Validation of HPV triage in cytology-based cervical cancer screening for ASC-US cases using Japanese data.

OBJECTIVE: In Japan, cervical cancer screening consists of a cytology examination performed once every 2 years. We verified whether the risk of cervical intraepithelial neoplasia (CIN) 3 disease or higher (CIN3+) was equivalent to that of cytology negative cases (negative for intraepithelial lesion or malignancy [NILM]) for patients with a cytological diagnosis of "atypical squamous cells of undetermined significance (ASC-US)" who tested negative for human papillomavirus (HPV). METHODS: Data from a total of 22,925 cases who had undergone cervical cancer screening at least twice or who had completed follow-up examinations after cervical screening at a single facility between April 2013 and April 2018 were analyzed. The cumulative incidence of CIN3+ was calculated for each category of initial cytology finding and HPV result (NILM, > ASC-US, ASC-US/HPV (unknown), ASC-US/HPV+, and ASC-US/HPV-). The statistical analysis was conducted using the Cox proportional hazards model. RESULTS: The hazard ratio for the cumulative incidence of CIN3+ in 2 years relative to that for NILM cases was 2.7 (95% confidence interval=1.0-7.8) for > ASC-US cases, 0.5 (0.1-1.7) for ASC-US/HPV (unknown), 0.8 (0.3-2.4) for ASC-US/HPV+ cases, and 0.3 (0.1-1.0) for ASC-US/HPV- cases. CONCLUSION: Because the cumulative incidence of CIN3+ at 2 years for the ASC-US/HPV- cases was sufficiently low, compared with that of the NILM cases, we considered it reasonable and safe to perform HPV triage for ASC-US cases and to allow HPV-negative cases to return for their next screening in 2 years, which is the same follow-up schedule as that for NILM cases.

The distribution of neuroligin4, an autism-related postsynaptic molecule, in the human brain.

NLGN4X was identified as a single causative gene of rare familial nonsyndromic autism for the first time. It encodes the postsynaptic membrane protein Neuroligin4 (NLGN4), the functions and roles of which, however, are not fully understood due to the lack of a closely homologous gene in rodents. It has been confirmed only recently that human NLGN4 is abundantly expressed in the cerebral cortex and is localized mainly to excitatory synapses. However, the detailed histological distribution of NLGN4, which may have important implications regarding the relationships between NLGN4 and autistic phenotypes, has not been clarified. In this study, we raised specific monoclonal and polyclonal antibodies against NLGN4 and examined the distribution of NLGN4 in developing and developed human brains by immunohistochemistry. We found that, in the brain, NLGN4 is expressed almost exclusively in neurons, in which it has a widespread cytoplasmic pattern of distribution. Among various types of neurons with NLGN4 expression, we identified consistently high expression of NLGN4 in hypothalamic oxytocin (OXT)/vasopressin (AVP)-producing cells. Quantitative analyses revealed that the majority of OXT/AVP-producing neurons expressed NLGN4. NLGN4 signals in other large neurons, such as pyramidal cells in the cerebral cortex and hippocampus as well as neurons in the locus coeruleus and the raphe nucleus, were also remarkable, clearly contrasting with no or scarce signals in Purkinje cells. These data suggest that NLGN4 functions in systems involved in intellectual abilities, social abilities, and sleep and wakefulness, impairments of which are commonly seen in autism.

The first-round results of a population-based cohort study of HPV testing in Japanese cervical cancer screening: baseline characteristics, screening results, and referral rate.

OBJECTIVE: In 2013, a cohort study aimed to clarify the positive and negative effects of introducing the human papillomavirus (HPV) testing for population-based cervical cancer screening has been launched in Japan. This study included four screenings during the subsequent 7-year follow-up period. We aim to describe the results of the first round of this study on cervical cancer screening here. METHODS: This study began in September 2013 with recruitment completed in March 2016. Women aged 30-49 years were divided into 2 groups: those who received uterine cervical cytology alone in the first year (control group), or those who received a combination of cytology and HPV testing (intervention group), based on their age. After first screening, women with positive result of cytology or positive HPV test required referral. We summarized the results of the first round of cervical cancer screening. RESULTS: Of the 25,074 women who were eligible for the study, 13,845 women (55.2%) were screened with cytology alone; 11,229 women (44.8%) received a combination of cytology and HPV testing. After screening, 407 women (2.9%) in the control group and 1,003 women (8.9%) in the intervention group required referral, respectively. Adding HPV testing increased referral rate significantly (p<0.001). CONCLUSION: After first screening, introduction of HPV testing appears to contribute to significantly higher referral rates, suggesting that the number of colposcopies as a detailed examination may increase. These preliminary findings suggest that if HPV testing is introduced into screening, medical institutions need to be prepared for an increasing number of follow-up examinations.

