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Blood-borne pathogen (BBP) infections can rapidly progress to life-threatening sepsis and must therefore be promptly eliminated by the host's immune system. Intravascular macrophages of the liver sinusoid, splenic marginal zone and red pulp and perisinusoidal macrophage protrusions in the bone marrow (BM) directly phagocytose BBPs in the blood as an innate immune response. The liver, spleen and BM thereby work together as the blood defence system (BDS) in response to BBPs by exerting their different immunological roles. The liver removes the vast majority of these invading organisms via innate immunity, but their complete elimination is not possible without the actions of antibodies. Splenic marginal zone B cells promptly produce IgM and IgG antibodies against BBPs. The splenic marginal zone transports antigenic information from the innate to the adaptive immune systems. The white pulp of the spleen functions as adaptive immune tissue and produces specific and high-affinity antibodies with an immune memory against BBPs. The BM works to maintain immune memory by supporting the survival of memory B cells, memory T cells and long-lived plasma cells (LLPCs), all of which have dedicated niches. Furthermore, BM perisinusoidal naïve follicular B cells promptly produce IgM antibodies against BBPs in the BM sinusoid and the IgG memory B cells residing in the BM rapidly transform to plasma cells which produce high-affinity IgG antibodies upon reinfection. This review describes the complete immune defence characteristics of the BDS against BBPs through the collaboration of the liver, spleen and BM with combined different immunological roles., (© 2024 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Background: This study developed a Japanese version of the Geriatric Anxiety Scale (GAS-J) and its short form (GAS-10-J) to evaluate anxiety in Japanese older adults and assess its psychometric properties using a cross-sectional design., Methods: A total of 331 community-dwelling older adult participants (208 men, 116 women, seven unknowns; mean age = 73.47 ± 5.17 years, range = 60-88 years) recruited from two Silver Human Resources Centres in the Kanto region, Japan, answered a set of self-report questionnaires. Of these respondents, 120 participated in a follow-up survey to evaluate test-retest reliability., Results: Confirmatory factor analysis suggested that, as with the original GAS, the GAS-J had a three-factor structure and the GAS-10-J had a unifactor structure with high standardised factor loadings. Test-retest correlations and internal consistency analyses indicated that these scales were reliable. Correlations between the GAS-J/GAS-10-J with the Geriatric Anxiety Inventory, Generalised Anxiety Disorder-7, Geriatric Depression Scale-15, World Health Organization-Five Well-Being Index, and Kihon Checklist were mostly consistent with our hypotheses, thereby supporting the construct validity of the GAS-J/GAS-10-J., Conclusions: The findings indicate that the GAS-J and GAS-10-J have robust psychometric properties for assessing late-life anxiety in Japanese older adults. Further GAS-J studies are required for clinical groups., (© 2023 Japanese Psychogeriatric Society.)

Cognitive processing therapy (CPT) is one of the most widely tested evidence-based treatments for posttraumatic stress disorder (PTSD). However, most studies on CPT have been conducted in Western cultural settings. This open-label, single-arm trial investigated the feasibility, acceptability, and preliminary efficacy of CPT for treating Japanese patients with PTSD. A total of 25 outpatients underwent 12 CPT sessions. The primary outcome was the assessment of PTSD symptoms using the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV); secondary outcomes included the assessment of subjective PTSD severity, depressive and anxiety symptoms, trauma-related cognitions, and subjective quality of life. All outcomes were evaluated at pretreatment (i.e., baseline), posttreatment, and 6- and 12-month follow-ups. On average, participants attended 13 sessions of CPT (SD = 1.38), with a completion rate of 96.0%. One serious adverse event (hospitalization) occurred. Significant within-subjects standardized mean differences in CAPS-IV scores were found from baseline to treatment completion, g = -2.28, 95% CI [-3.00, -1.56]; 6-month follow-up, g = -2.95, 95% CI [-3.79, -2.12]; and 12-month follow-up, g = -2.15, 95% CI [-2.89, -1.41]. Moderate-to-large effects, gs = -0.77 to -2.45, were found on secondary outcomes. These findings support the feasibility, acceptability, and preliminary efficacy of CPT in a Japanese clinical setting., (© 2022 International Society for Traumatic Stress Studies.)

Background: This study developed a Japanese version of the Geriatric Anxiety Inventory (GAI-J) and its short form (GAI-J-SF) to evaluate anxiety in older adults in Japan and assess these measures' psychometric properties with a cross-sectional design., Methods: Participants (N = 400; mean age: 75 years) were community-dwelling older adults who answered a set of self-report questionnaires. They were recruited from a community centre for older persons in the Kanto region of Japan. Of the respondents, 100 participated in a follow-up survey to evaluate test-retest reliability. Item response theory was adopted to evaluate item parameters., Results: Confirmatory factor analysis with categorical data suggested that, as with the original Geriatric Anxiety Inventory, the GAI-J/GAI-J-SF had a unifactor structure. Test-retest correlation and internal consistency analyses indicated that these scales had high reliability. Item response theory results showed that both measures' item parameters were acceptable. Correlations with the Penn State Worry Questionnaire, State Trait Anxiety Inventory-State Only, Generalized Anxiety Disorder-7 and Patient Health Questionnaire-9 were mostly consistent with our hypotheses. This supports the high convergent validity of the GAI-J/GAI-J-SF., Conclusions: The findings indicate that the GAI-J and the GAI-J-SF have robust psychometric properties for assessing late-life anxiety in older Japanese adults. Future GAI-J studies in clinical groups are needed., (© 2021 Japanese Psychogeriatric Society.)

