Systematic determination of thyroid volume by ultrasound examination from infancy to adolescence in Japan: the Fukushima Health Management Survey.

Although several reports have defined normal thyroid volume depending on either age or body surface, there are no sequential reference values on childhood thyroid volume evaluated by using ultrasonography and epidemiological analysis in Japan. The aim of the present study was to establish updated reference values for thyroid volume by ultrasound examination and epidemiological analysis in 0-19 year-old Japanese children. It is based on a cross-sectional study conducted from October 9, 2011 to March 31, 2012. The subjects were 38,063 children who were examined by ultrasonography as the initial preliminary survey of the Fukushima Health Management Survey in October 9, 2011 to March 31, 2012. The width, thickness, and height of each lobe were measured and the volume of each lobe was calculated by the mean of the elliptical shape volume formula. The values of thyroid volume at the 2.5 and 97.5 percentiles of age and body surface area for each gender group were obtained from 0-19 year-old children. Positive correlation was observed between thyroid volume and either age or body surface. The right lobe was significantly larger than the left lobe. The thyroid volume in females was larger than that in males after adjusting body surface area. The reference values of childhood thyroid for each age or body surface area were obtained by this extensive survey using ultrasound. These reference values may be used to define the normal size of thyroid gland by echosonography in Japanese children, although thyroid volume may be affected by dimorphic factors such as sex hormones.

Production of IFN-γ by CD4(+) T cells in response to malaria antigens is IL-2 dependent.

T-cell immune responses are critical for protection of the host and for disease pathogenesis during infection with Plasmodium species. We examined the regulation of CD4(+) T-cell cytokine responses during infection with Plasmodium berghei ANKA (PbA). CD4(+) T cells from PbA-infected mice produced IFN-γ, IL-4 and IL-10 in response to TCR stimulation at levels higher than those from uninfected mice. This altered cytokine response was dependent on parasitemia. To examine the specificity of the response, mice were adoptively transferred with CD4(+) T cells from OT-II TCR transgenic mice and were infected with PbA expressing OVA. Unexpectedly, CD4(+) T cells from the OT-II-transferred wild-type PbA-infected mice showed high levels of IFN-γ production after stimulation with OVA and the cells producing IFN-γ were not OT-II but were host CD4(+) T cells. Further investigation revealed that host CD4(+) T cells produced IFN-γ in response to IL-2 produced by activated OT-II cells. This IFN-γ response was completely inhibited by anti-CD25 mAbs, and this effect was not due to the block of the survival signals provided by IL-2. Furthermore, IFN-γ production by CD4(+) T cells in response to PbA antigens was dependent on IL-2. These findings suggest the importance of IL-2 levels during infection with malaria parasites and indicate that CD4(+) T cells can produce IFN-γ without TCR engagement via a bystander mechanism in response to IL-2 produced by other activated CD4(+) T cells.

Mutational and clinico-pathological analysis of papillary thyroid carcinoma in Serbia.

Molecular pathogenesis of papillary thyroid carcinoma (PTC) is largely associated with mutational changes in the BRAF, RAS family and RET genes. Our aim was to assess clinico-pathological and prognostic correlations of these PTC-specific gene alterations, with a particular emphasis on the BRAF mutation, in a group of 266 Serbian PTC patients, for the first time. The reference center-based retrospective cohort included 201 (75.6%) females and 65 (24.4%) males aged 48.0±16.1 years (8-83 years old, range) diagnosed and treated for PTC during 1993-2008. Follow-up period was 53.1±41.6 months (7-187 months, range). BRAF and RAS mutations were determined by direct sequencing of genomic DNA. RET/PTC rearrangements were analyzed by RT-PCR/Southern blotting. Genetic alterations were detected in 150/266 tumors (56.4%). One tumor displayed two genetic alterations. The BRAF(V600E) was found in 84/266 (31.6%) cases, RAS mutations in 11/266 (4.1%) and RET/PTC in 55/266 (20.7%; 42/266 (15.8%) RET/PTC1 and 13/266 (4.9%) RET/PTC3). On multivariate analysis BRAF(V600E) was associated with the classical papillary morphology (P = 0.05), the higher pT category (P = 0.05) and advanced clinical stage (P = 0.03). In a proportional hazard model, BRAF(V600E) did not appear to be an independent risk factor for the faster recurrence (P = 0.784). We conclude that under the extensive thyroid surgery and limited application of radioiodine ablation BRAF(V600E) may not be an indicator of poorer disease-free survival during the short to middle follow-up period. However, it has a potential to contribute to patients stratification into high- and low-risk groups.

