Myeloid ZFP36L1 does not regulate inflammation or host defense in mouse models of acute bacterial infection.

Zinc finger protein 36, C3H type-like 1 (ZFP36L1) is one of several Zinc Finger Protein 36 (Zfp36) family members, which bind AU rich elements within 3' untranslated regions (UTRs) to negatively regulate the post-transcriptional expression of targeted mRNAs. The prototypical member of the family, Tristetraprolin (TTP or ZFP36), has been well-studied in the context of inflammation and plays an important role in repressing pro-inflammatory transcripts such as TNF-α. Much less is known about the other family members, and none have been studied in the context of infection. Using macrophage cell lines and primary alveolar macrophages we demonstrated that, like ZFP36, ZFP36L1 is prominently induced by infection. To test our hypothesis that macrophage production of ZFP36L1 is necessary for regulation of the inflammatory response of the lung during pneumonia, we generated mice with a myeloid-specific deficiency of ZFP36L1. Surprisingly, we found that myeloid deficiency of ZFP36L1 did not result in alteration of lung cytokine production after infection, altered clearance of bacteria, or increased inflammatory lung injury. Although alveolar macrophages are critical components of the innate defense against respiratory pathogens, we concluded that myeloid ZFP36L1 is not essential for appropriate responses to bacteria in the lungs. Based on studies conducted with myeloid-deficient ZFP36 mice, our data indicate that, of the Zfp36 family, ZFP36 is the predominant negative regulator of cytokine expression in macrophages. In conclusion, these results imply that myeloid ZFP36 may fully compensate for loss of ZFP36L1 or that Zfp36l1-dependent mRNA expression does not play an integral role in the host defense against bacterial pneumonia.

Zcchc11 uridylates mature miRNAs to enhance neonatal IGF-1 expression, growth, and survival.

The Zcchc11 enzyme is implicated in microRNA (miRNA) regulation. It can uridylate let-7 precursors to decrease quantities of the mature miRNA in embryonic stem cell lines, suggested to mediate stem cell maintenance. It can uridylate mature miR-26 to relieve silencing activity without impacting miRNA content in cancer cell lines, suggested to mediate cytokine and growth factor expression. Broader roles of Zcchc11 in shaping or remodeling the miRNome or in directing biological or physiological processes remain entirely speculative. We generated Zcchc11-deficient mice to address these knowledge gaps. Zcchc11 deficiency had no impact on embryogenesis or fetal development, but it significantly decreased survival and growth immediately following birth, indicating a role for this enzyme in early postnatal fitness. Deep sequencing of small RNAs from neonatal livers revealed roles of this enzyme in miRNA sequence diversity. Zcchc11 deficiency diminished the lengths and terminal uridine frequencies for diverse mature miRNAs, but it had no influence on the quantities of any miRNAs. The expression of IGF-1, a liver-derived protein essential to early growth and survival, was enhanced by Zcchc11 expression in vitro, and miRNA silencing of IGF-1 was alleviated by uridylation events observed to be Zcchc11-dependent in the neonatal liver. In neonatal mice, Zcchc11 deficiency significantly decreased IGF-1 mRNA in the liver and IGF-1 protein in the blood. We conclude that the Zcchc11-mediated terminal uridylation of mature miRNAs is pervasive and physiologically significant, especially important in the neonatal period for fostering IGF-1 expression and enhancing postnatal growth and survival. We propose that the miRNA 3' terminus is a regulatory node upon which multiple enzymes converge to direct silencing activity and tune gene expression.

Terminal uridyltransferase enzyme Zcchc11 promotes cell proliferation independent of its uridyltransferase activity.

Zcchc11 is a uridyltransferase protein with enzymatic activity directed against diverse RNA species. On the basis of its known uridylation targets, we hypothesized that Zcchc11 might regulate cell proliferation. Confirming this, loss-of-function and complementary gain-of-function experiments consistently revealed that Zcchc11 promotes the transition from G(1) to S phase of the cell cycle. This activity takes place through both Rb-dependent and Rb-independent mechanisms by promoting the expression of multiple G(1)-associated proteins, including cyclins D(1) and A and CDK4. Surprisingly, a Zcchc11 construct with point mutations inactivating the uridyltransferase domain enhanced cell proliferation as effectively as wild-type Zcchc11. Furthermore, truncated mutant constructs revealed that the cell cycle effects of Zcchc11 were driven by the N-terminal region of the protein that lacks the RNA-binding domains and uridyltransferase activity of the full protein. Therefore, the N-terminal portion of Zcchc11, which lacks nucleotidyltransferase capabilities, is biologically active and mediates a previously unrecognized role for Zcchc11 in facilitating cell proliferation.

