Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.

BACKGROUND: Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. METHODS: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. RESULTS: Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse-free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare. CONCLUSION: The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/).

Comparison of risk factors for SARS-CoV-2 infection among healthcare workers during Omicron and Delta dominance periods in Japan.

BACKGROUND: The risk factors for coronavirus disease (COVID-19) among healthcare workers (HCWs) might have changed since the emergence of the highly immune evasive Omicron variant. AIM: To compare the risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among HCWs during the Delta- and Omicron-predominant periods. METHODS: Using data from repeated serosurveys among the staff of a medical research centre in Tokyo, two cohorts were established: Delta period cohort (N = 858) and Omicron period cohort (N = 652). The potential risk factors were assessed using a questionnaire. Acute/current or past SARS-CoV-2 infection was identified by polymerase chain reaction or anti-nucleocapsid antibody tests, respectively. Poisson regression was used to calculate the risk ratio (RR) of infection risk. FINDINGS: The risk of SARS-CoV-2 infection during the early Omicron-predominant period was 3.4-fold higher than during the Delta-predominant period. Neither working in a COVID-19-related department nor having a higher degree of occupational exposure to SARS-CoV-2 was associated with an increased infection risk during both periods. During the Omicron-predominant period, infection risk was higher among those who spent ≥30 min in closed spaces, crowded spaces, and close-contact settings without wearing mask (≥3 times versus never: RR: 6.62; 95% confidence interval: 3.01-14.58), whereas no such association was found during the Delta period. CONCLUSION: Occupational exposure to COVID-19-related work was not associated with the risk of SARS-CoV-2 infection in the Delta or Omicron period, whereas high-risk behaviours were associated with an increased infection risk during the Omicron period.

Nocturnal intermittent hypoxia and the development of type 2 diabetes: the Circulatory Risk in Communities Study (CIRCS).

AIMS/HYPOTHESIS: Although the associations between obstructive sleep apnoea and type 2 diabetes mellitus have been reported in cross-sectional design studies, findings on the prospective association between the two conditions are limited. We examined prospectively the association between nocturnal intermittent hypoxia as a surrogate marker of obstructive sleep apnoea and risk of type 2 diabetes. METHODS: A total of 4,398 community residents aged 40 to 69 years who had participated in sleep investigation studies between 2001 and 2005 were enrolled. Nocturnal intermittent hypoxia was assessed by pulse-oximetry and defined by the number of oxygen desaturation measurements < or =3% per h, with five to <15 per h corresponding to mild and 15 events or more per h corresponding to moderate-to-severe nocturnal intermittent hypoxia, respectively. The development of type 2 diabetes was defined by: (1) fasting serum glucose > or =7.00 mmol/l (126 mg/dl); (2) non-fasting serum glucose > or =11.1 mmol/l (200 mg/dl); and/or (3) initiation of glucose-lowering medication or insulin therapy. Multivariable model accounted for age, sex, BMI, smoking status, current alcohol intake, community, borderline type 2 diabetes, habitual snoring, excessive daytime sleepiness, sleep duration and (for women) menopausal status. RESULTS: By the end of 2007, 92.2% of participants had been followed up (median follow-up duration [interquartile range] 3.0 [2.9-4.0] years) and 210 persons identified as having developed diabetes. The multivariable-adjusted hazard ratio (95% CI) for developing type 2 diabetes was 1.26 (0.91-1.76) among those with mild nocturnal intermittent hypoxia and 1.69 (1.04-2.76) among those with moderate-to-severe nocturnal intermittent hypoxia (p = 0.03 for trend). CONCLUSIONS/INTERPRETATION: Nocturnal intermittent hypoxia was associated with increased risk of developing type 2 diabetes among middle-aged Japanese.

Cross-cultural comparison of the sleep-disordered breathing prevalence among Americans and Japanese.

The aim of the present study was to compare the prevalence of sleep-disordered breathing among Hispanic and white Americans and Japanese. A 1-night sleep study using a single-channel airflow monitor was performed on 211 Hispanics and 246 Whites from the Minnesota field centre (St Paul, MN, USA) of the Multi-Ethnic Study of Atherosclerosis (MESA), and 978 Japanese from three community-based cohorts of the Circulatory Risk in Communities Study (CIRCS) in Japan. The respiratory disturbance index and sleep-disordered breathing, defined as a respiratory disturbance index of > or =15 events x h(-1), were estimated. The prevalence of sleep-disordered breathing was higher in males (34.2%) than females (14.7%), and among Hispanics (36.5%) and Whites (33.3%) than among Japanese (18.4%), corresponding to differences in body mass index. Within body mass index strata, the race difference in sleep-disordered breathing was attenuated. This was also true when body mass index was adjusted for instead of stratification. The strong association between body mass index and sleep-disordered breathing was similar in Japanese and Americans. The prevalence of sleep-disordered breathing was lower among Japanese than among Americans. However, the association of body mass index with sleep-disordered breathing was strong, and similar among the race/ethnic groups studied. The majority of the race/ethnic difference in sleep-disordered breathing prevalence was explained by a difference in body mass index distribution.