Malaria-specific and nonspecific activation of CD8+ T cells during blood stage of Plasmodium berghei infection.

Cerebral malaria is one of the severe complications of Plasmodium falciparum infection. Studies using a rodent model of Plasmodium berghei ANKA infection established that CD8(+) T cells are involved in the pathogenesis of cerebral malaria. However, it is unclear whether and how Plasmodium-specific CD8(+) T cells can be activated during the erythrocyte stage of malaria infection. We generated recombinant Plasmodium berghei ANKA expressing OVA (OVA-PbA) to investigate the parasite-specific T cell responses during malaria infection. Using this model system, we demonstrate two types of CD8(+) T cell activations during the infection with malaria parasite. Ag (OVA)-specific CD8(+) T cells were activated by TAP-dependent cross-presentation during infection with OVA-PbA leading to their expression of an activation phenotype and granzyme B and the development to functional CTL. These highly activated CD8(+) T cells were preferentially sequestered in the brain, although it was unclear whether these cells were involved in the pathogenesis of cerebral malaria. Activation of OVA-specific CD8(+) T cells in RAG2 knockout TCR-transgenic mice during infection with OVA-PbA did not have a protective role but rather was pathogenic to the host as shown by their higher parasitemia and earlier death when compared with RAG2 knockout mice. The OVA-specific CD8(+) T cells, however, were also activated during infection with wild-type parasites in an Ag-nonspecific manner, although the levels of activation were much lower. This nonspecific activation occurred in a TAP-independent manner, appeared to require NK cells, and was not by itself pathogenic to the host.

Cancer mortality in residents of the terrain-shielded area exposed to fallout from the Nagasaki atomic bombing.

The health effects of radiation exposure from the atomic bomb fallout remain unclear. The objective of the present study is to elucidate the association between low-dose radiation exposure from the atomic bomb fallout and cancer mortality among Nagasaki atomic bomb survivors. Of 77 884 members in the Nagasaki University Atomic Bomb Survivors Cohort, 610 residents in the terrain-shielded area with fallout were selected for this analysis; 1443 residents in the terrain-shielded area without fallout were selected as a control group; and 3194 residents in the direct exposure area were also selected for study. Fifty-two deaths due to cancer in the terrain-shielded fallout area were observed during the follow-up period from 1 January 1970 to 31 December 2012. The hazard ratio for cancer mortality in the terrain-shielded fallout area was 0.90 (95% confidence interval: 0.65-1.24). No increase in the risk of cancer mortality was observed, probably because the dose of the radiation exposure was low for residents in the terrain-shielded fallout areas of the Nagasaki atomic bomb, and also because the number of study subjects was small.

Vitamin E prevents the neuronal cell death by repressing cyclooxygenase-2 activity.

The accumulation of damage caused by oxidative stress exacerbates cell death in many neurodegenerative diseases. We evaluated the mechanism of neuronal cell death raised by glutamate-induced toxicity, using the immortalized mouse hippocampal cell line HT-22. Our results showed that vitamin E prevented glutamate-induced cell death, accompanied by the decline of cyclooxygenase-2 expression confirmed by reverse transcriptase polymerase chain reaction and immunocytochemistry. Moreover, the neuroprotection was still effective even when vitamin E was supplied after glutamate treatment. The decline of cyclooxygenase-2 activity was also highly correlated with the neural protective effect against glutamate-induced toxicity. These results represent new insights about the timing of vitamin E supplementation after toxic stimulation and one mechanism by which vitamin E could prevent neuronal cell death by controlling cyclooxygenase-2 activity.

Non-cancer thyroid diseases among children in the Kaluga and Bryansk regions of the Russian Federation exposed to radiation following the Chernobyl accident.

