by clinical covariates, these associations persisted. CONCLUSION: We conclude that the HS-mGPS is useful as an independent prognostic factor in HNC.

Complication and surgical site infection for salvage surgery in head and neck cancer after chemoradiotherapy and bioradiotherapy.

OBJECTIVE: We aimed to investigate the complications, surgical site infection (SSI), and survival in salvage surgery without free-flap reconstruction for patients with head and neck squamous cell carcinoma who were treated by platinum-based chemoradiotherapy (Plat-CRT) or cetuximab-based bioradiotherapy (Cet-BRT). METHODS: Thirty-three patients treated by Plat-CRT and six treated by Cet-BRT had salvage surgery. We categorized postoperative complications according to the Clavien-Dindo classification and SSI according to the wound grading scale. Overall survival calculated by Kaplan-Meier method. RESULTS: Patients with Cet-BRT were significantly associated with the presence of SSI (P<0.01) and grades IIIb-V of the Clavien-Dindo classification (P<0.01) compared with those with Plat-CRT. Patients with Cet-BRT had a significantly lower overall survival than those with Plat-CRT (P<0.05). CONCLUSION: We demonstrated that patients with Cet-BRT were significantly more associated with the presence of SSI and grades IIIb-V in the Clavien-Dindo classification than those with CRT.

The nodal response to chemoselection predicts the risk of recurrence following definitive chemoradiotherapy for pharyngeal cancer.

CONCLUSIONS: The poor response of neck tumors to induction chemotherapy (ICT) as chemoselection is related to a significantly worse prognosis, including higher risks of local recurrence and/or distant metastasis, after definitive chemoradiotherapy (CRT). OBJECTIVES: Neck dissection is frequently performed to treat residual lymph nodes after CRT for the purpose of locoregional control; however, the prognosis of patients with pathologically proven residual neck tumors is poor, and no methods for predicting unfavorable results before CRT have been established. Therefore, in the present study, we focused on the response of lymph nodes to ICT and its relationship with the prognosis among patients treated with chemoselection. METHODS: We retrospectively reviewed a total of 27 oropharyngeal and 24 hypopharyngeal squamous cell carcinoma stage III/IV consecutive patients with cervical lymph node metastasis who exhibited a response of >50% in the primary tumor to ICT followed by concurrent definitive CRT. RESULTS: The relapse-free survival of the patients who responded (partial response/complete response, PR/CR) to ICT was significantly superior to that of the patients who did not respond (stable disease, SD) to ICT (p = 0.008).

Molecular basis for the activation of gonadotropin-inhibitory hormone gene transcription by corticosterone.

The inhibitory effect of stress on reproductive function is potentially mediated by high concentrations of circulating glucocorticoids (GCs) acting via the GC receptor (GR). Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that inhibits gonadotropin secretion. GnIH may mediate stress-induced reproductive dysfunction. However, it is not yet known whether GC-bound GR is directly involved in GnIH transcription. Here, we demonstrated the localization of GR mRNA in GnIH neurons in the paraventricular nucleus of quail, suggesting that GC can directly regulate GnIH transcription. We next showed that 24 hours of treatment with corticosterone (CORT) increase GnIH mRNA expression in the quail diencephalon. We further investigated the mechanism of activation of GnIH transcription by CORT using a GnIH-expressing neuronal cell line, rHypoE-23, derived from rat hypothalamus. We found the expression of GR mRNA in rHypoE-23 cells and increased GnIH mRNA expression by 24 hours of CORT treatment. We finally characterized the promoter activity of rat GnIH gene stimulated by CORT. Through DNA deletion analysis, we identified a CORT-responsive region at 2000-1501 bp upstream of GnIH precursor coding region. This region included 2 GC response elements (GREs) at -1665 and -1530 bp. Mutation of -1530 GRE abolished CORT responsiveness. We also found CORT-stimulated GR recruitment at the GnIH promoter region containing the -1530 GRE. These results provide a putative molecular basis for transcriptional activation of GnIH under stress by demonstrating that CORT directly induces GnIH transcription by recruitment of GR to its promoter.