The rising older population in Japan is associated with a rise in cases of dementia. Support for the increased number of family caregivers of people living with dementia is crucial, as caring may negatively affect a family caregiver's health. This study seeks to evaluate the feasibility and applicability of a recently developed Japanese version of START (STrAtegies for RelaTives). START is a psychosocial coping intervention program developed in the United Kingdom that has been shown to improve caregivers' mood and quality of life in a randomized controlled trial. We made changes to START (e.g., idioms, linguistic nuance, and providing care insurance information suited for Japan) to make it culturally appropriate. Fourteen Japanese female family caregivers of relatives with mild dementia (n = 10) or mild cognitive impairment (n = 4) were referred to the study, but six were excluded owing to illness and busyness. This single-arm study had a before-after trial evaluating psychological outcomes including depression, anxiety, quality of life, and subjective care burden. The acceptance retention and satisfaction rate suggest the feasibility and acceptability of the START program; 8/14 (>55%) eligible, prospective participants consented and were included in this study, all (8/8) of whom completed all START sessions. The mean program satisfaction score was 30.25 (standard deviation = 2.25) out of a potential 32. The results suggest that it is feasible and acceptable to deliver START in Japanese and based on the results of analysis using a linear mixed model, there is initial indication that the intervention improved family caregivers' quality of life, depressive symptoms, and care burden.

Background: More than 30 years have passed since the Japanese government announced its International Student 100,000 Plan in 1983. Today, the number of international students in the country exceeds 300,000. This study examines the relationship between factors affecting the mental health of international students and their satisfaction with having studied abroad in Japan., Methods: An online-questionnaire was given to 82 former Japanese government scholarship students who studied in Japan in the 1980s. The survey consisted of items related to the basic personal attributes of the participants, their lives in Japan during their period of study (20 items), their satisfaction level at having studied in Japan (10 items), and their current happiness level (4 items)., Results: A significant relationship was observed between the level of satisfaction at having studied in Japan and a number of the statements relating to respondents' lives in Japan as students, including: "I felt that the differences between Japan and my home country were interesting, and enjoyed these differences," and "Whenever I encountered a difficult situation, I attempted to find different approaches to deal with the problem." A similar relationship was also observed between these statements and subjective happiness., Conclusions: International students who were able to accept the differences and difficulties they confronted positively and respond to situations flexibly tended to report higher levels of satisfaction with their studies in Japan and higher levels of happiness, suggesting that individual psychological factors, such as situation perception and associated coping behaviors, have a defining impact on mental health.

Background: Studies of alexithymia have primarily targeted adult populations. Although some recent studies of alexithymia have focused on children and young adolescents, the literature is not sufficient for development of an assessment tool. The aim of this study was to develop, and evaluate the psychometric properties of, a new scale to measure alexithymia-like features in young adolescents., Methods: A total of 1,444 Japanese junior high school students (701 males, 743 females; age range 12-15; mean [SD] age, 13.37 [0.98] years) participated in 2 surveys conducted at their own schools., Results: First, exploratory factor analysis of the first survey data (n=981) demonstrated that this new scale had a unifactor structure, as determined by minimum average partial analysis and parallel analysis. Second, confirmatory factor analysis of the second survey data (n=463) confirmed the unifactor structure of this new scale and acceptable goodness of model fit. The new scale had modest internal consistency., Conclusions: The correlations of this new alexithymia scale with related variables were weak but significant, in accordance with our hypothesis. The scale had acceptable reliability and convergent validity and thus might be useful for measuring alexithymic tendency in young adolescents.

Blood-borne infections can develop into sepsis and are therefore a major human health risk. The responsible pathogens thus need to be eliminated rapidly. Intravascular macrophages in the liver and bone marrow (BM) sinuses, and in the red pulp and marginal zone of the spleen, remove the majority of these microorganisms via innate immunity. However, specific antibodies are essential for their complete elimination. Splenic marginal zone B cells simultaneously produce many of the IgM and IgG2 antibodies that target blood-borne pathogens within a few days of infection. Subsequently, follicular B cells of the white pulp of the spleen produce specific IgG antibodies against the invading pathogens, known as adaptive immunity. Although the liver, BM, and spleen work together to activate the defense response to blood-borne pathogens through innate and adaptive immunity, the spleen acts as the center of the blood defense system (BDS). The structure of the spleen is introduced in this review in relation to its function in the BDS as part of the response of the immune system and of functioning organs to blood-borne pathogens. The concept of a BDS is also important for hematological disorders, such as lymphomas and; therefore, may be useful to hematologists and pathologists.

This study investigated the feasibility of a cognitive behavioral therapy (CBT) program for improving mood and quality of life in an older woman with mild cognitive impairment (MCI), depression, and anxiety. The program comprised eight 30-minute weekly sessions; interventions included behavioral activation, relaxation, and cognitive reconstruction, in which the patient's caregiver also participated. The patient's condition was assessed before and immediately after the intervention. After 3 and 12 months, the caregiver reported the patient's behavioral and psychological symptoms by using self-reported psychological scales for depression, anxiety, and quality of life. Although CBT helped to improve mood and quality of life in the short term (3 months), the results were not sustained over the long term (12 months). Even though improvement in psychological symptoms did not persist and only one patient with MCI was evaluated, these results suggest that CBT is a feasible nonpharmacological treatment option and provide preliminary support for wider use of CBT in Japan. CBT programs should be tailored to the needs of patients with MCI and dementia, and regular follow-up sessions should be used to evaluate program feasibility and improvement in patient mental health.

A 70-year-old man visited our emergency department, whose laboratory test results revealed leucocytosis, anaemia, thrombocytopenia and high levels of serum lactate dehydrogenase. In addition, the peripheral blood smear revealed neutrophilic granulocytes with nuclear hypolobation (pseudo-Pelger-Hüet anomaly), hypogranulation and no myeloperoxidase reactivity. Genetic testing of the peripheral blood sample was as follows: G-band, 46XY,t(9;22)(q34;q11.2) (20/20); fluorescence in situ hybridisation BCR/ABL fusion signal, 97%; and analysis of exons 5-9 of the p53 gene, mutation (Pro72Arg) in exon 4 protein. On the basis of these findings, the patient was diagnosed with chronic myelogenous leukaemia (CML) in chronic phase with a p53 mutation and treated with hydroxyurea, dasatinib and nilotinib. Neutrophilic granulocytes with the anomalies were no longer observed after achieving cytogenetic remission. To the best of our knowledge, this is the first report of CML case with the anomalies, in which a p53 mutation without chromosome 17 abnormalities was identified., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

It is predicted that in the near future robot simulated patients (SPs) will come into use. Through the impressions of five SPs about robot SPs, we explored their vision of the future of medical education as an indicator of what ordinary citizens think. The opinions of SPs were collected using a semi-structured focus group interview, after which the perspectives provided were explored using a qualitative research method called Steps for Coding and Theorization (SCAT). Although SPs accepted the introduction of robot SPs, they regard them as potential substitutes. The use of robot SPs raised concerns about the level of response to human diversity and the level of emotional intelligence. The problem of how much diversity among patients and doctors is acceptable in the field of education was identified. On the part of citizens, there is not much expectation that artificial intelligence (AI) will lead to sophisticated machines capable of human conversation. However, looking ahead to the AI era, real SPs anticipate that, along with the evolution of AI, the next generation of SPs will have thought deeply about their role within a program employing both humans and robots.

