Etiologic link between sarcoidosis and Propionibacterium acnes

Propionibacterium acnes is the only microorganism isolated from sarcoid lesions by bacterial culture. Numerous P. acnes genomes are found in lymph node samples from Japanese and European patients with sarcoidosis, whereas a few genomes are found in some non-sarcoid samples. The high frequency and specificity of detecting P. acnes within sarcoid granulomas suggests that this indigenous bacterium causes granuloma formation in many patients with sarcoidosis. P. acnes is the most common commensal bacterium in the lungs and lymph nodes. Occasional detection of P. acnes in non-granulomatous areas of these organs from non-sarcoid patients suggests that host factors are more critical than agent factors in the etiology of sarcoidosis. A particular protein, i.e., trigger factor, from P. acnes causes a cellular immune response only in sarcoid patients. The P. acnes trigger-factor protein induces pulmonary granulomas in mice sensitized with the protein and adjuvant, but only in those with latent P. acnes infection in their lungs. Eradication of P. acnes by antibiotics prevents the development of granulomas in this experimental model. P. acnes can cause latent infection in the lung and lymph nodes and persists in a cell wall-deficient form. The dormant form is endogenously activated under certain conditions and proliferates at the site of latent infection. In patients with P. acnes hypersensitivity, granulomatous inflammation is triggered by intracellular proliferation of the bacterium. Proliferating bacteria may escape granulomatous isolation, spreading to other organs. Latent P. acnes infection in systemic organs can be reactivated by another triggering event, leading to systemic sarcoidosis.     

The relative contributions of immune system and target organ to variation in susceptibility of rats to experimental allergic thyroiditis

Previous investigations of the cellular basis of genetic susceptibility to experimental allergic thyroiditis (EAT) in semi-allogeneic mice bearing thyroid grafts from resistant, parental strain donors have indicated that these grafts remain relatively resistant to EAT when this is induced in the susceptible bearer. It was concluded that genetic control of susceptibility to EAT is expressed in both the immune system and the thyroid gland. Our experiments in which thyroid grafts were transferred to fully allogeneic, but immunologically tolerant, recipient rats indicate that thyroid tissue from an EAT-resistant strain of rat becomes entirely susceptible when transplanted into a susceptible host. The differing susceptibility of thyroid grafts in semi-allogeneic and tolerant allogeneic hosts may result from restrictions on interaction between host lymphocytes and the graft in the former situation. The present findings call into serious doubt the proposition that genetically determined resistance to EAT is mediated, to any extent, at the level of the target organ.     

Awake pronation of surgical patients with cervical spinal lesions

Positioning of patients with cervical spinal lesions under general anesthesia may lead to serious neurological complications. The authors attempted awake pronation in eighteen patients to minimize the risks. In all patients, cervical instability or cervical spinal cord compression was diagnosed, and posterior fusion or laminoplasty under general anesthesia was planned. Naso-tracheal intubation was performed by broncho-fiberoptic scope under topical anesthesia and light sedation. After tracheal intubation, pronation was completed while patients were still awake. Twelve patients could change their position almost by themselves, and needed only a little assistance of the medical staff. After the patients settled in appropriate position, general anesthesia was induced. Neurological status was assessed before and after the intubation, and just before the induction of general anesthesia, to prove the absence of complications. Operations were accomplished without major troubles in all patients. During post anesthetic interviews, eight patients had memory of the positioning, but none of them had any complaints about the procedure. Awake pronation may be useful to minimize the risk of neurological complications related to positioning of surgical patients, and also need less assistance by medical staff.     

Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study

Rationale

Blockade of α₂ adrenoceptors and histamine H₁ receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine.

Objectives

However, it remains unclear how mirtazapine’s actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei.

Method

Using dual-probe microdialysis, we determined the roles of α₂ and H₁ receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices.

Results

Mirtazapine (<30 μM) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT_1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H₁ receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H₁ agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H₁ receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN α₂ adrenoceptor blockade was attenuated by concurrent DRN H₁ blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN α₂ adrenoceptor inhibition was unaffected by concurrent MRN H₁ receptor blockade.

Conclusion

These results suggest that enhanced serotonergic transmission resulting from α₂ adrenoceptor blockade is offset by subsequent activation of 5-HT_1A receptors and, in the DRN but not MRN, H₁ receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions.     