[Occurrence of BOOP outside radiation field after radiation therapy for small cell lung cancer].

We report a case of bronchiolitis obliterans organizing pneumonia (BOOP) that occurred outside the radiation field after radiation therapy for small cell lung cancer. A 74-year-old woman received chemotherapy and a total of 60 Gy of radiation therapy to the right hilum and mediastinum for small cell carcinoma of the suprahilar area of the right lung. Radiation pneumonitis developed within the radiation port 3 months after the completion of radiation therapy. She complained of cough and was admitted 7 months after completion of the radiation therapy. Chest radiography and computed tomography demonstrated peripheral alveolar opacities outside the radiation field on the side contralateral to that receiving the radiation therapy. Bronchoalveolar lavage showed that the total cell count was increased, with a markedly increased percentage of lymphocytes. Transbronchial lung biopsy revealed a histologic pattern consistent with BOOP. Treatment with corticosteroids resulted in rapid improvement of the symptoms and complete resolution of the radiographic abnormalities of the left lung. Although some cases of BOOP following radiation therapy for breast cancer have been reported, none of BOOP after radiation therapy for lung cancer have appeared in the literature.

[Clinical comparison of Chlamydia pneumoniae pneumonia, ornithosis, and Mycoplasma pneumoniae pneumonia].

To elucidate the differences between the clinical aspects of Chlamydia pneumoniae (C. pn) pneumonia and those of two other atypical pneumonias, Chlamydia psittaci (C. ps) pneumonia and Mycoplasma pneumoniae (M. pn) pneumonia, we analyzed the symptoms and laboratory data on the cases of these three types of pneumonia: 46 cases of C. pn pneumonia, 39 cases of C. ps pneumonia, and 131 cases of M. pn pneumonia. C. pn pneumonia was significantly more frequent among the elderly (mean 70 +/- 16 years, p < 0.01) and patients were significantly more likely to be male (76%, p < 0.05). A white blood cell count of over 10,000 was seen in 46% of C. pn pneumonia cases, a higher proportion than those of C. ps pneumonia (15%, p = 0.03) or M. pn pneumonia (18%, p = 0.006) cases. The proportions of patients with these infections who had an elevated GOT or GPT were not significantly different. Maximum body temperature was higher in M. pn pneumonia than in C. pn pneumonia (p = 0.003). Purulent sputa were seen in 44% of C. pn pneumonia cases and 50% of M. pn pneumonia cases, and these rates were higher than that of 13% in C. ps pneumonia cases (p = 0.002, p = 0.004). Dyspnea and anorexia symptoms were the most frequent in C. pn pneumonia cases (24% and 29%, respectively, the highest of all three pneumonias). There were clinical differences between C. pn pneumonia and the other two atypical pneumonias. However, there was some difficulty in differentiating between C. pn pneumonia and typical bacterial pneumonia because mixed infections were common (24%) in C. pn pneumonia cases.

Vascular access via peripherally inserted central venous catheters (PICCs): experience in 40 patients with acute myeloid leukemia at a single institute.

Reliable long-term vascular access is essential for the treatment of patients with acute myeloid leukemia (AML). Although peripherally inserted central catheters (PICCs) have been in use for many years, little data exist on their use in patients receiving intensive chemotherapy. We retrospectively reviewed all AML patients who had a PICC inserted between July 95 and May 98. Fifty two PICCs were inserted in 40 patients with AML. Thirty three PICCs were inserted during severe thrombocytopenia (platelets < 50 x 10(9)/L), and 31 during severe neutropenia (neutrophils < 0.5 x 10(9)/L). Mean catheter duration was 82 (median 63, range 3-441) days for a total of 4274 catheter days. A mean of 1.8 chemotherapy courses were administered via each PICC. There were 5 early complications of PICC placement. Other mechanical complications occurred in 14 catheters and phlebitis in 12. Twenty blood stream infections (BSI) occurred in 17 patients. All BSIs occurred during neutropenia. Seventeen PICCs were removed due to the following complications - phlebitis (11), possible catheter related BSI (4), mechanical reasons in 3 (2 with concomitant phlebitis) and persistent fever (1). PICC duration was significantly shorter in these 17 catheters (52.9 v 96.4 days in the other 35, p=0.0289). We conclude that PICCs provide long-term vascular access with an acceptable complication rate in patients with AML. However, a randomised trial is required before PICCs can be considered an alternative to tunneled central venous catheters in these patients.

[Occurrence of BOOP outside radiation field after tangential radiation therapy for breast carcinoma].