Glycosphingolipids (GSLs) are abundant in plasma membranes of mammalian cells, and their synthesis is strictly regulated in the Golgi apparatus. Disruption of GSL homeostasis is the cause of numerous diseases. Hundreds of molecular species of GSLs exist, and the detailed mechanisms underlying their homeostasis remain unclear. We investigated the physiological significance of isoform production for β1,4-N-acetyl-galactosaminyl transferase 1/B4GALNT1 (B4GN1), an enzyme involved in synthesis of ganglio-series GSLs GM2/GD2/GA2. We discovered a new mRNA variant (termed variant 2) of B4GN1 through EST clone search. A new isoform, M1-B4GN1, which has an NH 2 -terminal cytoplasmic tail longer than that of previously-known isoform M2-B4GN1, is translated from variant 2. M1-B4GN1 has R-based motif (a retrograde transport signal) in the cytoplasmic tail. M1-B4GN1 is partially localized in the endoplasmic reticulum (ER) depending on the R-based motif, whereas M2-B4GN1 is localized in the Golgi. Stability of M1-B4GN1 is higher than that of M2-B4GN1 because of the R-based motif. M2-B4GN1 forms a homodimer via disulfide bonding. When M1-B4GN1 and M2-B4GN1 were co-expressed in CHO-K1 cells, the two isoforms formed a heterodimer. The M1/M2-B4GN1 heterodimer was more stable than the M2-B4GN1 homodimer, but the heterodimer was not transported from the Golgi to the ER. Our findings indicate that stabilization of M1-B4GN1 homodimer and M1/M2-B4GN1 heterodimer by R-based motif is related to prolongation of Golgi retention, but not to retrograde transport from the Golgi to the ER. Coexistence of several B4GN1 isoforms having distinctive characteristics presumably helps maintain overall enzyme stability and GSL homeostasis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Certain autoimmune conditions are associated with an increased risk of lymphoid malignancy. We report a 65-year old patient with autoimmune hemolytic anemia (AIHA) complicated by a follicular lymphoma (FL) in situ and other B-cell clones in the spleen. This diagnosis was made by immunohistochemistry, flow cytometry, and Southern blot analysis of the B-cell receptor. Chromosomal analysis revealed 46,XX,t(14;18)(q32;q21) 2/20, 46,XX,del(7)(q?),del(11)(q?) 2/20, and 46,XX 16/20. It has been speculated that these preneoplastic conditions do not progress to overt FL and other lymphomas without a second lymphomagenic insult. However, AIHA confers a 27.4-fold higher risk of such an insult leading to lymphoma compared with the normal healthy population. Without any therapy after splenectomy, our current study patient remained healthy with no lymphoma development for 28 months. Based on this case, we discuss the pathophysiology of lymphomagenesis in a spleen with AIHA and the roles of a splenectomy for preventing further lymphomagenesis in AIHA patients., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Aim: The purpose of this study is to present alternative diagnostic criteria of colposcopy using new parameters., Methods: Colposcopic photographs were reviewed in 1649 patients from the past 23 years, including 283 benign lesions, 327 low-grade squamous intraepithelial lesions (LSIL; cervical intraepithelial neoplasia 1), 549 high-grade squamous intraepithelial lesions (HSIL; cervical intraepithelial neoplasia 2/3), 78 microinvasive cancers, and 412 invasive cancers. Abnormal colposcopic findings were divided into: minor or major; single, or a combination of two or three findings; and under half or over half circumferential size. Histopathological backgrounds were investigated according to these new parameters of colposcopic findings., Results: Minor abnormal colposcopic findings were observed in 21% of LSIL, and major abnormal findings were seen in 52% of LSIL, 86% of HSIL, and 86% of microinvasions. A single major abnormal finding was observed in 64% of the cases with LSIL, while two abnormal findings were observed in 43% of HSIL, and three abnormal findings were observed in 44% of microinvasions. In qualifying major abnormal colposcopic findings, under half size was detected in 91% of LSIL and 74% of HSIL, and over half size was observed in 58% of microinvasions. From these results, the following diagnostic criteria were instituted: (i) LSIL - single, minor or major findings and under half size; (ii) HSIL - two or three major findings and under half size; (iii) microinvasion - three major findings and over half size; and (iv) invasive cancer - irregular surface with atypical vessels., Conclusion: Our new diagnostic criteria of colposcopy are fully acceptable, based on their similar level of accuracy to cytology., (© 2016 Japan Society of Obstetrics and Gynecology.)

Background: Epidemiological studies suggest that hyponutrition during the fetal period increases the risk of mental disorders such as attention deficit hyperactivity disorder and autism-spectrum disorder, which has been experimentally supported using animal models. However, previous experimental hyponutrition or protein-restricted (PR) diets affected stages other than the fetal stage, such as formation of the egg before insemination, milk composition during lactation, and maternal nursing behavior., Results: We conducted in vitro fertilization and embryo transfer in mice and allowed PR diet and folic acid-supplemented PR diet to affect only fetal environments. Comprehensive phenotyping of PR and control-diet progenies showed moderate differences in fear/anxiety-like, novelty-seeking, and prosocial behaviors, irrespective of folic-acid supplementation. Changes were also detected in gene expression and genomic methylation in the brain., Conclusions: These results suggest that epigenetic factors in the embryo/fetus influence behavioral and epigenetic phenotypes of progenies. Significant epigenetic alterations in the brains of the progenies induced by the maternal-protein restriction were observed in the present study. To our knowledge, this is first study to evaluate the effect of maternal hyponutrition on behavioral phenotypes using reproductive technology.

