Radiation effects on human heredity.

In experimental organisms such as fruit flies and mice, increased frequencies in germ cell mutations have been detected following exposure to ionizing radiation. In contrast, there has been no clear evidence for radiation-induced germ cell mutations in humans that lead to birth defects, chromosome aberrations, Mendelian disorders, etc. This situation exists partly because no sensitive and practical genetic marker is available for human studies and also because the number of people exposed to large doses of radiation and subsequently having offspring was small until childhood cancer survivors became an important study population. In addition, the genome of apparently normal individuals seems to contain large numbers of alterations, including dozens to hundreds of nonfunctional alleles. With the number of mutational events in protein-coding genes estimated as less than one per genome after 1 gray (Gy) exposure, it is unsurprising that genetic effects from radiation have not yet been detected conclusively in humans.

Monophosphoryl lipid A alleviated radiation-induced testicular injury through TLR4-dependent exosomes.

Radiation protection on male testis is an important task for ionizing radiation-related workers or people who receive radiotherapy for tumours near the testicle. In recent years, Toll-like receptors (TLRs), especially TLR4, have been widely studied as a radiation protection target. In this study, we detected that a low-toxicity TLR4 agonist monophosphoryl lipid A (MPLA) produced obvious radiation protection effects on mice testis. We found that MPLA effectively alleviated testis structure damage and cell apoptosis induced by ionizing radiation (IR). However, as the expression abundance differs a lot in distinct cells and tissues, MPLA seemed not to directly activate TLR4 singling pathway in mice testis. Here, we demonstrated a brand new mechanism for MPLA producing radiation protection effects on testis. We observed a significant activation of TLR4 pathway in macrophages after MPLA stimulation and identified significant changes in macrophage-derived exosomes protein expression. We proved that after MPLA treatment, macrophage-derived exosomes played an important role in testis radiation protection, and specially, G-CSF and MIP-2 in exosomes are the core molecules in this protection effect.

Radiation therapy and the risk of herpes zoster in patients with cancer.

BACKGROUND: The role and impact of radiation therapy (RT) on the development of herpes zoster (HZ) has not been well studied. The objective of this study was to investigate the association between RT and HZ. METHODS: A propensity score-matched, retrospective cohort study was conducted using institutional cancer registry data and medical records from 2011 to 2015. The risk of developing HZ in the RT and non-RT groups was compared using a Cox proportional hazards model. Associations also were explored between the RT field and the anatomic location of HZ in patients who developed HZ after RT. The expected number of HZ events within the radiation field was calculated according to the RT received by each patient; then, this number was compared with the observed number of in-field events. RESULTS: Of 17,655 patients, propensity score matching yielded 4350 pairs; of these, 3891 pairs were eligible for comparison. The cumulative incidence of HZ in the RT group (vs the non-RT group) during the first 5 years after the index date was 2.1% (vs 0.7%) at 1 year, 3.0% (vs 1.0%) at 2 years, 3.4% (vs 1.3%) at 3 years, 4.1% vs 1.7% at 4 years, and 4.4% vs 1.8% at 5 years. The RT group showed a significantly higher risk of HZ than the non-RT group (hazard ratio, 2.59, 95% CI, 1.84-3.66). In the 120 patients who developed HZ after RT, HZ events were observed significantly more frequently within the RT field than expected (74 vs 43.8 events; P < .001). CONCLUSIONS: Patients with cancer who received RT showed a significantly higher risk of HZ, which was commonly observed within the radiation field.

Second cancer risk after primary cancer treatment with three-dimensional conformal, intensity-modulated, or proton beam radiation therapy.