Clinical impact of intraoperative histological examination of the ductal resection margin in extrahepatic cholangiocarcinoma.

BACKGROUND: Although ductal resection margin status in extrahepatic cholangiocarcinoma is evaluated by intraoperative histological examination of frozen sections, its clinical relevance remains controversial. METHODS: Material taken from patients who underwent R0 or R1 resection for extrahepatic cholangiocarcinoma with intraoperative histological examination of the final ductal resection margins between 1994 and 2003 were reviewed. The following histological classification was used: insufficient, negative for malignancy (NM), undetermined lesion (UDL) or positive for malignancy (PM). Multivariable analyses of overall survival and anastomotic recurrence in relation to ductal margin status were performed. RESULTS: Resection material from 363 patients was identified. For the proximal ductal margin, only PM in intramural lesions was significantly associated with poor survival (hazard ratio (HR) 1.72, 95 per cent confidence interval (c.i.) 1.06 to 2.74) and anastomotic recurrence (HR 6.39, 95 per cent c.i. 1.89 to 21.62) compared with NM. In analysis of overall survival according to distal ductal margin status, the HRs for UDL and PM lesions in comparison with NM were not significant. CONCLUSION: PM in intramural lesions found during intraoperative histological examination of the proximal ductal resection margin was related to clinical outcome. This finding favours additional resection of the bile duct. A similar association was not found for histology results of the distal resection margin.

Hearing, single-unit analysis, and vocalizations in songbirds.

Auditory neurons in the avian cochlear nucleus are systematically arranged according to their best frequencies. The thresholds of single auditory neurons at their best frequencies match the thresholds of hearing obtained by behavioral methods for the same frequencies. The upper range of single-unit best frequencies shows distinct interspecific variation which is correlated with the differences in the range of vocal frequencies. Most songbirds do not seem to produce frequencies below I kilohertz but can hear them.

Hormone-induced sexual differentiation of brain and behavior in zebra finches.

The male zebra finch sings, whereas the female does not. This behavioral dimorphism is correlated with the presence of morphological sex differences within the neural substrate that mediates this behavior, the song system. When a female chick is exposed to 17beta-estradiol her song system is subsequently masculinized. Either testosterone or 5alpha-dihydrotestosterone may then induce such a female to sing when an adult.

Center-surround organization of auditory receptive fields in the owl.

The spinal receptive fields of specialized auditory units in the midbrain of the barn owl (Tyto abla) contain two functionally antagonistic areas: an excitatory center and an inhibitory surround. The response of these units represents the balance of acoustic activation of the two areas, which in turn depends upon the location, intensity, and spectral content of the sound stimulus.

The oilbird: hearing and echolocation.

Oilbirds can navigate in total darkness by echolocation. The sound energy in their sonar cries is unevenly distributed over the range from about 1 to 15 kilohertz, with a dominant frequency range of 1.5 to 2.5 kilohertz. This corresponds to the most sensitive range of their hearing as determined by neurophysiological methods. Behavioral tests in their home cave indicate that the smallest object avoided by this is a disk 20 centimeters in diameter.

Neurons selective for orientation and binocular disparity in the visual Wulst of the barn owl (Tyto alba).

The visual response properties of single neurons in the owl's visual Wulst suggest that this forebrain structure is an analog of the mammalian visual cortex. Features in common with the cat and the monkey visual cortex include a precise topographic organization, a high degree of binocular interaction, and selectivity for orientation, direction of movement, and binocular disparity of straight-line contours.

A neural map of auditory space in the owl.

Auditory units that responded to sound only when it originated from a limited area of space were found in the lateral and anterior portions of the midbrain auditory nucleus of the owl (Tyto alba). The areas of space to which these units responded (their receptive fields) were largely independent of the nature and intensity of the sound stimulus. The units were arranged systematically within the midbrain auditory nucleus according to the relative locations of their receptive fields, thus creating a physiological map of auditory space.

Auditory spatial receptive fields created by multiplication.

Examples of multiplication by neurons or neural circuits are scarce, although many computational models use this basic operation. The owl's auditory system computes interaural time (ITD) and level (ILD) differences to create a two-dimensional map of auditory space. Space-specific neurons are selective for combinations of ITD and ILD, which define, respectively, the horizontal and vertical dimensions of their receptive fields. A multiplication of separate postsynaptic potentials tuned to ITD and ILD, rather than an addition, can account for the subthreshold responses of these neurons to ITD-ILD pairs. Other nonlinear processes improve the spatial tuning of the spike output and reduce the fit to the multiplicative model.