Aims: This study investigated the efficacy of structured writing on reducing self-harm ideations and enhancing emotion regulation., Methods: Japanese university students (N=22) participated in the study. Participants were randomly assigned to the structured writing group (n=10; 70% female), or an assessment only control group (n=12; 67% female). For three consecutive days, participants in the intervention group performed structured writing that included psycho-education and self-reflection about emotions. The Self-Harm Ideation Scale, the Generalized Expectancy for Negative Mood Regulation Scale, and the Acceptance and Action Questionnaire-II were used to assess outcomes., Results: Structured writing had a short-term effect on expectancies for self-regulation of negative moods and acceptance of negative emotions, but had a limited effect on self-harm ideations., Conclusion: This study presents preliminary evidence that increasing awareness, learning, and reflection about emotions resulting from using a structured writing program is particularly useful for regulating emotions. J. Med. Invest. 64: 74-78, February, 2017.

In the Golgi maturation model, the Golgi cisternae dynamically mature along a secretory pathway. In this dynamic process, glycosyltransferases are transported from the endoplasmic reticulum (ER) to the Golgi apparatus where they remain and function. The precise mechanism behind this maturation process remains unclear. We investigated two glycosyltransferases, ST3Gal5 (ST3G5) and B4GalNAcT1 (B4GN1), involved in ganglioside synthesis and examined their signal sequences for ER export and Golgi retention. Reports have suggested that the [R/K](X)[R/K] motif functions as an ER exporting signal; however, this signal sequence is insufficient in stably expressed, full-length ST3G5. Through further analysis, we have clarified that the (2)R(3)R(X)(5) (9)K(X)(3) (13)K sequence in ST3G5 is essential for ER export. We have named the sequence the R/K-based motif. On the other hand, for ER export of B4GN1, the homodimer formation in addition to the R/K-based motif is required for ER export suggesting the importance of unidentified lumenal side interaction. We found that ST3G5 R2A/R3A and K9A/K13A mutants localized not only in Golgi apparatus but also in endosomes. Furthermore, the amounts of mature type asparagine-linked (N)-glycans in ST3G5 R2A/R3A and K9A/K13A mutants were decreased compared with those in wild-type proteins, and the stability of the mutants was lower. These results suggest that the R/K-based motif is necessary for the Golgi retention of ST3G5 and that the retention is involved in the maturation of N-glycans and in stability. Thus, several basic amino acids located on the cytoplasmic tail of ST3G5 play important roles in both ER export and Golgi retention., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sirh7/Ldoc1 [sushi-ichi retrotransposon homolog 7/leucine zipper, downregulated in cancer 1, also called mammalian retrotransposon-derived 7 (Mart7)] is one of the newly acquired genes from LTR retrotransposons in eutherian mammals. Interestingly, Sirh7/Ldoc1 knockout (KO) mice exhibited abnormal placental cell differentiation/maturation, leading to an overproduction of placental progesterone (P4) and placental lactogen 1 (PL1) from trophoblast giant cells (TGCs). The placenta is an organ that is essential for mammalian viviparity and plays a major endocrinological role during pregnancy in addition to providing nutrients and oxygen to the fetus. P4 is an essential hormone in the preparation and maintenance of pregnancy and the determination of the timing of parturition in mammals; however, the biological significance of placental P4 in rodents is not properly recognized. Here, we demonstrate that mouse placentas do produce P4 in mid-gestation, coincident with a temporal reduction in ovarian P4, suggesting that it plays a role in the protection of the conceptuses specifically in this period. Pregnant Sirh7/Ldoc1 knockout females also displayed delayed parturition associated with a low pup weaning rate. All these results suggest that Sirh7/Ldoc1 has undergone positive selection during eutherian evolution as a eutherian-specific acquired gene because it impacts reproductive fitness via the regulation of placental endocrine function., (© 2014. Published by The Company of Biologists Ltd.)

Uterine cervical cancer is the most common primary gynecologic malignant tumor in Japan. Conventional cervical screening Papanicolaou (Pap) test has been shown to be extremely effective in reducing cervical cancer incidence and mortality, but the consultation rate for cancer screening in Japan is markedly low, at 20% of prescribed subjects, in comparison with other developed countries. In 2001, 15,501 women (6.8%) received a Pap test in Kitakyushu City, and that was less than half of national average. From 2009, free coupons for uterine cervical cancer screening were distributed to Japanese woman who were 20, 25, 30, 35 or 40 years of age as part of the project for women-specific cancer screening. The rate of participation in Pap testing was 22.3% in 2012, with 31,970 women receiving cervical tests. It was almost as high as the national level. It's obvious that high risk human papillomavirus (HPV) is responsible for cervical cancer incidence and HPV mainly infects through sexual practice. The rate of early cervical neoplasms and invasive cancers is currently increasing in young women. Abnormal Pap tests were detected in 2.3% of the women in 2008. To increase the population's participation in this screening process, a cost-effective and efficient system should be established. National and local governments, medical institutions, companies, and educational institutions must have an accurate understanding of the current situation, and take an assertive approach in order to decrease the mortality rate of uterine cervical cancer.

The effect of self-evaluation of emotions on subjective adaption to school was investigated among junior high school students (n = 217: 112 boys, 105 girls) who participated in a questionnaire survey. Hierarchical multiple regression analysis indicated that for boys "Infringement and maladjustment" differed based on their self-evaluation of anger and anxiety. For girls, on the other hand, the self-evaluation of anger alleviated psychological stress, worsened the "Relationship with the teacher" and the "Relationship with the class", whereas self-evaluation of anxiety played a role in increasing psychological stress and deteriorating the "Relationship with the class." Furthermore, negatively evaluating either anger or anxiety heightened the "Motivation for learning" in girls. These results suggest that the evaluation of emotions is different in boys and girls and for different emotions.

