Cortical Granularity Shapes the Organization of Afferent Paths to the Amygdala and Its Striatal Targets in Nonhuman Primate.

The prefrontal cortex (PFC) and insula, amygdala, and striatum form interconnected networks that drive motivated behaviors. We previously found a connectional trend in which granularity of the ventromedial and orbital PFC/insula predicted connections to the amygdala, and also the breadth of amygdalo-striatal efferents, including projections beyond the "classic" ventral striatum. To further interrogate connectional relationships among the cortex, amygdala, and striatum, and to further define the "limbic" (amygdala-recipient) striatum, we conducted tract tracing studies in two cohorts of macaques (male n = 14, female n = 1). We focused on the cortico-amygdalo-striatal (indirect) and cortico-"limbic" striatal (direct) paths originating in the entire PFC and insula. Larger datasets and a quantitative approach revealed "cortical rules" in which cortical granularity predicts the complexity and location of projections to both the basal nucleus of the amygdala and striatum. Remarkably, projections from "cortical-like" basal nucleus to the striatum followed similar patterns. In both "direct" and "indirect" paths to the "limbic" striatum, agranular cortices formed a "foundational," broad projection, and were joined by inputs from progressively more differentiated cortices. In amygdalo-striatal paths, the ventral basal nucleus was the "foundational" input, with progressively more dorsal basal nucleus regions gradually adding inputs as the "limbic" striatum extended caudally. Together, the "indirect" and "direct" paths followed consistent principles in which cortical granularity dictated the strength and complexity of projections at their targets. Cluster analyses independently confirmed these connectional trends, and also highlighted connectional features that predicted termination in specific subregions of the basal nucleus and "limbic" striatum.SIGNIFICANCE STATEMENT The "limbic" system broadly refers to brain circuits that coordinate emotional responses. Here, we investigate circuits of the amygdala, which are involved in coding the emotional value of external cues, and their influence on the striatum. Regions of prefrontal cortex (PFC) and insula form gradients of overlapping inputs to the amygdala's basal nucleus, which feed forward to the striatum. Direct cortical inputs to these "amygdala-recipient" striatal areas are surprisingly organized according to similar principles but subtly shift from the "classic" ventral striatum to the caudal ventral striatum. Together, these distinct subsystems, cortico-amygdalo-striatal circuits and direct cortico-striatal circuits, provide substantial opportunity for different levels of internal, sensory, and external experiences to be integrated within the striatum, a major motor-behavioral interface.

The interferon-γ-induced protein 10/CXCR3 axis is associated with human herpesvirus-6 reactivation and the development of sequelae in drug reaction with eosinophilia and systemic symptoms.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a condition caused by a drug-induced immune response. Previous reports have found that CXCL10, also known as interferon-γ-induced protein (IP)-10, may participate in the pathogenesis of cutaneous adverse drug reactions. However, the exact role of IP-10 in DRESS and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) has remained unknown. OBJECTIVES: This comparative prospective cohort study aimed to ascertain the roles of the IP-10/CXCR3 axis in DRESS and SJS/TEN. METHODS: Plasma IP-10 levels were analysed, and univariate analyses were conducted to assess the relationship between IP-10, human herpesvirus (HHV)-6 reactivation and the development of long-term sequelae. We also performed immunohistochemical staining using skin specimens and flow cytometry to determine the expression of CXCR3 in peripheral blood mononuclear cells (PBMCs). RESULTS: Significantly higher plasma IP-10 levels were observed in patients with DRESS with long-term sequelae (effect size 0·81) and also in those with HHV-6 reactivation (effect size 0·83). By immunohistochemistry, more abundant IP-10+ and CXCR3+ cells were demonstrated in the skin lesions of patients with DRESS with HHV-6 reactivation. The percentages of CLA+  CXCR3+  CD4+ cells and CLA+  CXCR3+  CD8+ cells were also higher in the PBMCs of HHV-6-reactivated patients with DRESS than in those of patients with SJS/TEN. CONCLUSIONS: Higher plasma IP-10 levels are associated with the development of long-term sequelae in DRESS. Higher IP-10/CXCR3 expression in skin and more abundant CLA+  CXCR3+  CD4+ cells and CLA+  CXCR3+  CD8+ cells were observed in patients with DRESS with HHV-6 reactivation. The IP-10/CXCR3 axis is associated with HHV-6 reactivation and development of long-term sequelae in DRESS. What is already known about this topic? Elevated levels of interferon-γ-induced protein-10 (IP-10) have been observed in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Patients with DRESS tend to develop long-term autoimmune sequelae, including type 1 diabetes and autoimmune thyroiditis. IP-10 has been associated with these autoimmune diseases in previous studies. What does this study add? The patients with DRESS with HHV-6 reactivation exhibited higher levels of IP-10 in the plasma and skin than the patients with DRESS without HHV-6 reactivation and the patients with SJS/TEN. Patients with DRESS with higher plasma IP-10 levels tended to develop sequelae during long-term follow-up. What is the translational message? IP-10 is a useful biomarker to predict the development of long-term sequelae in patients with DRESS. Linked Comment: Belloón and Kardaun. Br J Dermatol 2020; 183:804-805.