BACKGROUND: The comparative risks of a second cancer diagnosis are uncertain after primary cancer treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam radiotherapy (PBRT). METHODS: Pediatric and adult patients with a first cancer diagnosis between 2004 and 2015 who received 3DCRT, IMRT, or PBRT were identified in the National Cancer Database from 9 tumor types: head and neck, gastrointestinal, gynecologic, lymphoma, lung, prostate, breast, bone/soft tissue, and brain/central nervous system. The diagnosis of second cancer was modeled using multivariable logistic regression adjusting for age, follow-up duration, radiotherapy (RT) dose, chemotherapy, sociodemographic variables, and other factors. Propensity score matching also was used to balance baseline characteristics. RESULTS: In total, 450,373 patients were identified (33.5% received 3DCRT, 65.2% received IMRT, and 1.3% received PBRT) with median follow-up of 5.1 years after RT completion and a cumulative follow-up period of 2.54 million person-years. Overall, the incidence of second cancer diagnosis was 1.55 per 100 patient-years. In a comparison between IMRT versus 3DCRT, there was no overall difference in the risk of second cancer (adjusted odds ratio [OR], 1.00; 95% CI, 0.97-1.02; P = .75). By comparison, PBRT had an overall lower risk of second cancer versus IMRT (adjusted OR, 0.31; 95% CI, 0.26-0.36; P < .0001). Results within each tumor type generally were consistent in the pooled analyses and also were maintained in propensity score-matched analyses. CONCLUSIONS: The risk of a second cancer diagnosis was similar after IMRT versus 3DCRT, whereas PBRT was associated with a lower risk of second cancer risk. Future work is warranted to determine the cost-effectiveness of PBRT and to identify the population best suited for this treatment.

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer.

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS-STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS-STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer-highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS-STING signaling, deleterious effects associated with cGAS-STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS-STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study.

BACKGROUND: Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. METHODS AND FINDINGS: In this nationwide register study, all singletons born in Sweden 1994-2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19-1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment-to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54-1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25-4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995-2000-both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. CONCLUSIONS: No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.

Associations of clinical and dosimetric parameters with late rectal toxicities after radical intensity-modulated radiation therapy for prostate cancer: a single-centre retrospective study.

INTRODUCTION: This study assessed the incidence of late rectal toxicities and evaluated potential predictive factors for late proctitis in patients treated with prostate-specific intensity-modulated radiotherapy in Hong Kong. METHODS: This retrospective longitudinal observational study included patients with localised prostate cancer who were treated with intensity-modulated radiation therapy in an oncology unit in Hong Kong between January 2007 and December 2011, and who had >1 year of follow-up. Clinical, pharmacological, and radiation parameters were recorded. Toxicities were measured by Common Terminology Criteria for Adverse Events version 4. RESULTS: In total, 232 patients were included in this analysis. The mean follow-up time was 7.3 ± 2.1 years and 46.5% of the patients had late rectal toxicities. Late proctitis occurred in 30.5% of patients; 25% of the patients with late proctitis exhibited grade ≥2 toxicity. Median onset times for late proctitis and rectal bleeding were 15 and 18.4 months, respectively. Multivariable regression showed increased odds for the occurrence of late proctitis in patients with older age (odds ratio [OR]=1.11, 95% confidence interval [CI]=1.04-1.19, P=0.003), higher V70 (OR=1.08, 95% CI=1.01-1.15, P=0.027), and presence of acute rectal toxicities (OR=4.47, 95% CI=2.37-8.43, P<0.001). Antiplatelet use was not significantly associated with the occurrence of late proctitis (OR=1.98, 95% CI=0.95-4.14, P=0.07). CONCLUSIONS: The incidence of late rectal toxicities was considerable among patients in this study. Clinicians should consider the possibility of late proctitis for patients with older age, acute rectal toxicities, and higher V70. High doses to rectal volumes should be limited because of the significant association with V70.

Therapeutic Effect of Ecdysterone Combine Paeonol Oral Cavity Direct Administered on Radiation-Induced Oral Mucositis in Rats.