This paper presents results of estimated radiation risks of non-cancer thyroid diseases in the people from Kaluga and Bryansk regions of the Russian Federation exposed in their childhood to radioiodine as a result of the Chernobyl accident. This work was carried out under the Joint Medical Research Project on non-cancer thyroid diseases conducted by Sasakawa Memorial Health Foundation and the Medical Radiological Research Center of the Russian Academy of Medical Sciences. The subjects were 2,457 people who underwent health examinations from 1997 to the end of 1999 who had individual radiometric thyroid data obtained between May and June 1986 and were aged 10 y or less at the time of exposure. The thyroid absorbed doses from incorporated 131I were estimated on the basis of measurements of exposure dose rate in the vicinity of the subject's thyroid and liver. A compartment model accounting for 131I metabolism in humans and cows was used. The estimated dose varied from 0 to 6 Gy, and its distribution was approximately lognormal with a mean of 0.132 Gy and standard deviation of 0.45 Gy. The prevalence of diffuse goiter in males showed a significant dose-response (p = 0.03) with an estimated odds ratio 1.36 at 1 Gy.

Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas.

A high prevalence of the activating BRAF mutation, BRAF(T1796A), is observed in adult papillary thyroid carcinomas (PTCs). The prognosis of childhood PTCs is generally fairly good despite the fact that distant metastases are often documented in these cases. To investigate the differences between the characteristics of childhood and adult PTCs, we analyzed both BRAF(T1796A) and RAS mutations in 31 Japanese and 48 post-Chernobyl Ukrainian thyroid carcinomas. In the 31 Japanese childhood cases, BRAF(T1796A) was found in only one instance (3.2%), and no RAS mutations were detected. In the Ukrainian subjects, of the 15 childhood and the 33 adolescent and young adult PTCs examined, the BRAF(T1796A) mutation was found in zero and eight cases, respectively, and RAS mutations were found in two of the young adult cases. In addition, 17 of the 48 Ukrainian cases showed expression of the RET tyrosine kinase region, indicating the existence of RET/PTC rearrangements. Unlike adult PTCs, we could detect no positive association between BRAF(T1796A) mutations and clinical parameters in the childhood carcinomas, suggesting that a low prevalence of BRAF(T1796A) is a common feature of PTCs in children regardless of radiation exposure levels. The differences in the prevalence of BRAF(T1796A) mutations between childhood and adult cases of PTC may well reflect inherent differences in the clinical features of these cancers between the two age groups.

Lower-extremity muscle forces measured by a hand-held dynamometer and the risk of falls among day-care users in Japan: using multinomial logistic regression analysis.

PURPOSE: To assess the relationship between the lower extremity muscle forces and risk of falls among the elderly who were using day-care services in the long-term care insurance system. METHOD: The study population comprised 96 women aged 69 - 91 years. At baseline, we assessed ADL, functional capacity, isometric muscle forces of knee extension and ankle dorsiflexion obtained with a hand-held dynamometer. After 1 year, we asked subjects about falls during the follow up period. RESULTS: In univariate analysis, only the knee extensor strength (p = 0.003) and ankle dorsiflexor strength (p = 0.02) differed significantly according to the fall status. After adjustment for age using multinomial logistic regression analysis, the weak quadriceps group was 7.50 times more likely than the strong group to fall once (p = 0.02), and 5.00 times more likely to fall twice or more (p = 0.02). The weakest ankle dorsiflexor group was 5.09 times more likely than the strongest group to fall twice or more (p = 0.05). CONCLUSIONS: Our results indicated that the forces of knee extensor and ankle dorsiflexor were strongly associated with falls among day-care users. Physiotherapy should focus on the lower-extremity muscle strength to prevent falls and deterioration of physical ability among elderly persons who are partially dependent and need support.

Future population of atomic bomb survivors in Nagasaki.

The Nagasaki University Atomic Bomb Survivor Database, which was established in 1978 for elucidating the long-term health effects of the atomic bombing, has registered since 1970 about 120,000 atomic bomb survivors with a history of residence in Nagasaki city. Since the number of atomic bomb survivors has steadily been decreasing, prediction of future population is important for planning future epidemiologic studies, and we tried to predict the population of atomic bomb survivors in Nagasaki city from 2008 to 2030. In addition, we evaluated our estimated population comparing with the actual number from 2008 to 2011.

Assessment and follow-up of intercostal nerve damage after video-assisted thoracic surgery.