International accreditation of medical education was introduced in Japan in 2013 and is planning to be applied in late 2014 or 2015. Students will need to cope with the resulting changes and to recognize by what route they will learn medicine. Therefore, a freshman orientation course, which was based on problem-based learning (PBL) and had been held for first-year students, was modified as an awareness reform program in which students would learn "how to learn medicine." We investigated whether this program has led to useful changes in students' recognition of the way of learning in medical school and their directions as learners. The program was held for 114 first-year medical school students in 2013 and consisted of PBL tutorials, large-classroom lectures, simulation learning using role-play with simulated patients, and team-based learning (TBL), presented in this order. Learning modules that is made with an integration of the clinical sciences with the basic biomedical and the behavioral and social sciences were provided. A nonanonymous questionnaire survey asking" what learning methods are effective for you?" was conducted before and after completion of the course. Furthermore, group answers obtained in TBL were investigated. The score for the question" To what extent can you imagine your route of learning during your 6 years?" significantly increased from 3.1±0.99 (mean±SD) before the course to 3.5±0.88 (p<0.01) after the course. The score for the question" To what extent is the small-group learning, such as PBL, useful for you?" significantly increased from 3.9±0.73 to 4.2±0.71 (p<0.05). Group responses in TBL sessions indicated that students desired classes that presented tasks and regarded" emphasis on reflection" and" observation of senior physicians as role models" as the most important methods for learning interview skills. We believe students should acquire active learning attitudes as adults early in their 6 years of medical school. The level of understanding of" how to learn as adults" was 3.7 and indicated a moderate result. This course employed many educational strategies, and we believe it helped students understand what they learn and how to learn during their 6 years of medical and to get an overview of the learning roadmap.

Primary hepatic and hepatosplenic diffuse large B-cell lymphomas (DLBCLs) are rare cancers and form nodules in most instances. However, very rare cases can diffusely infiltrate the whole liver without nodules. The general clinicopathological features of these lymphomas have not been reported to date. In our current study, we attempted to elucidate the features of these lesions through our direct observations and by reviewing the current literature. We describe the characteristics of 2 patients with hepatic and hepatosplenic DLBCL by autopsy. The lymphoma cells showed diffuse infiltration of the liver, red pulp of the spleen, and bone marrow with intrasinusoidal and interstitial lymphomatous infiltration of the organs. We discuss our observations in relation to previously reported DLBCLs with a similar pathology.

Achievement of complete molecular response in patients with chronic phase chronic myeloid leukemia has been recognized as an important milestone in therapy cessation and treatment-free remission; the identification of predictors of complete molecular response in these patients is, therefore, important. This study evaluated complete molecular response rates in imatinib-treated chronic phase chronic myeloid leukemia patients with major molecular response by using the international standardization for quantitative polymerase chain reaction analysis of the breakpoint cluster region-Abelson1 gene. The correlation of complete molecular response with various clinical, pharmacokinetic, and immunological parameters was determined. Complete molecular response was observed in 75/152 patients (49.3%). In the univariate analysis, Sokal score, median time to major molecular response, ABCG2 421C>A, and regulatory T cells were significantly lower in chronic phase chronic myeloid leukemia patients with complete molecular response than in those without complete molecular response. In the multivariate analysis, duration of imatinib treatment (odds ratio: 1.0287, P=0.0003), time to major molecular response from imatinib therapy (odds ratio: 0.9652, P=0.0020), and ABCG2 421C/C genotype (odds ratio: 0.3953, P=0.0284) were independent predictors of complete molecular response. In contrast, number of natural killer cells, BIM deletion polymorphisms, and plasma trough imatinib concentration were not significantly associated with achieving a complete molecular response. Several predictive markers for achieving complete molecular response were identified in this study. According to our findings, some chronic myeloid leukemia patients treated with imatinib may benefit from a switch to second-generation tyrosine kinase inhibitors (ClinicalTrials.gov, UMIN000004935).

This study examined the effect of writing about the perceived benefits (WPB) of an interpersonal transgression on subjective well-being and feelings of hostility. Participants (N = 74) who reported experiencing a highly stressful interpersonal trouble within the past year were randomly assigned to one of four conditions that consisted of 20-minute writing tasks conducted over a three-day period in which they wrote about either (a) the perceived benefits resulting from the trouble, (b) the features of the trouble, (c) the features in the first 10 minutes and the perceived benefits of the trouble in the last 10 minutes, or (d) a control topic that was unrelated to the trouble. Results of analysis of covariance revealed that group A had significantly decreased hostility. Furthermore groups A and B showed a significant increase in subjective well-being compared to the control condition. Issues related to WPB are discussed.

Background: Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism). We developed a highly-structured manualized eight-session cognitive-behavioral program with a focus on subthreshold depression in the workplace and to be administered via telephone by trained psychotherapists (tCBT)., Methods: We conducted a parallel-group, non-blinded randomized controlled trial of tCBT in addition to the pre-existing Employee Assistance Program (EAP) versus EAP alone among workers with subthreshold depression at a large manufacturing company in Japan. The primary outcomes were depression severity as measured with Beck Depression Inventory-II (BDI-II) and presenteeism as measured with World Health Organization Health and Work Productivity Questionnaire (HPQ). In the course of the trial the follow-up period was shortened in order to increase acceptability of the study., Results: The planned sample size was 108 per arm but the trial was stopped early due to low accrual. Altogether 118 subjects were randomized to tCBT+EAP (n = 58) and to EAP alone (n = 60). The BDI-II scores fell from the mean of 17.3 at baseline to 11.0 in the intervention group and to 15.7 in the control group after 4 months (p<0.001, Effect size = 0.69, 95%CI: 0.32 to 1.05). However, there was no statistically significant decrease in absolute and relative presenteeism (p = 0.44, ES = 0.15, -0.21 to 0.52, and p = 0.50, ES = 0.02, -0.34 to 0.39, respectively)., Conclusion: Remote CBT, including tCBT, may provide easy access to quality-assured effective psychotherapy for people in the work force who present with subthreshold depression. Further studies are needed to evaluate the effectiveness of this approach in longer terms. The study was funded by Sekisui Chemicals Co. Ltd., Trial Registration: ClinicalTrials.gov NCT00885014.