Radiation-induced oral mucositis represents an influential factor in cancer patients' accepted radiation therapy, especially in head and neck cancer. This research investigates the treatment effect of Ecdysterone (a steroid derived from the dry root of Achyranthes bidentate) and Paeonol (a compound derived from Cortex Moutan) on radiation-induced oral mucositis and possible underlying mechanisms. Concisely, 20 Gy of X-rays (single-dose) irradiated the cranial localization in rats for the modeling of oral mucositis. The therapeutic effects of Ecdysterone-Paeonol oral cavity directly administered on radiation-induced oral mucositis were investigated by weight changes, direct observations, visual scoring methods, ulcer area/total area, and basic recovery days. Assessments of tumor necrosis factor α and interleukin-6 were performed to evaluate the inflammatory cytokines secretion in the damaged areas of tongues harvested post-treatment, and changes in signaling pathways were investigated by Western blotting. System Drug Target (SysDT) methods revealed the targets of Ecdysterone-Paeonol in order to support compound-target network construction. Four representative targets with different functions were chosen. The binding interactions between the compound and receptor were evaluated by molecular docking to investigate the binding affinity of the ligand to their protein targets. Ecdysterone-Paeonol, administered orally, effectively improved radiation-induced oral mucositis in rats, and the therapeutic effect was better than Ecdysterone administered orally on its own. In this study, calculational chemistry revealed that Ecdysterone-Paeonol affected 19 function targets associated with radiation-induced oral mucositis, including apoptosis, proliferation, inflammation, and wound healing. These findings position Ecdysterone-Paeonol as a potential treatment candidate for oral mucositis acting on multiple targets in the clinic.

Utility of polaprezinc in reducing toxicities during radiotherapy: a literature review.

Chemoradiotherapy is important for treating malignancies. However, radiation-induced toxicities develop as chemoradiotherapy-related complications. Various agents reduce or prevent toxicities, but there are no standard treatments. Polaprezinc (PZ), a chelating compound used for gastric ulcers, has antioxidant and free radical scavenging effects. Although few studies have evaluated PZ and radiation-induced normal tissue damage, several clinical studies have shown the efficacy of PZ for oral mucositis, esophagitis, proctitis and taste alterations during and after radiotherapy. Moreover, preclinical data support the clinical data, indicating good potential of testing PZ in future trials. However, as there are only few well-documented review articles on PZ use in cancer treatment, we conducted this literature review. PZ reduced several radiation-induced toxicities and improved the quality of life.

Autologous fat graft in irradiated orbit postenucleation for retinoblastoma.

Autologous fat grafting has been extensively and successfully adopted in a number of pathologic conditions in regenerative surgery especially on irradiated fields in order to improve pain symptoms and tissue trophism promoting scar release. In the present study, we report our experience with autologous fat grafting for the treatment of postirradiation fibrosis and pain on three consecutive patients undergoing orbital enucleation for locally advanced retinoblastoma (RB) and subsequent radiotherapy. We selected three consecutive patients who underwent orbital enucleation for locally advanced RB and subsequent local radiotherapy showing severe reduction in orbital volume and eyelid length and retraction due to fibrosis, spontaneous local pain exacerbated after digital pressure with no possibility to place an ocular implant. They underwent autologous fat grafting in the orbital cavity and results were evaluated by clinical examination at 5 and 14 days, and 1, 3, 6 months, and 1 year after surgery. A significant release of scar retraction, reduction of fibrosis and orbital rim contraction together with an important improvement of pain symptoms was observed in all patients. The local changes observed enabled an ease placement of an ocular prosthetic implant (implant). No local or systemic complication occurred. Fat grafting is a promising treatment for patients showing radiotherapy related complication in the orbital area and it should be adopted by all oculoplastic surgeon in order to improve pain syndrome creating the ideal local conditions for the placement of an ocular prosthetic implant.

The Cellular and Molecular Mechanism of Radiation-Induced Lung Injury.