Receptive fields of auditory neurons in the owl.

The influence of sound location on the responses of auditory neurons in the forebrain of the owl (Tyto alba) was studied directly by using a remotely controlled, movable sound source under free-field, anechoic conditions. Some auditory neurons demonstrated well-defined receptive fields that were (i) restricted both in elevation and in azimuth and (ii) relatively independent of the intensity and the nature of the sound stimulus. The majority of the fields were located frontally and contralateral to the recording site.

Contributions of bird studies to biology.

Birds are widely distributed, highly diversified, and exhibit behavior and social organizations equal in complexity to mammals, yet they are generally more conspicuous and approachable in natural environments. These attributes make birds excellent subjects in many areas of biological research. The topics in which studies on birds have figured prominently include the mechanisms of species formation, the regulation of the distribution and abundance of animals, the effects of the environment on behavior and physiology, the biological and evolutionary significance of variations in social organizations, the encoding of information in animal communication, the sensory basis for migration and navigation, the effects of hormones on nerve cells and behavior, the ontogeny of brain and behavior, and the structure and function of the vertebrate brain. The outstanding record of avian research suggests that birds will continue to provide important models for developing and testing new ideas in various fields of biology.

Evaluation of the effect of 4 months of risedronate therapy on femoral strength using femoral strength analysis tools.

The effect of risedronate (2.5 mg once daily) on femoral strength was evaluated using Advanced Hip Assessment (AHA) for the first time in Japan. In total, 104 patients with primary osteoporosis and available data on bone mineral density (BMD; lumbar spine/proximal femur), urinary NTx (cross-linked N-telopeptides of type I collagen) and AHA-based parameters collected before and after 4 months of risedronate therapy were included in the analyses. Change and percentage change from baseline in these parameters were determined. Percentage change in femur strength index was 7.9 +/- 21.1% and 5.5 +/- 18.0% for the right and left femurs, respectively; both increases were statistically significant. Cross-sectional moment of inertia, cross-sectional area and mean neck width in the femoral neck region of interest also increased significantly in both femurs. Percentage change in lumbar spine BMD (L2 - L4) was 3.0 +/- 3.7%, and proximal femoral BMD was 1.1 +/- 3.1% and 0.7 +/- 3.2% in the right and left femurs, respectively, all showing a significant increase from baseline. Percentage change in urinary NTx was -41.5 +/- 30.5%, which was a significant decrease. Using AHA, this study showed that, in patients with primary osteoporosis, risedronate improved BMD and bone quality, thereby enhancing femoral strength as early as 4 months after treatment initiation.

A monoclonal antibody specific to a song system nuclear antigen in estrildine finches.

This paper describes a monoclonal antibody that recognizes a molecule whose expression is mostly restricted to some of the forebrain areas that control singing behavior in adult estrildine species studied, including the zebra, Bengalese, and spice finches. When the song system displays extreme sexual dimorphism, as in these species, antibody staining occurs only in the male's song nuclei. However, protein expression is identical in both sexes of estrildine finches, in which females also have a well-developed song system. Canaries appear to lack the protein, but it can be induced in female zebra finches by early estrogen treatment. Antibody staining patterns in the zebra finch show that the protein's expression is developmentally regulated to coincide with the abrupt increase in the volume and cell size of the male's or the estrogen-treated female's song system.

Effects of interaural decorrelation on neural and behavioral detection of spatial cues.

The detection of interaural time differences (ITDs) for sound localization critically depends on the similarity between the left and right ear signals (interaural correlation). We show that, like humans, owls can localize phantom sound sources well until the correlation declines to a very low value, below which their performance rapidly deteriorates. Decreasing interaural correlation also causes the response of the owl's tectal auditory neurons to decline nonlinearly, with a rapid drop followed by a more gradual reduction. A detection-theoretic analysis of the statistical properties of neuronal responses could account for the variance of behavioral responses as interaural correlation is decreased. Finally, cross-correlation analysis suggests that low interaural correlations cause misalignment of cross-correlation peaks across different frequencies, contributing heavily to the nonlinear decline in neural and ultimately behavioral performance.

Gating of auditory responses in the vocal control system of awake songbirds.

Nucleus HVc of the avian song system is a forebrain structure critical in song production, perception and learning. Here we show that most HVc neurons that respond to auditory stimuli under anesthesia show no responses to the same stimulus in the awake, unrestrained bird. This suppression of auditory responses in awake birds does not occur in the forebrain field L complex, which is one of the auditory input stages for HVc. Gating of auditory input at the junction between the auditory and vocal control system may be essential for regulating auditory feedback signals necessary for song learning and maintenance.