An autopsy case of granulocyte-colony-stimulating-factor-producing extrahepatic bile duct carcinoma

A 79-year-old man was referred to this department due to the presence of extrahepatic bile duct carcinoma with a tumor at the left chest wall. The lesion was suspected to be a metastasis of bile duct carcinoma to the left wall, however, computed tomography （CT） revealed no regional lymph node or liver metastases. In addition, cytological and pathological examinations did not show malignancy. At the time of admission, the white blood cell count was 21 460 cells/μL （neutrophils, 18 240 cells/μL） and this elevated to 106 040 before death. In addition, serum granulocyte colony-stimulating factor （G-CSF） was elevated. At 28 d after admission, the patient died. An autopsy showed a poorly differentiated adenocarcinoma with sarcomatous change, which had slightly invaded into the pancreas around the bile duct, and was found in the distal bile duct with multiple metastases to the chest wall, lung, kidney, adrenal body, liver, mesentery, vertebra and mediastinal and para-aortic lymph nodes, without locoregional lymph node and liver metastasis. The cancer cells showed positive immunohistochemical staining for anti-G-CSF antibody. This is believed to be the first report of an extrahepatic bile duct carcinoma that produces G-CSF. Since G-CSF-producing carcinoma and sarcomatous change of the biliary tract leads to poor prognosis, early diagnosis and treatment are needed. When infection is ruled out, the G-CSF in serum should be examined. In addition, examinations such as bonescintigraphy and chest CT should also be considered for distant metastasis.     

Temporal Prediction Signals for Periodic Sensory Events in the Primate Central Thalamus

Prediction of periodic event timing is an important function for everyday activities, while the exact neural mechanism remains unclear. Previous studies in nonhuman primates have demonstrated that neurons in the cerebellar dentate nucleus and those in the caudate nucleus exhibit periodic firing modulation when the animals attempt to detect a single omission of isochronous repetitive audiovisual stimuli. To understand how these subcortical signals are sent and processed through the thalamocortical pathways, we examined single-neuron activities in the central thalamus of two macaque monkeys (one female and one male). We found that three types of neurons responded to each stimulus in the sequence in the absence of movements. Reactive-type neurons showed sensory adaptation and gradually waned the transient response to each stimulus. Predictive-type neurons steadily increased the magnitude of the suppressive response, similar to neurons previously reported in the cerebellum. Switch-type neurons initially showed a transient response, but after several cycles, the direction of firing modulation reversed and the activity decreased for each repetitive stimulus. The time course of Switch-type activity was well explained by the weighted sum of activities of the other types of neurons. Furthermore, for only Switch-type neurons the activity just before stimulus omission significantly correlated with behavioral latency, indicating that this type of neuron may carry a more advanced signal in the system detecting stimulus omission. These results suggest that the central thalamus may transmit integrated signals to the cerebral cortex for temporal information processing, which are necessary to accurately predict rhythmic event timing.SIGNIFICANCE STATEMENT Several cortical and subcortical regions are involved in temporal information processing, and the thalamus will play a role in functionally linking them. The present study aimed to clarify how the paralaminar part of the thalamus transmits and modifies signals for temporal prediction of rhythmic events. Three types of thalamic neurons exhibited periodic activity when monkeys attempted to detect a single omission of isochronous repetitive stimuli. The activity of one type of neuron correlated with the behavioral latency and appeared to be generated by integrating the signals carried by the other types of neurons. Our results revealed the neuronal signals in the thalamus for temporal prediction of sensory events, providing a clue to elucidate information processing in the thalamocortical pathways.     