Objective: Conventional diagnosis of bacterial vaginosis contains some controversial points. To understand accurately the relationship between clinical stages and the microbiotas, the intravaginal microbial flora was analyzed by the clone library method., Study Design: Vaginal fluid samples from 31 patients were examined. Lactobacillary grade, Nugent score, culture-based method, and clone library analysis using the 16SrRNA gene sequencing were performed and were compared with each other., Results: Patients were categorized by Lactobacillary grade as I (normal) (n = 6), II (intermediate) (n = 11), and III (bacterial vaginosis) (n = 14). The clone library analysis detected 36 bacterial genera and 60 species from all 31 samples. A principal component analysis of the microbial proportions revealed a novel classification, which suggested the significance of the relative ratio of Lactobacillus iners, Atopobium vaginae and anaerobes in bacterial vaginosis., Conclusion: Clone library analysis in combination with the conventional method provides substantial information for diagnosis of bacterial vaginosis., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era., Patients and Methods: We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab., Results: No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease., Conclusions: Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

We present here seven cases of idiopathic multicentric Castleman's disease (MCD) showing effusion at the initial clinical presentation. This series includes a high proportion of middle-aged and elderly females (5/7). Various autoantibodies were detected in six cases. Anemia (Hb < 10 g/dl) was detected in four cases, leukocytosis (WBC > 10 × 10(9)/l) in three and thrombycytopenia (<100 × 10(9)/l) in five. Positivity for C-reactive protein or elevated erythrocyte sedimentation rate was recorded in all seven cases. Elevated serum IgG level (>2000 mg/dl) was recorded in only three cases. Elevated serum interleukin-6 level was recorded in all four cases examined. At the onset of disease, four cases were associated with idiopathic thrombocytic purpura. During the course of disease, one case each was diagnosed as systemic sclerosis + Sjögren's syndrome (SJS) and SJS. Histologically, five lesions exhibited a mixed type of Castleman's disease, and one case each exhibited a hyaline-vascular type and plasma cell type. The non-neoplastic nature of the B-lymphocytes was demonstrated by immunohistochemistry and polymerase chain reaction. There were no human herpes type-8 virus-positive cells in any of the seven lesions. Good responsiveness to glucocorticoid therapy has been seen in all six cases treated. From a therapeutic perspective, it is important to discriminate this subtype of MCD.

Despite the outstanding results generally obtained with imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), some patients show a poor molecular response. To evaluate the relationship between steady-state trough plasma IM concentration (IM-C(min)) and clinical response in CML patients, we integrated data from six independent Japanese studies. Among 254 CML patients, the mean IM-C(min) was 1,010.5 ng/ml. Importantly, IM-C(min) was significantly higher in patients who achieved a major molecular response (MMR) than in those who did not (P = 0.002). Multivariate analysis showed that an MMR was associated with both age (odds ratio (OR) = 0.97 (0.958-0.995); P = 0.0153) and with IM-C(min) (OR = 1.0008 (1.0003-1.0015); P = 0.0044). Given that patients with IM-C(min) values >1,002 ng/ml had a higher probability of achieving an MMR in our large cohort (P = 0.0120), the data suggest that monitoring of IM levels in plasma may improve the efficacy of IM therapy for CML patients.

Heparin sodium and heparin calcium, which are widely used as anti-coagulants, are known to potentially contain the natural impurity dermatan sulfate (DS). Recently serious adverse events occurred in patients receiving heparin sodium in the US, and a contaminant oversulfated chondroitin sulfate (OSCS) was found to be a cause of the events. To ensure the quality and safety of pharmaceutical heparins, there is need of a physicochemical identification test that can discriminate heparin from the heparin-related substances as well as a sensitive purity test for OSCS. Recently, HPLC with a strong-anion exchange column was proposed as the methods for identifying heparin and determination of OSCS in heparin sodium. Although this method is convenient and easy to perform, the only column suitable for this purpose is the Dionex IonPac AS11-HC column. In this study, we developed alternative identification test and test for OSCS in both heparin sodium and heparin calcium using a weak anion-exchange column. The identification test allowed for separation of heparin from the impurity DS and contaminant OSCS in a shorter time. The purity test provided enough sensitivity, specificity, linearity, recovery and repeatability for OSCS. We believe that our methods will be useful for quality control of pharmaceutical heparins., (Copyright 2010 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.)

Lymph node lesions in infectious mononucleosis (IM) show a marked histologic diversity. We report here three cases of IM lymphadenitis with histologic findings indistinguishable from those of toxoplasmic lymphadenitis. The histologic findings of the three cases presented here showed a histologic triad of toxoplasmic lymphadenitis, including (i) numerous lymphoid follicles with hyperplastic germinal centers; (ii) small clusters or single epithelioid histiocytes; and (iii) multiple foci of monocytoid B-cells. Moreover, all three lesions contained isolated or small clusters of epithelioid histiocytes within the hyperplastic germinal centers and the periphery of lymphoid follicles, which are the most specific histologic findings of toxoplasmic lymphadenitis. However, serologic findings confirmed EBV infection in all three cases. On in situ hybridization, numerous Epstein-Barr virus (EBV)-encoded small RNA (EBER)-positive cells were demonstrated in the germinal center, as well as in interfollicular areas in all three cases. Toxoplasmosis gondii infection was excluded in at least one case, based on serologic findings. Polymerase chain reaction analysis also demonstrated that there was no T. gondii DNA in the remaining two cases. Two of our three cases showed atypical clinical presentations, including an absence of atypical lymphocytosis in peripheral blood in two cases, age more than 30 years, and an absence of systemic symptoms in one case. It appears that previous descriptions emphasize the differential diagnostic problems between IM lymphadenitis and malignant lymphomas. However, from a therapeutic perspective, it is important to discriminate IM lymphadenitis from toxoplasmic lymphadenitis particularly in patients showing atypical clinical features., (2010 Elsevier GmbH. All rights reserved.)

