Induction of 4-1BB (CD137) expression by DNA damaging agents in human T lymphocytes

4-1BB(CD137) is a member of the tumour necrosis factor receptor superfamily and is expressed on activated T cells, monocytes and natural killer (NK) cells. The interaction of 4-1BB and 4-1BB ligand provides a costimulatory signal leading to T-cell activation. The expression of 4-1BB has been known to be activation dependent. Interestingly, we found that expression of 4-1BB increased in human peripheral blood mononuclear cells after exposure to mitomycin C. Thus, we tested whether the treatment with other DNA-damaging agents, such as doxorubicin, bleomycin, and gamma-irradiation, could induce 4-1BB expression. The data indicated that 4-1BB expression increased dose-dependently by these agents reaching maximum at 2-3 days after the exposure. We found that the major 4-1BB-expressing population was CD3+ T cells, although a moderate number of CD14+ cells and a few NKB1+ cells also expressed 4-1BB. The levels of 4-1BB expression induced by anticancer drugs, were relatively lower than that induced by CD3 ligation. Interestingly, at subcytotoxic concentrations, doxorubicin and bleomycin considerably enhanced 4-1BB expression induced by CD3 ligation in CEM cells. The ligation of the damage-induced 4-1BB by monoclonal antibody enhanced the viability and proliferating capacity of the cells. In conclusion, the expression of 4-1BB might be one of the cellular responses of the immune cells against various genotoxic stresses.     

Immunocytochemical localization of metallothionein and its relation to doxorubicin toxicity in transgenic mouse heart

Previous studies using a cardiac-specific metallothionein-overexpressing transgenic mouse model have demonstrated that metallothionein protects the heart from doxorubicin toxicity. The present study was undertaken to determine cellular and subcellular distribution of metallothionein and located the antioxidant action of this protein in the transgenic heart. Using light microscopic immunoperoxidase method, it was identified that the overexpressed metallothionein is localized exclusively in cardiomyocytes. The electron microscopic immunogold method revealed that elevated metallothionein is in nucleus, myofibers, and sarcoplasm. In contrast with these distributions, metallothionein in nontransgenic myocardium was undetectable by immunoperoxidase light microscopy and was seldom found in nucleus and myofibers by immunogold electron microscopy. Treatment with doxorubicin induced cytoplasmic vacuolization and severe damages in myofilaments and nucleus in nontransgenic myocardium. The most prominent injury, however, occurred in mitochondria, including striking size and shape changes, focal swelling and loss of cristae. These damages were rarely found in the doxorubicin-treated transgenic myocardium. In particular, the internal morphology of mitochondria was maintained essentially normal, although metallothionein was not localized in this compartment in transgenic hearts. This study thus demonstrates that although the subcellularly localized action of metallothionein is important, it also plays a significant role in protection against oxidative injury by doxorubicin in remote organelles.     

Two cases of lichen planus pigmentosus presenting with a linear pattern

We report two cases of lichen planus pigmentosus (LPP) that developed in a unilateral linear pattern. The patients presented with unilateral linear brown macules on the extremities. Skin biopsy showed orthokeratosis, basal hydropic degeneration with scarce lymphohistiocytic infiltrates, and numerous melanophages in both patients. These patients, to the best of our knowledge, are the first cases of LPP presenting with a linear pattern. LPP should be considered in the differential diagnosis of linear hyperpigmented skin lesions.     

Secondary amenorrhea caused by hydrocephalus due to aqueductal stenosis : report of two cases

Amenorrhea is rarely presented as a manifestation of endocrinological disturbances in patients of chronic hydrocephalus. We describe two cases of secondary amenorrhea caused by hydrocephalus due to aqueductal stenosis. Two female patients of age 30 and 20 yr presented with amenorrhea and increasing headache. Magnetic resonance images revealed marked, noncommunicating hydrocephalus without any tumorous lesion. In one patient, emergent extraventricular drainage was necessary because of progressive neurological deterioration. Each patient underwent surgical intervention for the hydrocephalus-ventriculoperitoneal shunt and endoscopic third ventriculostomy. Both resumed normal menstruation continuing so far with further normal menstrual bleeding. These two cases and others reported in the literature indicated that the surgical intervention for hydrocephalus resolves amenorrhea in all the cases of amenorrhea due to hydrocephalus. The suspected role of the surgery is the correction of increased intracranial pressure, which is an important pathogenetic factor in the development of amenorrhea.     