The lung is one of several moderately radiosensitive organs. Radiation-induced lung injury (RILI), including acute radiation pneumonitis and chronic radiation-induced pulmonary fibrosis, occurs most often in radiotherapy of lung cancer, esophageal cancer, and other thoracic cancers. Clinical symptoms of RILI include dry cough, shortness of breath, chest pain, fever, and even severe respiratory failure and death. The occurrence of RILI is a complex process that includes a variety of cellular and molecular interactions which ultimately leads to large fibroblast accumulation, proliferation, and differentiation, resulting in excessive extracellular matrix deposits, causing pulmonary fibrosis. The progress that has been made in recent years in the understanding of cellular and molecular mechanisms of RILI is summarized in this review.

The use of prophylactic Nunchaku stents to reduce the risk of nasolacrimal duct obstruction in patients with midfacial tumours undergoing radiotherapy.

The treatment of midfacial tumours with radiotherapy, chemotherapy and radio-iodine can cause nasolacrimal duct fibrosis resulting in epiphora. Nasolacrimal patency can be maintained by stenting. We report our experience of prophylatic Nunchaku stent insertion in 5 patients prior to midfacial radiotherapy. Four out of 5 patients (80%) had patent nasolacrimal ducts without any symptoms of epiphora following removal of the stents. One patient was initially asymptomatic with patent nasolacrimal duct, but subsequently developed epiphora. Nunchaku stents may provide a simple and effective way of preventing epiphora, obviate the need for nasal retrieval that is required for other nasolacrimal stents, and reduce the risk of requiring further lacrimal surgery.

Social behavioral testing and brain magnetic resonance imaging in chicks exposed to mobile phone radiation during development.

BACKGROUND: The potential adverse effect of mobile phone radiation is currently an area of great concern in the field of public health. In the present study, we aimed to investigate the effect of mobile phone radiation (900 MHz radiofrequency) during hatching on postnatal social behaviors in chicks, as well as the effect on brain size and structural maturity estimated using 3.0 T magnetic resonance imaging. At day 4 of incubation, 76 normally developing chick embryos were divided into the control group (n = 39) and the radiation group (n = 37). Eggs in the radiation group were exposed to mobile phone radiation for 10 h each day from day 4 to 19 of incubation. Behavioral tests were performed 4 days after hatching. T2-weighted MR imaging and diffusion tensor imaging (DTI) were subsequently performed. The size of different brain subdivisions (telencephalon, optic lobe, brain stem, and cerebellum) and corresponding DTI parameters were measured. The Chi-square test and the student's t test were used for statistical analysis. P < 0.05 was considered statistically significant. RESULTS: Compared with controls, chicks in the radiation group showed significantly slower aggregation responses (14.87 ± 10.06 vs. 7.48 ± 4.31 s, respectively; P < 0.05), lower belongingness (23.71 ± 8.72 vs. 11.45 ± 6.53 s, respectively; P < 0.05), and weaker vocalization (53.23 ± 8.60 vs. 60.01 ± 10.45 dB/30 s, respectively; P < 0.05). No significant differences were found between the radiation and control group for brain size and structural maturity, except for cerebellum size, which was significantly smaller in the radiation group (28.40 ± 1.95 vs. 29.95 ± 1.41 cm(2), P < 0.05). The hatching and heteroplasia rates were also calculated and no significant difference was found between the two groups. CONCLUSIONS: Mobile phone radiation exposure during chick embryogenesis impaired social behaviors after hatching and possibly induced cerebellar retardation. This indicates potential adverse effects of mobile phone radiation on brain development.

Maternal exposure to radiographic exams and major structural birth defects.