It is not easy to diagnose lumbar disc herniation during pregnancy due to the limitation of the examinations and it is also difficult to control the severe pain during this time. A pregnant woman with lumbar disc herniation was transferred to our hospital at the 23rd week of gestation. The pain was successfully controlled with opioids and epidural anesthesia. At the 35th week of gestation, she delivered a girl weighing 2316 g smoothly with an Apgar score of 8/9 without neonatal abstinence syndrome from morphine. In this case, opioid administration was found to be useful for perinatal care with lumbar disc herniation.

Despite the proven effectiveness of cytological uterine cervical cancer screening, the consultation rate for cancer screening in Japan is markedly low in comparison with other developed countries. Although the mortality of this cancer has been steadily decreasing, it has been on the rise in the recent several years. It is evident that human papillomavirus (HPV) is involved in the occurrence of uterine cervical cancer, and, because of changes in sexual awareness and the diversification of sexual behavior, the increase in the incidence of uterine cervical cancer, especially among young adults, has become a major social problem. There is a false negative rate of about 10% in cytological uterine cervical cancer screening, seen mostly in cervical adenocarcinoma cases. As there is a limit to the effectiveness of cancer screening by cytology alone, there is a movement in Japan to increase the accuracy of cytological screening by using liquid-based cytology (LBC) and adopting HPV testing. There are various problems in cytological cancer screening, but the national and local governments, medical institutions, companies, and educational institutions must have an accurate understanding of the current situation and take an assertive approach in order to decrease the mortality rate of uterine cervical cancer.

Rationale: Modulating the low-grade chronic inflammation in chronic obstructive pulmonary disease remains challenging. Clarithromycin (CAM), a macrolide antibiotic, reportedly ameliorates chronic inflammation via mechanisms independent of its antibacterial activity., Objectives: The aim of this study was to examine whether CAM can prevent or reduce emphysema induced by chronic cigarette smoke exposure., Methods: Mice were exposed to cigarette smoke daily for 6 months and treated with orally administered CAM at doses of 25 to 100 mg/kg twice a day throughout the course of the experiment to test the preventive effects. The administration of CAM at 50 or 100 mg/kg was performed during the second half of a 6-month exposure period to assess the therapeutic effects. Histologic analysis was performed to evaluate the effect of CAM., Measurements and Main Results: CAM treatment for 6 months decreased airspace enlargement and the destruction of the alveolar walls and impaired the accumulation of macrophages in bronchoalveolar lavage fluid in a dose-related fashion. The administration of clarithromycin at 100 mg/kg in the therapeutic protocol reduced emphysema compared with the smoke-exposed group without treatment. An immunohistologic analysis revealed that CAM reduced the number of F4/80-positive macrophages in the lung parenchyma. In an in vitro test, CAM at 5 to 20 microM directly suppressed the activation of macrophages stimulated with tumor necrosis factor-alpha., Conclusions: Our data demonstrated that CAM at a clinically achievable dose prevented cigarette smoke-induced emphysema by modulating lung inflammation. This study supports the possibility that low-dose CAM treatment might provide a new therapeutic strategy for chronic obstructive pulmonary diseases.

This study was undertaken to establish reliable factors in order to identify chlamydial cervicitis among suspicious patients. Between January and December 2007, 406 patients who were suspected to have cervicitis due to clinical symptoms, were tested with polymerase chain reaction (PCR) for Chlamydia trachomatis (CT), vaginal pH and Nugent score (NS) in our University hospital and related clinics. During the same period, 67 patients who were diagnosed as having other sexually transmitted diseases (Neisseria gonorrhoeae (NG), Trichomonas vaginalis, Condyloma acuminatum and genital herpes) were also made to participate in this study. Eighty-nine women (22%) were positive for CT PCR. Bacterial vaginosis (BV)-positive women were tested positive for CT PCR (75/288), significantly higher than those without BV (6/66, P = 0.01). In addition, under 20-years old women were positive for CT PCR (24/57), significantly higher than those who were over 30 years old (16/113, P = 0.001). The proportion of patients with high NS (>7) in CT, NG and T. vaginalis cases were 75/89 (84.3%), 22/27 (81.5%) and 11/14 (78.6%), respectively. Whereas the high NS of the C. acuminatum and genital herpes groups were recorded at 7/14 (50%) and 4/12 (33.3%), respectively. Younger women with BV could be at a higher risk for STDs, especially for CT cervicitis.

We evaluated six cases of diffuse large B-cell lymphoma (DLBCL) involving the red pulp of the spleen. All had B symptoms and an aggressive clinical course. The lymphoma cells proliferated diffusely and non-cohesively in the cords of the red pulp. The lymphoma involved the bone marrow in four of the five patients and the liver in all four of the patients examined. However, lymph node (LN) involvement was rare at presentation, and systemic LN involvement was not observed even in the terminal phase. The lymphoma cells infiltrated the intrasinusoidal/intravascular and interstitial spaces of the involved tissues and were detected in the peripheral blood in two of the six patients. CD5-expressing lymphoma cells were detected in four of the five patients examined. Because these cases had some unique clinical features and occurred in distinct splenic sites, we proposed that primary splenic DLBCL manifesting in red pulp is a distinct clinicopathological entity.

To clarify the clinicopathologic findings of idiopathic multicentric Castleman disease among Japanese, 28 cases were studied. Two variants were delineated by the clinicopathologic findings (1) idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (n = 18) and (2) nonidiopathic plasmacytic lymphadenopathy type (n= 10). Clinicopathologically, idiopathic plasmacytic lymphadenopathy was defined by the prominent polyclonal hyperimmunoglobulinemia, normal germinal centers, and sheet-like infiltration of plasma cells in the interfollicular area of the lymph node. Histologically, the nonidiopathic plasmacytic lymphadenopathy type was characterized by hyaline-vascular germinal centers of the lymph node lesion. In comparison with idiopathic plasmacytic lymphadenopathy, patients with nonidiopathic plasmacytic lymphadenopathy showed infrequent prominent polyclonal hyperimmunoglobulinemia and frequent association with autoimmune disease. However, there was no difference in the overall 5-year survival between the 2 subtypes. Compared with idiopathic multicentric Castleman disease in Western countries, the chronic course of the disease of idiopathic multicentric Castleman disease in Japan appears to be related to negativity for human herpesvirus 8 infection.