Identification, expression, and physiological functions of Siberian hamster gonadotropin-inhibitory hormone.

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that inhibits gonadotropin secretion in birds and mammals. To further understand its physiological roles in mammalian reproduction, we identified its precursor cDNA and endogenous mature peptides in the Siberian hamster brain. The Siberian hamster GnIH precursor cDNA encoded two RFamide-related peptide (RFRP) sequences. SPAPANKVPHSAANLPLRF-NH(2) (Siberian hamster RFRP-1) and TLSRVPSLPQRF-NH(2) (Siberian hamster RFRP-3) were confirmed as mature endogenous peptides by mass spectrometry from brain samples purified by immunoaffinity chromatography. GnIH mRNA expression was higher in long days (LD) compared with short days (SD). GnIH mRNA was also highly expressed in SD plus pinealectomized animals, whereas expression was suppressed by melatonin, a nocturnal pineal hormone, administration. GnIH-immunoreactive (-ir) neurons were localized to the dorsomedial region of the hypothalamus, and GnIH-ir fibers projected to hypothalamic and limbic structures. The density of GnIH-ir perikarya and fibers were higher in LD and SD plus pinealectomized hamsters than in LD plus melatonin or SD animals. The percentage of GnRH neurons receiving close appositions from GnIH-ir fiber terminals was also higher in LD than SD, and GnIH receptor was expressed in GnRH-ir neurons. Finally, central administration of hamster RFRP-1 or RFRP-3 inhibited LH release 5 and 30 min after administration in LD. In sharp contrast, both peptides stimulated LH release 30 min after administration in SD. These results suggest that GnIH peptides fine tune LH levels via its receptor expressed in GnRH-ir neurons in an opposing fashion across the seasons in Siberian hamsters.

RNA interference of gonadotropin-inhibitory hormone gene induces arousal in songbirds.

Gonadotropin-inhibitory hormone (GnIH) was originally identified in quail as a hypothalamic neuropeptide inhibitor of pituitary gonadotropin synthesis and release. However, GnIH neuronal fibers do not only terminate in the median eminence to control anterior pituitary function but also extend widely in the brain, suggesting it has multiple roles in the regulation of behavior. To identify the role of GnIH neurons in the regulation of behavior, we investigated the effect of RNA interference (RNAi) of the GnIH gene on the behavior of white-crowned sparrows, a highly social songbird species. Administration of small interfering RNA against GnIH precursor mRNA into the third ventricle of male and female birds reduced resting time, spontaneous production of complex vocalizations, and stimulated brief agonistic vocalizations. GnIH RNAi further enhanced song production of short duration in male birds when they were challenged by playbacks of novel male songs. These behaviors resembled those of breeding birds during territorial defense. The overall results suggest that GnIH gene silencing induces arousal. In addition, the activities of male and female birds were negatively correlated with GnIH mRNA expression in the paraventricular nucleus. Density of GnIH neuronal fibers in the ventral tegmental area was decreased by GnIH RNAi treatment in female birds, and the number of gonadotropin-releasing hormone neurons that received close appositions of GnIH neuronal fiber terminals was negatively correlated with the activity of male birds. In summary, GnIH may decrease arousal level resulting in the inhibition of specific motivated behavior such as in reproductive contexts.

Implantation of pacemaker for sick sinus syndrome in a patient with persistent left superior vena cava and absent right superior vena cava.

Absent right superior vena cava with persistent left superior vena cava in normal situs is an exceedingly rare congenital anomaly. In such cases, pacemaker implantation (PMI) is very difficult or even impossible. We report the case of a patient with sick sinus syndrome in whom PMI was easily performed via the left superior vena cava by using a steerable stylet.