Patients with chronic urticaria have a higher risk of psychiatric disorders: a population-based study.

BACKGROUND: The prevalence of psychiatric comorbidities in patients with chronic urticaria (CU) in a national population is largely unknown. OBJECTIVES: To investigate the prevalence of psychiatric disorders and psychiatric medication use in patients with CU in Taiwan. METHODS: Data were sourced from Taiwan's National Health Insurance Research Database for 2011. Patients who had a primary/secondary International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of 708·1, 708·8 or 708·9 during 2011 with at least two outpatient visits and an antihistamine prescription were identified as CU cases. Patients with CU were classified into three disease severity groups according to their medication types. Psychiatric disorders were identified by patients having three outpatient visits with a primary or secondary diagnosis of a given psychiatric disease. Psychiatric medication use was defined by having at least four outpatient visits with prescriptions for anxiolytics, antidepressants or sleeping pills in 2010 or 2011. RESULTS: Of the 167 132 patients with CU, 82·5% had mild CU, 17·0% had moderate CU and 0·4% had severe CU. Patients with CU had a higher prevalence of psychiatric disorders and psychiatric medication prescription than control groups. The relative risk (RR) of psychiatric disorders was 1·43 for patients with mild, 1·50 for patients with moderate and 2·32 for patients with severe CU vs. the controls (P < 0·001). For psychiatric medication prescription, the RRs were 1·95, 2·70 and 2·09, respectively, vs. controls (P < 0·001). CONCLUSIONS: Patients with CU had a higher prevalence and risk of psychiatric disorders and psychiatric medication prescription than control groups. What's already known about this topic? Previous studies have shown a high prevalence of psychiatric comorbidities in patients with chronic urticaria (CU), with rates ranging from 35% to 60%. Anxiety, depression and somatoform disorders have been reported as the most prevalent mental disorders in patients with CU. What does this study add? Patients with CU had a higher prevalence of psychiatric disorders and psychiatric medication use than control groups in the general population. The relative risk (RR) of psychiatric disorders was 1·43 for those with mild CU, 1·50 for those with moderate CU and 2·32 for those with severe CU vs. controls. The RR for psychiatric medication use was 1·95 for those with mild CU, 2·70 for those with moderate CU and 2·09 for those with severe CU vs. controls. Mental health evaluations and management are important elements in CU management.

Using a novel scoring system for paronychia related to oncologic treatments (SPOT) for assessing paronychia severity and its correlation with pain index and quality of life.