BACKGROUND: An increasing number of radiologic exams are performed in the United States, but very few studies have examined the effects of maternal exposure to radiologic exams during the periconceptional period and birth defects. OBJECTIVES: To assess the association between maternal exposure to radiologic exams during the periconceptional period and 19 categories of birth defects using a large population-based study of birth defects. METHODS: We studied 27,809 case mothers and 10,200 control mothers who participated in the National Birth Defects Prevention Study and delivered between 1997 and 2009. Maternal exposure to radiologic exams that delivered ionizing radiation to the urinary tract, lumbar spine, abdomen, or pelvis were identified based on the mother's report of type of radiologic exams, organ or body part scanned and the month during which the exam occurred RESULTS: Overall, 0.9% of mothers reported exposure to one of these types of radiographic exams during the periconceptional period. We observed significant associations between maternal exposure during the first trimester and isolated Dandy-Walker malformation (odds ratio = 7.7; 95% confidence interval, 1.8-33) and isolated d-transposition of the great arteries (odds ratio = 3.8; 95% confidence interval, 1.4-10.3). However, the result for isolated Dandy-Walker malformation was based on only two exposed cases. CONCLUSION: These results should be interpreted cautiously because multiple statistical tests were conducted and measurements of exposure were based on maternal report. However, our results may be useful for generating hypotheses for future studies. Birth Defects Research (Part A) 106:563-572, 2016. © 2016 Wiley Periodicals, Inc.

Evidence for a teratogenic risk in the offspring of health personnel exposed to ionizing radiation?!

BACKGROUND: The evidence concerning safety of occupational exposure to ionizing radiation on teratogenic effects mainly relies on animal models, disaster epidemiology and experience in cancer etiology. Following an explorative result on maternal exposure in medical occupations we conducted a feasibility study, addressing congenital anomalies (CA) in the offspring of health workers potentially exposed to radiation. METHODS: In a prospective follow-up study, we enrolled women, identified by mandatory registration at the office of radiation protection as wearing a dosimeter. The participating women answered a questionnaire and if pregnant agreed to an examination of their infant. CA were diagnosed and categorized, and demographic and anamnestic findings (including dosimeter values) were ascertained. Mainz Birth Registry data were used for comparison, and a nonresponder analysis was performed. RESULTS: Answers were received from 286 of 604 (51%) women exposed and 183 (30.3%) of them participated in the study including 88 nonparticipants who provided exposure data only. Further sources of ionizing radiation and other factors relevant for CA did not differ between the groups. Thirty pregnancies occurred among the participants. Eight of the resulting 27 infants were diagnosed with CA (30%) compared with 6.2% of the comparison group. CONCLUSION: Previous explorative findings were corroborated by this feasibility study. The increased prevalence for CA could not be explained by any other factor. A preferable prospective active design is achievable, and the participation rate is essential to calculate valid results and answer this important issue. Birth Defects Research (Part A) 106:475-479, 2016. © 2016 Wiley Periodicals, Inc.

TREATMENT OF LOCAL RADIATION LESIONS IN BREAST CANCER PATIENTS.

The purpose of this paper is the demonstration and analysis of the effectiveness of spinal cord stimulation in treatment of chronic drug-resistant neuropathy pain in a patient with radiation-induced plexopathy. She underwent radiation therapy for cancer of the right breast in 2000. Ten years later she complained with pain and weakness her right arm. After physical examination and investigation right-side brachial plexopathy was diagnosed. Antidepressant and anticonvulsant had positive effect during one year but then pain appeared again. That is why the patient has been implanted the system of epidural electrostimulation of thickening of the cervical spinal cord. During the post-operative period significant improvement of pain relief was noted. The doses of analgesics were decreased. Spinal cord stimulation efficacy for treatment of chronic pain was repeatedly proved in clinical investigation and meta-analyses. Nevertheless spinal cord stimulation effects on radiation-induced neurological disorders and possible pathophysiological mechanisms are not enough examined. All these facts require further investigation.

Maternal occupational exposure to ionizing radiation and major structural birth defects.