We report three cases of bronchiolitis obliterans organizing pneumonia (BOOP) that occurred outside the radiation field after radiation therapy using tangential fields for breast carcinoma. All patients complained of a cough between 14 and 20 weeks after completion of radiation therapy. Fever also developed in two of the three. Chest radiography and computed tomography demonstrated peripheral alveolar opacities outside the radiation field on the same side as the radiation therapy. Laboratory data showed an increased level of C-reactive protein and an increased erythrocyte sedimentation rate. Bronchoalveolar lavage showed an elevated total cell count with a very high percentage of lymphocytes. Transbronchial lung biopsy revealed a histologic pattern consistent with BOOP. Treatment with corticosteroids resulted in rapid clinical improvement and complete resolution of the radiographic abnormalities. This pulmonary disorder appears to be induced by radiation, especially when a tangential field is employed for breast carcinoma, though the etiology has not been fully investigated. It is important to be aware of this type of pulmonary complication in patients given radiotherapy for breast carcinoma.

Malignant thymoma with direct invasion into the peritoneal cavity: report of a case.

Extrathoracic invasions or metastases from thymomas are extremely rare. We describe herein the case of a patient with malignant thymoma which recurred three times during an 8-year period and invaded directly into the peritoneal cavity, involving the gastrointestinal tract. The huge thymoma was completely resected, along with the fornix of the stomach, the transverse colon, and the 8th, 9th, and 10th ribs. Careful observation and multidisciplinary treatment against recurrent thymoma will be requisite for this patient, even though the tumor has been completely resected.

[A case of Pryce type I intrapulmonary sequestration].

A twenty-year-old asymptomatic man hospitalized because of a vascular murmur and abnormal shadow in the left lower lung on X-ray film. An aortogram revealed an abnormal artery arising from the descending thoracic aorta and supplying the left basal segment, which had no other pulmonary arteries. Although lung ventilation scintigraphy demonstrated reduced ventilation to the left lower lobe, bronchogram showed an almost normal bronchial tree except that peripheral branches were slightly thin. A clinical diagnosis of Pryce type I intrapulmonary sequestration was made, and left lower lobectomy was performed successfully. We have analyzed 31 cases of Pryce type I intrapulmonary sequestration in Japan. A vascular murmur is often heard, and a chest X-ray usually shows either a mass shadow or increased vascular markings. In most of those cases, an abnormal artery arises from the descending thoracic aorta and it supplies the left basal segment. Because this type of sequestration causes hemoptysis and infections, surgical intervention is indicated.

[A case of unusual shaped pulmonary arteriovenous fistula].

Autopsy findings of pulmonary arteriovenous fistula (PAVF) was initially described by Churton in 1897. Since then, several hundreds of cases have been reported in Europe and the United States. In Japan, there has recently been an increase in case reports of PAVF. PAVF seems to be no longer a rare disorder in Japan. Several morphological classifications of PAVF have been reported. One of these classifies PAVF into 1) solitary types 2) multiple types and 3) diffuse telangiectasia. Another, for example, classifies the disorder into the following 3 types: 1) multiple telangiectasia 2) pulmonary arterial aneurysm and 3) pulmonary artery-left atrial communications. Many other classifications have been proposed. In the solitary type (PA aneurysmal type), fistulas are located at the relatively large, central vessels. Here we report a case of PAVF which presented not as a solitary aneurysm but rather as a distended and tortuous anomalous vessel.

[Thirty-eight operative cases of mediastinal cyst: with particular reference to bronchogenic cyst].

Thirty-eight patients (16 males and 22 females) with mediastinal cysts have been treated at the Second Department of Surgery at Okayama University from 1978 to 1989. There were thirteen cases of thymic cyst, nine cases of pericardial cyst one case of pericardial diverticulum, eight cases of bronchogenic cyst, two cases of dermoid cyst, two cases of cystic lymphangioma, one case of esophageal cyst, one case of gastroenteric cyst, and one case of aneurysmal bone cyst. MRI seemed to be useful for the qualitative diagnosis of mediastinal tumors as cystic or solid. Based on Maier's classification and considering the result of this study, bronchogenic cysts may be divided into the following groups: 1) paratracheal, 2) carinal, 3) hilar, 4) paraesophageal [a) upper (Iu), b) lower (Im, Ei)], 5) cephalad recess of the azygos vein (CRAzV) and 6) miscellaneous. According to this new classification, these bronchogenic cysts could be allocated to (3) hilar: 1 cyst, (4-a) paraesophageal-upper: 1 cyst, (4-b) paraesophageal-lower: 1 cyst, (5) CRAzV: 4 cysts, and (6) miscellaneous: 2 cysts.

[A case of acute lupus pneumonitis followed by high-resolution CT].