BACKGROUND: Oncologic treatments may lead to the development of paronychia, which may cause severe pain and disability. However, a detailed objective scoring system is lacking. OBJECTIVE: To develop an objective scoring system to quantify the severity of paronychia and also examine the correlation of this score with a pain index and patients' quality of life. METHODS: A novel scoring system for paronychia related to oncologic treatments (SPOT), consisting of four parameters, namely redness, oedema, discharge and granulation tissue, was designed to assess the severity of paronychia. The visual analogue scale (VAS) and Dermatology Quality of Life Index (DLQI) were recorded, and their association with the SPOT scores was analysed. RESULTS: Ninety patients were enrolled from three medical centres in Taiwan. Severity of paronychia was determined by the scores of SPOT. Patients in the severe group had higher DLQI scores (severe vs. mild: P = 0.0018; severe vs. moderate: P = 0.0015). Both the DLQI and pain index scores were significantly higher in patients with higher dominant hand SPOT scores. CONCLUSIONS: The SPOT scores demonstrated the association of the paronychia severity with DLQI and pain. It may thus be useful in clinical practice and future studies.

Co-existence of histopathological features is characteristic in drug reaction with eosinophilia and systemic symptoms and correlates with high grades of cutaneous abnormalities.

BACKGROUND: Only few studies had investigated the histopathological presentations of drug reaction with eosinophilia with systemic symptoms (DRESS). The results of these studies were diverse and not conclusive. A characteristic histopathological feature is still lacking. OBJECTIVE: We tempted to identify characteristic histopathological features in DRESS and to correlate them with clinical presentations. METHODS: We retrospectively collected data from patients treated from 1998 through 2015. Available skin specimens from probable or definite cases according to the RegiSCAR criteria were analysed for histopathological patterns, which were then compared with the patients' clinical presentations. Chi-squared test was used for comparisons, while Bonferroni correction was applied if multiple comparison tests were encountered. RESULTS: Fifty-six patients with an average age of 52 years were identified, including 22 definite cases. The single most common histopathological pattern was interface dermatitis (75%). The co-existence of two or more patterns in a skin specimen was common (62.5%). In such cases, the co-existence of three patterns (the eczematous pattern, the interface dermatitis pattern and the vascular damage pattern) was most frequently encountered. It exhibited a significantly higher likelihood of being definite cases (P = 0.004) and was significantly associated with high grades of cutaneous abnormalities (P < 0.001). It showed a trend towards having higher grades of haematological abnormalities in patients with co-existence of three patterns (P = 0.04). In addition, patients with the co-existence of three patterns tended to have a higher rate of reactivation of human herpesvirus-6 than those with other patterns but not statistically significant (P = 0.052). CONCLUSION: The co-existence of three histopathological patterns in a skin specimen is characteristic in DRESS and shows a significant association with clinical severity.

Unmet medical needs for chronic spontaneous urticaria patients: highlighting the real-life clinical practice in Taiwan.

BACKGROUND: Treatment guidelines for chronic spontaneous/idiopathic urticaria (CSU) are available; however, only 50% of patients are well controlled with approved doses of H1-antihistamines, and certain patients remain symptomatic despite receiving up to 4× the approved dose of H1-antihistamines plus H2 antihistamines and/or leucotriene-receptor antagonists. OBJECTIVES: To highlight real-life clinical practice in Taiwan and to understand the unmet medical needs of CSU patients. METHODS: A nationwide cross-sectional, observational survey of 50 dermatologists and 200 CSU patients was conducted between June 2013 and November 2013. Face-to-face interviews of dermatologists and online interviews of CSU patients were conducted independently. RESULTS: Dermatologists reported that dermographism and blood tests were the most commonly used diagnostic methods to confirm the diagnosis. The key driving factor for most clinic-based dermatologists (70%) in choosing a treatment was 'response to my medicines', and most preferred H1-antihistamines and steroids for treating CSU patients, whereas most hospital-based dermatologists (85%) gave higher priority to 'severity and impact of the conditions'. Patients were reported to have high psychological pressures and significant impact of CSU on their daily activity. In addition, CSU patients were not satisfied with their current treatment and 69% of patients switched their first-consulted physician. Furthermore, lack of information and concerns about side-effects were major factors which held back patients from seeking Western treatment. CONCLUSIONS: There is an unmet medical need of CSU patients in Taiwan highlighting gaps among guidelines, real-life clinical practice, patients' perceptions and patients' knowledge of their disease.