A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer

Currently, no prospective data exists to support a "stop-and-go" modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0-2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48% (80% confidence interval [CI]; 38.2-58) with outcomes as follows: complete response, n?=?1; partial response, n?=?23; stable disease, n?=?21; progression, n?=?1; and not evaluated, n?=?4. Median time to treatment failure was 7.7 months (80% CI: 6.2-8.0), and median progression-free survival was 12.8 months (80% CI: 10.8-14). Grade 3/4 toxicities included neutropenia (40%), nausea (4%), diarrhea (14%), thrombosis (4%), and hypertension (4%) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38%, 40%, and 10% of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients.     

Irinotecan monotherapy as third-line or later treatment in advanced gastric cancer

Background

Patients with advanced gastric cancer (AGC) are often treated with irinotecan monotherapy as salvage-line therapy. However, the survival benefit of this therapy remains to be elucidated.

Methods

Medical records of AGC patients who were treated with irinotecan monotherapy as salvage-line treatment in six institutions from 2007 to 2014 were reviewed.

Results

A total of 146 patients had prior fluoropyrimidine and taxane therapies, and 75.3% had prior platinum therapy. The median age was 66 (range 27–81) years, and 102 males (69.9%) were included. Performance status (PS) was 0/1/2/3 in 53/70/19/4 patients. Eighty-nine patients (61.0%) had two or more metastatic sites. Irinotecan monotherapy as 3rd-/4th-line therapy was performed in 135/11 (92.5%/7.5%). The median number of administrations was 4 (range 1–62). Forty-six patients (31.5%) required initial dose reduction at the physician’s discretion. The overall response rate was 6.8%, and the disease control rate was 43.1%. The median PFS was 3.19 months [95% confidence interval (CI) 2.30–4.08 months], and the median OS was 6.61 months (95% CI 5.94–7.28 months). Grade 3/4 adverse events were hematological toxicity (46 patients, 31.5%) and non-hematological toxicity (50 patients, 34.2%). Hospitalization due to adverse events was required in 31 patients (21.2%). Patients with relative dose intensity (RDI) less than 80% showed similar survival to those with RDI 80% or higher.

Conclusions

Irinotecan monotherapy was relatively safely performed as salvage-line treatment for AGC in Japanese clinical practice. Careful patient selection and intensive modification of the dose of irinotecan might possibly be associated with favorable survival.

     

Perioperative management of a patient requiring surgery for pituitary apoplexy and severe angina pectoris

We describe the management of a 71-yr-old man with pituitaryapoplexy and severe angina pectoris who underwent treatmentof an intra-cranial haemorrhage and open-heart surgery requiringanticoagulant therapy within a very short period. Subtotal removalof the pituitary tumour was undertaken under stable cardiovascularconditions. But ventricular fibrillation occurred after theneurosurgery in the intensive care unit. After the patient wasdefibrillated, intra-aortic balloon pumping was necessary toassist coronary artery blood flow. Twenty hours after neurosurgery,oozing from the surgical wound stopped and coronary artery bypassgrafting with full heparinization was performed uneventfully. Br J Anaesth 2000; 85: 800–2 ^* Corresponding author     

Helicobacter pylori invades the gastric mucosa and translocates to the gastric lymph nodes

Helicobacter pylori has been considered to be non-invasive and to rarely infiltrate the gastric mucosa, even though there is an active Th1 immune response in the lamina propria of the H. pylori-infected stomach. To elucidate whether H. pylori invades the lamina propria and translocates to the gastric lymph nodes, we examined H. pylori in formalin-fixed and paraffin-embedded tissue sections of stomach and gastric lymph nodes obtained from 51 cancer patients using real-time PCR and immunohistochemistry (IHC) with a novel anti-H. pylori monoclonal antibody that recognizes lipopolysaccharides. Fresh gastric lymph nodes were used to culture for H. pylori. In 46 patients with H. pylori in the stomach, the bacterium was found in the lymph nodes from 21 patients by culture, 37 patients by PCR, and 29 patients by IHC. H. pylori captured by macrophages was found in the lamina propria of 39 patients. In the lymph nodes, the bacterium was found in many macrophages and a few interdigitating dendritic cells at the paracortical areas. H. pylori was also found in the intracellular canaliculi of parietal cells in 21 patients, but intracytoplasmic invasion into gastric epithelial cells was not identified. When compared to the commercially available anti-H. pylori antibodies, the novel antibody showed the highest sensitivity to detect H. pylori-positive macrophages, whereas no difference was found for H. pylori in the mucous layer. The H. pylori-positive macrophages in the lamina propria correlated with chronic gastritis as well as translocation of such cells to the lymph nodes. These results suggest that H. pylori-induced gastric epithelial damage allows the bacteria to invade the lamina propria and translocate to the gastric lymph nodes, which may chronically stimulate the immune system. The bacteria captured by macrophages, whether remaining alive or not, may contribute to the induction and development of H. pylori-induced chronic gastritis.