A 43-year-old woman was admitted to our hospital because of fever and dyspnea. She had facial rash, hair-loss, arthralgia, urinary casts, thrombocytopenia, lymphocytopenia, and deposits of IgG, IgM, C3 in the epidermis. SLE was diagnosed. She also had severe dyspnea, which gradually progressed. In spite of steroid pulse therapy and cyclophosphamide, she eventually died about two months after admission. Chest X-ray film showed bilateral ground-glass shadow and volume-loss. High-resolution CT of the lung showed marked high density area with airbronchogram in the posterior part and a gradually enlarging slight high density area in the anterior area. Pathological findings of the posterior area were atelectasis and dense fibrosis. The findings of the anterior area were collapsed alveoli and dilated alveolar ducts. These findings might suggest that alveolar collapse play a major role in the course of pulmonary fibrosis of this patient.

Detection of varicella-zoster virus DNA by field-inversion gel electrophoresis.

A new method for detection of varicella-zoster virus (VZV) DNA using field-inversion gel electrophoresis (FIGE) was devised. VZV-genomic DNA could be differentiated from the host cell DNA of human embryonic lung (HEL) fibroblasts infected with VZV under electrophoretic conditions allowing resolution of linear and double-stranded DNAs in the 49-230 kilobase pairs (Kb) range. The detection of VZV-genomic DNA from infected HEL cells was successful regardless of whether the VZV was a laboratory strain, live vaccine strain, or fresh isolate. Under the same electrophoretic conditions, DNA of VZV-infected HEL cells could be clearly differentiated from DNA obtained from HEL cells infected with herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), or human cytomegalovirus (HCMV). Furthermore, VZV genomic DNA could be detected from as small a sample as 1.9 x 10(4) VZV-infected HEL cells. Finally, we could detect VZV genomic DNA from 10 samples of vesicle tissue (blister lids, each about 1-4 mm2) and one sample of vesicle fluid (about 5 microliters) obtained from patients diagnosed as having herpes-zoster. The results of this study indicate that FIGE is a simple and promising method for the detection of VZV from clinical materials as well as infected in vitro cultured cells.

Ventricular premature contraction after repair of tetralogy of Fallot--the influence of postoperative factors, particularly the right ventricular regional wall motion.

The presence and severity of ventricular premature contraction (VPC) in 35 patients with tetralogy of Fallot (TF) were studied, 5 to 10 years after intracardiac repair (ICR), using treadmill exercise testing and 24-hour ambulatory monitoring. VPCs were observed in 24 patients (68.6%). The patients were classified into two groups according to the types of VPCs: group A (23 patients) without VPCs or with VPCs of Lown's grade 1 and group B (12 patients) with VPCs of Lown's grade 2, 3 or 4. Group B patients were found to have significantly higher right to left ventricular peak-systolic pressure ratios and higher right ventricular peak systolic pressures than those of group A. But there were no significant differences between the two groups in operative age, the time lapse between ICR and evaluation, the duration of exercise and so on. Group B patients also showed significantly decreased right ventricular regional wall motions in the right ventricular outflow tracts (ROTs), indicating akinetic or paradoxical movements than group A patients. It is thought that postoperative right ventricular hypertension and the akinetic or paradoxical wall movement of the ROT may have some effect on the genesis of postoperative VPCs after repair of TF.

[Risk scores for ventricular premature contraction and exercise--performance after repair of tetralogy of Fallot].

Thirty-five patients with tetralogy of Fallot (TF), were studied for the postoperative factors which might have some effect on the presence and severity of ventricular premature contraction (VPC) and exercise performance (EP). Using the factors, we tried to make VPC- and EP-scores. Of the 35 patients, 12 (34%) showed VPCs of Lown's grade 2 or higher (group B) and 23 (66%) were free from significant VPCs (group A). Group B patients were found to have significantly higher postoperative right to left ventricular peak systolic pressure ratios (RV/LV) and higher right ventricular peak systolic pressures (RVP) than those of group A. The right ventricular regional wall motion (RVRWM) in the right ventricular outflow tracts of group B patients showed akinetic or paradoxical movements. VPC-scores using RV/LV, RVP and RVRWM showed that 11 patients, whose score were 0, were free from significant VPCs and showed that 6 of 7 patients (86%), whose score were 3, demonstrated significant VPCs. It was shown that RV/LV, left ventricular ejection fraction (LVEF), CTR and pulmonary regurgitation (PR) affected the exercise tolerance. In the case of EP-scores, using RV/LV, LVEF, CTR and PR, the endurance times of the patients who had higher scores seemed to be shorter. VPC- and EP-scores as a tool for predicting the presence of VPCs and the level of exercise performance seem to be quite useful.