Human herpes virus reactivations and dynamic cytokine profiles in patients with cutaneous adverse drug reactions --a prospective comparative study.

BACKGROUND: Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV-6, HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined. METHODS: A prospective study was conducted to monitor the viral statuses of patients with different cADRs by polymerase chain reaction and serum-specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples. RESULTS: Among the various cADRs, HHV-6 reactivation was only observed in DRESS, but EBV and CMV could be detected in other cADRs. Many proinflammatory cytokines and chemokines, including interleukin (IL)-1ß, IL-2, IL-6, interferon-γ, tumor necrosis factor-α, were significantly lower in DRESS patients with HHV-6 reactivation when compared to those without HHV-6 reactivation. In addition, these mediators were significantly lower before and during HHV-6 reactivation, compared to cytokine levels after HHV-6 reactivation in the same patient. CONCLUSION: HHV-6 reactivation was only observed in DRESS patients, not in any other cADR. In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV-6 reactivation.

Gender differences of suicide in Japan, 1947-2010.

BACKGROUND: The effects of socio-economic factors on suicide were gender-dependent. Japanese suicide mortality gender ratio (male: female) had gradually increased during the twentieth century. METHODS: With the data covering 1947-2010 collected from Japanese official websites, we conducted non-parametric rank test, curve estimations, spearman ranking correlation and quantile regression in succession with Stata version 12.0. RESULTS: The suicide mortality rate in male with a "U" shape had been always higher than that in female with a "J" shape. The male suicide mortality peaked around in 1955 (38.5 per 100,000 populations), dropped quickly afterwards until the 1970s; it increased in the 1980s with another peak in 2003 (33.2 per 100,000 populations). For female, an overall decreasing trend was seen with a peak during the 1950s (23.5 per 100,000 populations in 1958). It dropped gradually afterwards with small variations in 1970s and 80s, and was stabilized after 1995 (9.3 per 100,000 populations). The unemployment rate could be used as a single positive predictor of suicide mortality for men (p<0.01), while the total fertility rate (TFR) (p<0.01) and divorce rate (p<0.01) were significantly associated positively and negatively with women's suicide, respectively. LIMITATIONS: The impact of mental disorders was not analyzed and age-specific analysis was not conducted. CONCLUSION: The findings of these gender differences in, and the associated factors with, suicide in Japan, warranted further studies including delineation of the implications of differential economic pressure between genders, as well as child-rearing pressure and marriage satisfaction.

Heterogeneous dopamine populations project to specific subregions of the primate amygdala.

Amygdala dysfunction has been reported among patients with various psychiatric disorders, and dopamine is critical to the amygdala's ability to mediate fear conditioning. Recent work indicates that the midbrain dopaminergic neurons have heterogeneous receptor and membrane channel profiles, as well as differential physiologic responses to discrete stimuli. To begin understanding how dopamine affects amygdala physiology and pathology in higher primates, we mapped the inputs from the midbrain dopaminergic neurons to various amygdala nuclei in the monkey using retrograde and anterograde tracing techniques, and single and double immunofluorescence histochemistry for tracer and tyrosine hydroxylase, a dopamine marker. Our results show that the primate amygdala as a whole receives broad input, mostly from the dorsal tier of the substantia nigra, pars compacta, and the A8-retrorubral field. Input from the A10-ventral tegmental area, while present, was less prominent. These results differ from data in the rat, where the midline A10-ventral tegmental area is a major source of dopamine to the amygdala "mesolimbic" pathway. Both the "amygdala proper" and the "extended amygdala" receive the majority of their input from the dorsal tier of the substantia nigra and A8-retrorubral field, but the extended amygdala receives additional modest input from the ventral tier. In addition, the "extended amygdala" structures have a denser input than the "amygdala proper," with the exception of the lateral core of the central nucleus, which receives no input. Our anterograde studies confirm these findings, and revealed fine, diffuse terminal fibers in the amygdala proper, but a denser network of fibers in the extended amygdala outside the lateral core of the central nucleus. These results indicate that the entire extent of the dorsal tier beyond the A10-ventral tegmental area may regulate the amygdala in primates, and subsequently serve as a source of dysfunction in primate psychopathology.