BACKGROUND: Ionizing radiation (IR) is known to be carcinogenic and mutagenic, but little is known about the association between maternal occupational exposure to IR and birth defects. METHODS: We studied 38,009 mothers who participated in the National Birth Defects Prevention Study and delivered between 1997 and 2009. We assessed odds ratios [ORs] for the association between maternal occupations with potential exposure to IR and 39 birth defects. RESULTS: We observed significant odds ratios (ORs) for isolated hydrocephaly (adjusted OR [AOR], 2.1; 95% confidence interval [CI], 1.1-4.2), isolated anotia/microtia (AOR, 2.0; 95% CI, 1.0-4.0), isolated colonic atresia (crude OR, 7.5; 95% CI, 2.5-22.3), isolated omphalocele (AOR, 2.3; 95% CI, 1.1-4.6) and isolated anencephaly (crude OR, 0.23; 95% CI, 0.06-0.94). We also observed a nonsignificant OR for birth defects in aggregate (AOR, 2.0; 95% CI, 0.9-4.6) among mothers with potential occupational exposure to fluoroscopy. CONCLUSION: We assessed 39 birth defects, observing that maternal occupations with potential exposure to IR were associated with a significantly increased risk for 4 birth defects and a significantly protected risk for 1 birth defect. These results should be interpreted cautiously because our measurement of exposure is qualitative, some of these associations may be due to occupational exposures that are correlated with IR and some may be due to chance. However, these findings serve as the first evaluation of these relationships in a large study and may be useful for generating hypotheses for future studies.

Sex ratio at birth: scenario from normal- and high-level natural radiation areas of Kerala coast in south-west India.

Newborns were monitored for congenital malformations in four government hospitals located in high-level (ambient dose >1.5 mGy/year) and normal-level (≤ 1.5 mGy/year) natural radiation areas of Kerala, India, from August 1995 to December 2012. Sex ratio at birth (SRB) among live singleton newborns and among previous children, if any, of their mothers without history of any abortion, stillbirth or twins is reported here. In the absence of environmental stress or selective abortion of females, global average of SRB is about 1050 males to 1000 females. A total of 151,478 singleton, 1031 twins, 12 triplets and 1 quadruplet deliveries were monitored during the study period. Sex ratio among live singleton newborns was 1046 males (95 % CI 1036-1057) for 1000 females (77,153 males:73,730 females) and was comparable to the global average. It was similar in high-level and normal-level radiation areas of Kerala with SRB of 1050 and 1041, respectively. It was consistently more than 1000 and had no association with background radiation levels, maternal and paternal age at birth, parental age difference, gravida status, ethnicity, consanguinity or year of birth. Analysis of SRB of the children of 139,556 women whose reproductive histories were available suggested that couples having male child were likely to opt for more children and this, together with enhanced rate of males at all birth order, was skewing the overall SRB in favour of male children. Though preference for male child was apparent, extreme steps of sex-selective abortion or infanticide were not prevalent.

TRPC3 mediates hyperexcitability and epileptiform activity in immature cortex and experimental cortical dysplasia.

Neuronal hyperexcitability plays an important role in epileptogenesis. Conditions of low extracellular calcium (Ca) or magnesium (Mg) can induce hyperexcitability and epileptiform activity with unclear mechanisms. Transient receptor potential canonical type 3 (TRPC3) channels play a pivotal role in neuronal excitability and are activated in low-Ca and/or low-Mg conditions to depolarize neurons. TRPC3 staining was highly enriched in immature, but very weak in mature, control cortex, whereas it was strong in dysplastic cortex at all ages. Depolarization and susceptibility to epileptiform activity increased with decreasing Ca and Mg. Combinations of low Ca and low Mg induced larger depolarization in pyramidal neurons and greater susceptibility to epileptiform activity in immature and dysplastic cortex than in mature and control cortex, respectively. Intracellular application of anti-TRPC3 antibody to block TRPC3 channels and bath application of the selective TRPC3 inhibitor Pyr3 greatly diminished depolarization in immature control and both immature and mature dysplastic cortex with strong TRPC3 expression. Epileptiform activity was initiated in low Ca and low Mg when synaptic activity was blocked, and Pyr3 completely suppressed this activity. In conclusion, TRPC3 primarily mediates low Ca- and low Mg-induced depolarization and epileptiform activity, and the enhanced expression of TRPC3 could make dysplastic and immature cortex more hyperexcitable and more susceptible to epileptiform activity.