National screening programs for cervical cancer in Asian countries.

Cervical cancer is still one of the most common female cancers in Asia and the leading cause of cancer-related deaths in low- and middle-income countries. Nowadays, national screening programs for cervical cancer are widely provided in Asian countries. We reviewed the National Cancer Screening Program (NCSP) in China, India, Indonesia, Japan, Korea, and Thailand. The NCSP were established at varying times, from 1962 in Japan to 2014 in Indonesia. The primary screening method is based on cytology in all countries except for India and Indonesia. In India and Indonesia, visual inspection of the cervix with acetic acid (VIA) is mainly used as a primary screening method, and a "see and treat" strategy is applied to women with a positive VIA result. The starting age of NCSP ranges from 18 years in China to 30 years in Thailand. The screening interval is 2 years in all countries except for China and Indonesia, in which it is 3 years. Uptake rates of NCSP vary from 5.0%-59.7%. Many women in low- and middle-income countries still do not participate in NCSP. To improve uptake rates and thereby prevent more cases of cervical cancer, Asian countries should continue to promote NCSP to the public using various approaches.

[Genetics and epigenetics in autism].

Autism is a behaviorally defined syndrome characterized by impaired social interaction and communication, and restricted, stereotyped interests and behaviors. Several lines of evidence support the contention that genetic factors are a large component to autism etiology. However, in spite of vigorous genetic studies, no single causative or susceptibility gene common in autism has been identified. Thus multiple susceptibility genes in interaction are considered to account for the disorder. Furthermore, environmental risk factors can accelerate the autism development of. Recent advances in understanding the epigenetic regulation may shed light on the interaction among multiple genetic factors and environmental factors.

Distribution of OL-protocadherin in axon fibers in the developing chick nervous system.

OL-protocadherin (OL-pc) is a homophilic cell adhesion molecule that belongs to the cadherin gene superfamily. We cloned and characterized the chicken homologue of OL-pc and examined its expression pattern in chick embryos mainly from embryonic day (E) 3.5 to E6.5. The structure of chick OL-pc was found to be essentially the same as that of mammalian OL-pc's except for some small deletions and insertions in the amino acid sequence. OL-pc protein was detected prominently along developing axonal fibers in the brain and also in the peripheral nervous system. In addition, it was detected in some mesenchymal cells and in the embryonic ectoderm of the mandible and limb bud. In the spinal cord, OL-pc was specifically expressed in motor neurons, and the protein was distributed along motor nerves. Motor nerves merged gradually with sensory nerves showing negative/faint OL-pc expression, but their fibers remained separated as small bundles in the nerves. Interestingly, OL-pc-positive motor nerves such as those to the sternocoracoideus became segregated from OL-pc-faint/weak motor nerves at the plexus region. Moreover, OL-pc was distributed along the path of the branchial nerves. These results suggest that OL-pc might play some roles in axon navigation such as in axon elongation, selective fasciculation, and pathfinding in the early stage of neural development.

Distribution of nestin and other stem cell-related molecules in developing and diseased human spinal cord.

In mammalian spinal cords, no neurogenesis has been observed after initial development. However developed mammalian spinal cords seemingly contain neural stem cells (NSC), which can give rise to neurons and glial cells when they are placed in appropriate environments. The purpose of the present paper was to investigate the developing, developed, and diseased human spinal cord to see which cell types have an immunophenotype similar to NSC. In 12 specimens from preterm neonates and term infants up to 14 months old, nestin was expressed in cells that extended fibrous processes and were located around the midline in the ependymal layer. In all the preterm neonates, Musashi-1 and glial fibrillary acidic protein (GFAP) were also expressed in this subpopulation, whereas Lewis X was detected in a less restricted subpopulation. Nestin expression by these cells was not detected in most adult spinal cords, but was observed in three spinal cords from 13 amyotrophic lateral sclerosis patients and eight of 14 spinal cords involved by the tumor. The present observations suggest that during gestation a subpopulation of cells in the ependymal layer remains undifferentiated as potential NSC/neural progenitor cells, and becomes unidentifiable in early infancy. These cells, however, appear in response to disease conditions, especially tumor involvement.