Factors affecting measurement of specific methanogenic activity.

Specific methane production (SMP) tests have been used to determine the potential loading rate capacity of anaerobic reactors, to characterize biomass prior to its use as an inoculum for new anaerobic reactors, to detect changes in biomass activity during operation, or to assess the occurrence of toxic conditions. SMP tests also provide a basis for estimating specific methanogenic activity in mixed anaerobic cultures. SMP protocols used to date have varied widely in both procedure and objective. Tests conducted by the present authors indicated that biomass concentration, substrate type and concentration, and mixing intensity are factors that can affect the results of SMP tests.

Simultaneous temperature and strain measurement with combined spontaneous Raman and Brillouin scattering.

We report on a novel method for simultaneous distributed measurement of temperature and strain based on spatially resolving both spontaneous Raman and Brillouin backscattered anti-Stokes signals. The magnitude of the intensity of the anti-Stokes Raman signal permits the determination of the temperature. The Brillouin frequency shift is dependent on both the temperature and the strain of the fiber; once the temperature has been determined from the Raman signal, the strain can then be computed from the frequency measurement of the Brillouin signal.

Comparison of the methods for discriminating temperature and strain in spontaneous Brillouin-based distributed sensors.

A recently proposed method of measuring the two Brillouin frequencies in a multicompositional fiber core for unambiguously resolving temperature and strain in a distributed sensor is compared with the previously established technique of measuring the intensity and frequency of the single Brillouin peak in a standard single-mode fiber.

50-km single-ended spontaneous-Brillouin-based distributed-temperature sensor exploiting pulsed Raman amplification.

We demonstrate enhanced performance of a single-ended spontaneous-Brillouin-intensity-based distributed-temperature sensor with a sensing length of 50 km and a spatial resolution of 15 m by use of Raman amplification of the probe pulse within the sensing fiber. The Raman amplification was achieved with a copropagating pump pulse at 1450 nm. The standard deviation error of the temperature resolution was 1 degree C at the front end and increased to less than 13 degrees C at 50 km with Raman pulse amplification.

Effective induction, purification and characterization of Trichoderma koningii G-39 beta-xylosidase with high transferase activity.

A beta-xylosidase was induced and purified from the culture filtrate of Trichoderma koningii G-39, grown in a medium containing 1% oat spelts xylan and 0.1% xylose. The presence of xylose unequivocally enhanced the induction of beta-xylosidase. The purified enzyme, which exhibited a significant alpha-arabinosidase activity, was obtained with high yield simply via ethanol precipitation and a single anion-exchange chromatography and was characterized as a monomeric glycoprotein with an estimated molecular mass of 104 kDa and a pI of 4.6. The K(m) values towards p-nitrophenyl beta-D-xylopyranoside and p-nitrophenyl alpha-L-arabinopyranoside are 0.04 and 7.5 mM, respectively. It is stable at pH 2.5-7.4, 37 degrees C. The pH and temperature optima are in the range of 3.5-4.0 and 55-60 degrees C, respectively. Contrary to most beta-xylosidases from other sources, Hg(2+) (up to 25 mM) has no effect on enzyme activity. Xylose was shown to inhibit the purified enzyme with a moderate K(i) value of 5 mM. The enzyme exhibited transxylosylation activity and was characterized as a 'retaining' enzyme, catalysing the hydrolysis of substrate with the retention of anomeric configuration.

Isolated pulmonary mucormycosis in an apparently normal host: a case report.

Mucormycosis is a rare fungal disease commonly affecting individuals with diabetes mellitus, hematological malignancy, and immune deficiency. Isolated pulmonary mucormycosis is extremely rare. This article reports a case of isolated pulmonary mucormycosis that presented as a solitary cavity infiltrate in a patient with no underlying risk factors.