Background: The invasion of first trimester extravillous trophoblast (EVT) to decidua is an important event in placentation. Leukemia inhibitory factor (LIF) is an essential factor for mouse implantation, and it is reported that LIF may be involved in human first trimester EVT invasion. Prostaglandin E2 (PGE2) is also known as a critical factor for first trimester EVT invasion. In this study, we investigated the role of LIF in PGE2 production and EVT invasion using a human first trimester EVT cell line, HTR-8/SVneo., Methods and Results: Co-stimulation with LIF and IL-1beta induced higher amounts of PGE2 production and further migration of HTR-8/SVneo cells compared with that by stimulation with LIF or IL-1beta alone. Enhanced PGE2 production was most probably due to the enhanced expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1). PGE2 produced by HTR-8/SVneo cells promoted the migration of HTR-8/SVneo cells. A COX-2 inhibitor suppressed PGE2 production and the migration of HTR-8/SVneo cells. Agonists to PGE2 receptors, EP1, EP2 and EP4, promoted the migration of HTR-8/SVneo cells. Moreover, stimulation with LIF up-regulated EP1, EP2 and EP4 expression in HTR-8/SVneo cells., Conclusions: It is suggested that LIF participates in placentation through EVT invasion by up-regulating PGE2 production and PGE2 receptor expression in first trimester EVT.

Objective: To determine the significance of pregnancy-related cells in endometrial smears., Study Design: Pregnancy-related cells in 4429 endometrial smear samples were retrospectively analyzed and evaluated for clinicopathologic and cytomorphologic features., Results: Of the 4429 endometrial smears taken for cancer screening, pregnancy-related cells were detected in 12 cases (0.3%). They were estimated cytologically as negative or suspicious and confirmed as cases ofspontaneous abortion (8 cases), placental site nodule (3 cases), and partial hydatidiform mole (1 case). Decidual cells were observed in all cases, and some of these showed atypia. Trophoblasts were observed in 5 (41.7%) of the 12 cases. Syncytiotrophoblasts were observed in 1 case (8.3%) and nonsyncytiotrophoblasts in 5 (41.7%) of the 12 cases. Pregnancy-related cells were observed in an endometrial smear in 7 cases; other cases were missed during cytologic examination and were retrospectively identified., Conclusion: Pregnancy-related cells are likely to be missed because they are difficult to identify or are surrounded by a cluster of endometrial cells. The decidual cell is a key cell for the cytologic diagnosis of pregnancy-related cells. Determining the existence of pregnancy-related cells in endometrial smears is important for the further assessment of patients and the differential diagnosis of several endometrial lesions.

We report six cases of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) in middle-aged and elderly patients exhibiting atypical clinical findings. The patients, two males and four females, ranged in age from 52 to 74 years, with a median age of 64 years. Clinically, they were characterized by tonsillar tumor, cervical lymphadenopathy, and absence of atypical lymphocytosis of the peripheral blood. "B"symptoms were recorded in only two cases. Pancytopenia was recorded in one case during the disease course. The clinical course was self-limited. Histologically, all lesions were characterized by effacement of the follicles and expansion of the interfollicular area with proliferation of small vessels, indicating atypical lymphoid proliferation. In the interfollicular area, there was a mixed infiltrate, including small-to-medium-sized lymphocytes, plasma cells, and T-and B-immunoblasts. Immunoblasts resembling Reed-Sternberg cells were observed in four lesions. Three lesions contained numerous mature plasma cells, plasmacytoid cells, and immature plasma cells in some areas. In situ hybridization demonstrated a varying number of EBV-infected lymphocytes in the interfollicular area. The overall histomorphologic findings of the present six cases were similar to those of infectious mononucleosis (IM) in younger patients. However, the clinical findings were quite different from those of IM in the younger age population. To avoid overdiagnosis and overtreatment, we emphasize the need to be aware of the atypical clinical presentation of EBV-related LPDs in middle-aged or elderly patients, and to turn careful attention to these clinical and laboratory findings as well as to the morphologic features.

The purpose of this study is to investigate the side effect in patients who survived for more than 5 years after initial treatment for invasive cervical cancer. Between January 1984 and December 1997, 341 patients underwent primary treatment for invasive cervical cancer. One hundred nine patients who underwent medical examinations at 5 years after primary treatment were reviewed. The patients were divided into three groups: radical surgery alone (group A), radiotherapy alone (group B), and radical surgery with postoperative radiotherapy (group C). Dysuria was seen in 8%, and positive catheterized urine culture was noted in about 20% of groups A and C. Hydronephrosis was seen in 2% and 9% of groups A and B, respectively. Colitis or ulcer detected by proctosigmoidoscopy was noted in 15%, 50%, and 43% of groups A, B, and C, respectively, frequently observed in radiotherapy group (P= 0.0029). Lymphocyst was still present in 6% of group A, and leg edema was noted in 14%, 6%, and 15% of groups A, B, and C, respectively. Long-standing abnormal findings including urinary and bowel complications were presented in this study. Periodic physical examination after treatment should be performed because complications existed over a long time.

Maternal alcohol use during pregnancy may result in facial dysmorphism, growth retardation and central nervous system deficits. This has been found in infants ranging from fetal alcohol effects (FAE) to fetal alcohol syndrome (FAS), or alcohol related neurodevelopment disorders (ARND) and alcohol related birth defects (ARBD). In this study, we report a FAE case with orofacial cleft due to mother's alcohol use during her pregnancy. A 32-year-old Japanese woman, para2, gravida3. She was drinking alcohol while this pregnancy. At 39th week, a girl was delivered vaginally. Her birth weight is 3860gr. Apgar score is seven points at one minutes and eight points at 10 minutes. Orofacial cleft and sinus tachycardia were diagnosed postnatally. From a brain-computed tomography (CTscan), it showed a normal finding. Karyotype was normal female phenotype (46, XX). It is important to note that the obstetrician had to advise the women not to have alcohol use during pregnancy in order to prevent her baby from fetal alcohol effects or toxic effect of alcohol on the fetus.