OBJECTIVE: Chronic pain is a common complication after thoracic surgery. The most important factor appears to be intercostal nerve damage. The purpose of this prospective study was to objectively evaluate intercostal nerve damage associated with post-thoracotomy pain after three surgical procedures using current perception threshold testing. METHODS: The 32 patients were classified into three groups: the video-assisted thoracic surgery group (n=7), the video-assisted minithoracotomy with metal retractors group (n=15), and the conventional thoracotomy group (n=10). Intercostal nerve function was assessed by a series of 2000-Hz (Aß fiber), 250-Hz (Aδ fiber), and 5-Hz (C fiber) stimuli using current perception threshold testing (Neurometer CPT/C). The current perception threshold values were measured before and 1, 2, 4, 12, and 24 weeks after surgery. The intensities of ongoing pain were also assessed using a numeric rating scale (0-10). RESULTS: The video-assisted thoracic surgery group showed no changes in any current perception threshold values and no residual pain more than 12 weeks after surgery. The video-assisted minithoracotomy with metal retractors group and the conventional thoracotomy group showed significantly higher current perception threshold values at 2000 Hz 1 week after surgery (p=0.0013, p=0.0012, respectively), with pain in approximately 70% of patients 12 weeks after surgery. The correlation between current perception threshold values at 2000 Hz and the intensities of ongoing pain 4 and 12 weeks after surgery was significant (p=0.03, p=0.04, respectively). CONCLUSIONS: This is the first study that objectively evaluated pain after video-assisted thoracic surgery. The results suggest that the Aß and Aδ fibers play a significant role in the development of intercostal nerve damage. The current perception threshold values clearly demonstrated that video-assisted thoracic surgery is a less-invasive procedure resulting in less post-thoracotomy pain and, they have some possibilities to objectively evaluate the ongoing pain after surgery.

Radiation exposure does not significantly contribute to the risk of recurrence of Chernobyl thyroid cancer.

CONTEXT: Papillary thyroid carcinoma (PTC) in patients exposed to environmental radioiodine after the Chernobyl accident is thought to have a relatively aggressive clinical course. Long-term results of treatment are not well known, especially in comparison with sporadic PTC. OBJECTIVE: The determination of risk factors for PTC recurrence in a controlled for baseline factors group of patients with radiation-related and sporadic PTC. DESIGN: Retrospective cohort study involving patients treated for PTC and followed-up in 1991-2008. Risk factors were assessed by stratified analysis using the proportional hazard model. SETTING: Referral center-based. PATIENTS: A total of 497 patients were enrolled. Patients exposed to radioiodine were 172 individuals with reconstructed individual radiation thyroid doses ranging 51-3170 mGy. Patients with sporadic PTC included 325 individuals matched to exposed patients for sex, age ± 5 yr and time to treatment ± 2 yr. MAIN OUTCOME MEASURE: Cancer recurrence. RESULTS: Nodal disease increased the recurrence rate (HR = 5.21; 95% CI = 1.63-16.7) while the presence of tumor capsule (HR = 0.17; 95% CI = 0.06-0.45) and, particularly, treatment according to the Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer significantly reduced it (HR = 0.16; 95% CI = 0.06-0.42). None of the tested variables interacted with radiation factor. CONCLUSIONS: PTC developing after internal exposure to radioiodine does not display specific risk factors for recurrence different from those in sporadic PTC. Common treatment approaches for patients with PTC should be recommended regardless of a history of radiation exposure.

Donepezil significantly improves abilities in daily lives of female Down syndrome patients with severe cognitive impairment: a 24-week randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Down syndrome (DS) patients share certain neuropathological features with Alzheimer disease patients. A randomized, double-blind, placebo-controlled study was performed to investigate the efficacy and safety of donepezil, an Alzheimer disease drug, for DS patients. METHOD: Twenty-one DS patients with severe cognitive impairment were assigned to take donepezil (3 mg daily) or a placebo for 24 weeks, and evaluated for activities in daily lives by concisely modified International Classification of Functioning, Disability and Health (ICF) scaling system. RESULTS: ICF scores significantly increased without any adverse effects in the donepezil group in comparison to those in the placebo control. Among the individual functions tested, there was a dramatic improvement in the global mental functions and in specific mental functions. CONCLUSIONS: Donepezil may effectively and safely improve overall functioning of DS patients with severe cognitive impairment.