Mutation Analysis of the IL36RN Gene in 14 Japanese Patients with Generalized Pustular Psoriasis

Generalized pustular psoriasis (GPP) is a rare, potentially life threatening, and aggressive form of psoriasis, which is characterized by sudden onset with repeated episodic skin inflammation leading to pustule formation. Familial GPP is known to be caused by recessively inherited mutations in the IL36RN gene, which encodes interleukin 36 receptor antagonist (IL‐36Ra). In this article, we performed mutation analysis of the IL36RN gene in 14 Japanese patients with GPP, and identified mutations in two of these patients analyzed. One patient was compound heterozygous for mutations c.115+6T>C and c.368C>G (p.Thr123Arg), whereas the other carried compound heterozygous mutations c.28C>T (p.Arg10*) and c.115+6T>C in the IL36RN gene. Expression studies using total RNA from the patients’ skin revealed that the mutation c.115+6T>C resulted in skipping of exon 3, leading to a frameshift and a premature termination codon (p.Arg10Argfs*1). The protein structure analysis suggested that the missense mutation p.Thr123Arg caused misfolding and instability of IL‐36Ra protein. In vitro studies in cultured cells showed impaired expression of the p.Thr123Arg mutant IL‐36Ra protein, which failed to antagonize the IL‐36 signaling pathway. Our data further underscore the critical role of IL36RN in pathogenesis of GPP.     

Does oral dryness influence pressure pain sensitivity in the oral mucosa of removable denture wearers?

Clinical Oral Investigations - This study aimed to determine if oral dryness is associated with oral pain sensitivity in removable denture wearers. The pressure pain threshold (PPT) in the mucosa...     

Measurement of endogenous plasma granulocyte colony-stimulating factor in patients with acquired aplastic anemia by a sensitive chemiluminescent immunoassay

Endogenous plasma granulocyte colony-stimulating factor (G-CSF) concentrations were serially measured in 68 patients with acquired aplastic anemia (AA). A very sensitive chemiluminescent immunoassay (CLEIA) was used to measure the plasma G-CSF concentration. The minimum detection limit of this assay (0.5 pg/mL) was sufficient for the determination of G-CSF concentrations in patients and normal subjects. The plasma G-CSF concentrations were significantly higher in 51 AA patients without signs of infection as compared with healthy control subjects. In AA patients with signs of infection, the G-CSF concentrations appeared to increase during the acute phase. There was a significant negative correlation between plasma G-CSF concentrations and absolute neutrophil counts (ANC) in AA patients without signs of infection. Although a decrease in the plasma G-CSF concentration was observed in all patients who achieved self-sustaining hematopoiesis following bone marrow transplantation (BMT) or immunosuppressive (IS) therapy, it was lower in patients undergoing BMT as compared with those receiving IS therapy for any given degree of neutropenia. Plasma G-CSF concentrations were higher in patients responding to IS therapy than in nonresponders. This study demonstrated the negative feedback regulation of G-CSF that plasma G-CSF concentrations may be useful in predicting the clinical response to IS therapy.     

Atrial natriuretic polypeptide is removed by the lungs and released into the left atrium as well as the right atrium in humans

To examine the sites of release and removal of plasma atrial natriuretic polypeptide plasma levels in the femoral vein, right atrium, pulmonary artery, pulmonary capillary bed, left atrium and aortic root were measured in 11 control subjects and 22 patients with mitral stenosis. Mean plasma natriuretic polypeptide levels in the femoral vein, right atrium, pulmonary artery, pulmonary capillary bed, left atrium and aortic root were, respectively, 64 +/- 29, 124 +/- 72, 103 +/- 44, 83 +/- 30, 106 +/- 46 and 101 +/- 35 pg/ml in the control subjects and 321 +/- 170, 500 +/- 234, 458 +/- 266, 356 +/- 209, 434 +/- 222 and 432 +/- 217 pg/ml in the patients with mitral stenosis. In both the control subjects and the patients with mitral stenosis, there was a significant increase between the femoral vein and the right atrium and between the pulmonary capillary bed and the left atrium and a significant decrease between the pulmonary artery and the pulmonary capillary bed. Blood samples were also taken simultaneously from the pulmonary vein and the pulmonary capillary bed, as well as from the pulmonary artery and the left atrium, in 25 patients (11 control subjects, 5 patients with mitral stenosis and 9 patients with atrial septal defect). There was no difference in plasma atrial natriuretic polypeptide levels between the pulmonary capillary bed and the pulmonary vein in these 25 patients. It is concluded that atrial natriuretic polypeptide 1) is released into the left as well as the right atrium, and 2) is removed by the lungs.