Influence of prosthetic heart valve sound on a patient's quality of life.

PURPOSE: To elucidate the effects of prosthetic valve sound on a patient's quality of life (QOL). METHODS: We compared the valve sounds of ATS, SJM, and Carbomedics (CM) based on assessments by 248 patients who underwent mechanical valve replacements from January 2000 to August 2003 at seven facilities in Japan. We used a self-administered questionnaire for evaluating patients' assessments of valve sounds and the Japanese version of SF-36 for measuring their health-related QOL. RESULTS: With respect to the valve-sound level perceived immediately after surgery, we considered the ATS and SJM valves quieter than the CM valve, but others have considered the ATS valve quieter than the SJM and CM valves. Regarding the time when the valve sound stopped bothering patients, a significant difference was observed between the ATS and CM valves and between the SJM and CM valves. The logistic regression analysis on patients' perceptions of valve sounds indicated that the influences of age, gender, and valve position are significant. Furthermore, a survey with SF-36 indicated that a long valve sound will affect a patient's health-related QOL. CONCLUSION: The present study suggested that the ATS valve surpassed the other two valves on the whole in audibility of valve sound and patient health-related QOL. However, further studies, including the ongoing prospective study, are necessary for a more comprehensive and accurate evaluation of the ATS valve.

The usual ultrasonographic features of thyroid cancer are less frequent in small tumors that develop after a long latent period after the Chernobyl radiation release accident.

BACKGROUND: The Chernobyl accident resulted in an unprecedented number of radiation-induced thyroid cancers in young individuals as detected by national and international screening programs. The vast majority of thyroid malignancies were papillary carcinomas that, despite being similar by histopathology, displayed large variability in clinical course. The correlations between ultrasound (US) and clinicopathological features in young patients with radiation-induced thyroid cancer, however, have not been well studied. Because of the importance of US for deciding which subjects should have fine-needle aspiration biopsy, we assessed the US features of papillary thyroid carcinoma in patients exposed to Chernobyl fallouts. DESIGN: We performed a retrospective multivariate logistic regression analysis of US features, clinicopathological data, and the latency period between radiation exposure and the diagnosis of cancer in 94 patients who were 10.6-34.3 years old (16.5 +/- 6.2, mean +/- standard deviation) at the time of diagnosis and 0.1-18.0 years old (5.6 +/- 4.2) at the time of the Chernobyl accident. RESULTS: Nodules greater than 10 mm were associated with the higher frequency of irregular margins (p = 0.001), longer period of latency (p = 0.016), and bilateral lymph node involvement (p = 0.025). Irregular tumor margins correlated with the shorter period of latency (p = 0.009) and unilateral nodal disease (p = 0.010). Hypoechoic nodules were observed more frequently in female patients (p = 0.012), in the absence of halo (p = 0.003) or calcifications (p = 0.005). Hypoechogenicity also correlated with the shorter latency (p = 0.015) and younger age of patients (p = 0.048). CONCLUSIONS: Irregular nodule margins, a usual sign of malignancy, are less useful in detecting thyroid cancers in radiation-exposed patients with tumors less than 10 mm. Thyroid cancers that are detected after longer latent periods display less of the US features characteristic of a malignant process, while benign US features are observed more frequently. Therefore, we recommend fine-needle aspiration biopsy to ensure early diagnosis of thyroid cancer for patients with a history of radiation exposure, even if their nodules are less than 10 mm.

Bedtime administration of cilnidipine controls morning hypertension.

Morning blood pressure (BP) level plays an important role in the incidence of cardiovascular disease. Recently, Kario, et al proposed the usefulness of ME difference (morning minus evening systolic BP) and ME average (average of morning and evening systolic BP) for the evaluation of antihypertensive treatment. Cilnidipine is a novel calcium channel blocker (CCB) that exerts inhibitory actions not only on L-type but also on N-type calcium channels. We investigated the effect of bedtime administration of cilnidipine (10 mg) in addition to the antihypertensive treatment for uncontrolled morning hypertension. Twenty-three hypertensive outpatients (13 males and 10 females; mean age, 66.9 years) with stable antihypertensive medication and uncontrolled morning BP were studied using self-measured BP monitoring in the morning and evening. Morning SBP (P < 0.001) and DBP (P < 0.001) decreased significantly from 150.2 +/- 8.7 and 87.8 +/- 9.3 to 132.7 +/- 7.4 and 77.5 +/- 8.5 mmHg, respectively, after the addition of cilnidipine. Morning heart rate did not change (63.3 +/- 7.0 to 64.1 +/- 9.4). The evening SBP, but not DBP, decreased significantly after treatment. Both the ME average (P < 0.001) and ME difference (P < 0.01) significantly decreased from 143.0 +/- 9.2 and 14.3 +/- 12.4 to 131.3 +/- 7.2 and 2.8 +/- 9.2 mmHg after treatment, respectively. The microalbuminuria decreased from 39.6 +/- 13.2 to 27.3 +/- 8.4 mg/g Cr. In conclusion, L-/N-type CCB cilnidipine may be useful for patients with uncontrollable morning hypertension by reducing both ME average and ME difference.

Immunohistochemical analysis of connexin43 expression in infertile human testes.

Connexin43 (Cx43) is abundantly expressed in mammalian testes and implicated in the regulation of cell-to-cell interaction between germ cells and Sertoli cells, which is essential to the normal process of spermatogenesis. In the present study, we investigated the relation between Cx43 expression and the degree of spermatogenesis in infertile human testes. Immunohistochemical analysis of Cx43 was performed on testicular biopsies from 29 patients with azoospermia (n=23) and severe oligospermia (n=6), who gave informed consent to this experiment. The degree of testicular spermatogenesis was evaluated by Johnsen score. In the interstitium, immunostaining for Cx43 was localized to some focal parts of plasma membrane between neighboring Leydig cells. In seminiferous tubules with normal spermatogenesis, Cx43 expression was found between Sertoli cells and germ cells. However, Cx43 expression in maturation arrest was decreased and located mainly in the basal compartment of seminiferous tubules. Finally, there was a significant positive correlation between histological score of spermatogenesis and intensity of Cx43 (p=0.0294). These data suggest that the alteration of Cx43 expression may be involved in spermatogenic impairment, and that the communication between Sertoli cells and germ cells through Cx43 may be important for maturation of spermatogenesis.

A strong association between human earwax-type and apocrine colostrum secretion from the mammary gland.

Here we provided the first genetic evidence for an association between the degree of apocrine colostrum secretion and human earwax type. Genotyping at the earwax-type locus, rs17822931 within the ABCC11 gene, revealed that 155 of 225 Japanese women were dry-type and 70 wet-type. Frequency of women without colostrum among dry-type women was significantly higher than that among wet-type women (P<0.0002), and the measurable colostrum volume in dry-type women was significantly smaller than in wet-type women (P=0.0341).

Cancer consequences of the Chernobyl accident: 20 years on.

26 April 2006 marks the 20th anniversary of the Chernobyl accident. On this occasion, the World Health Organization (WHO), within the UN Chernobyl Forum initiative, convened an Expert Group to evaluate the health impacts of Chernobyl. This paper summarises the findings relating to cancer. A dramatic increase in the incidence of thyroid cancer has been observed among those exposed to radioactive iodines in childhood and adolescence in the most contaminated territories. Iodine deficiency may have increased the risk of developing thyroid cancer following exposure to radioactive iodines, while prolonged stable iodine supplementation in the years after exposure may reduce this risk. Although increases in rates of other cancers have been reported, much of these increases appear to be due to other factors, including improvements in registration, reporting and diagnosis. Studies are few, however, and have methodological limitations. Further, because most radiation-related solid cancers continue to occur decades after exposure and because only 20 years have passed since the accident, it is too early to evaluate the full radiological impact of the accident. Apart from the large increase in thyroid cancer incidence in young people, there are at present no clearly demonstrated radiation-related increases in cancer risk. This should not, however, be interpreted to mean that no increase has in fact occurred: based on the experience of other populations exposed to ionising radiation, a small increase in the relative risk of cancer is expected, even at the low to moderate doses received. Although it is expected that epidemiological studies will have difficulty identifying such a risk, it may nevertheless translate into a substantial number of radiation-related cancer cases in the future, given the very large number of individuals exposed.