A case of minute intraductal papillary mucinous tumor of the pancreas presenting with recurrent acute pancreatitis

Intraductal papillary mucinous tumor (IPMT) of the pancreas, a lesion consisting of mucin-producing cells with neoplastic potential, is characterized by duct ectasia, mucin hypersecretion, often extensive papillary intraductal growth, varying degrees of cytologic atypia, and relatively indolent growth. The clinical presentation of IPMT of the pancreas is characterized by chronic or recurrent attacks of abdominal discomfort often in association with low level pancreatic enzyme elevations. Less commonly these lesions may be detected as asymptomatic radiographic abnormalities. Interestingly, a case of a minute IPMT (2 mm in height and 7 mm in length, adenoma) in the main pancreatic duct presenting with acute pancreatitis in a 55 year-old man has been reported in the Japanese literature. Recently, we also experienced a case of a minute IPMT in a branch pancreatic duct causing repeated bouts of acute pancreatitis in a 75 year-old man. A filling defect at the neck of the main pancreatic duct seen on an endoscopic retrograde pancreatogram performed after recovery of the second attack of acute pancreatitis led the patient to undergo an exploratory laparotomy. After a near-total pancreatectomy was carried out, a minute (3 x 7 mm) IPMT of borderline malignancy was discovered in a branch duct at the head portion near the pancreatic neck without any lesions in the main pancreatic duct. Surprisingly, despite the resective surgery the patient died of carcinomatosis 8.5 months after the operation. We herein report a case of a minute but aggressive IPMT of the pancreas with a review of the literature.     

Cooperative transformation of murine fibroblast NIH3T3 cells by hepatitis C virus core protein and hepatitis B virus X protein

Co-infection with hepatitis B virus (HBV) and hepatitis C Virus (HCV) is associated with increased frequency in the development of hepatocellular carcinoma (HCC). Here, we demonstrated that HBV X protein (HBx) and HCV core cooperate to transform mouse fibroblast NIH3T3 cells. They additively stimulated cell growth, especially in the absence of serum growth factors. In addition, co-expression of HBx and HCV core had additive effects on the induction of anchorage-independent cell growth as well as on the secretion of matrix metalloproteases, which may contribute to increased metastatic potential. Furthermore, the cells expressing both viral proteins exhibited higher tumorigenicity, as demonstrated in athymic nude mice.     

A new haplogroup pattern displayed in Fujian Han in China

Human Y-chromosomal binary polymorphisms have been considered to preserve the paternal genetic legacy and provide evidence on human evolution and the genetic relationships among and demographic history of different populations. To reveal the genetic origin and immigration of the Fujian Han, 13 binary markers on the Y chromosome were used to screen Fujian Han by allele-specific polymerase chain reaction. The results indicated that the M₉G marker was highly prevalent (96.20%), suggesting a significant genetic drift. In addition, M₁₂₂C frequency was only 22.78%, and M₄₅A and M₁₀₃T were default. The distinctive haplogroup frequencies (H₁, H₅, and H_6/7/8) imply that the haplogroup pattern is a relatively ancestral and interim type. Received: October 13, 2001 / Accepted: December 3, 2001     

Laser doppler imaging of menstrual symptoms

In this paper, the skin blood flow for the stomach and forehead regions of 36 female patients with menstrual symptoms was studied using a moorLDI laser Doppler imager in which the results of 6 typical patients are included. The patterns obtained at the two sites are common to all women in the sample who have menstrual symptoms. Cold stress testing was also investigated to see if it was effective in bringing out any skin blood flow fluctuation at these regions caused by menstrual symptoms. Each patient attended two scanning sessions: one before and the other during menstruation. During each session, the patient was scanned three consecutive times, each on the stomach and the forehead skin regions. For each region, the first measurement was a bare scanning whereas for the second and the third, 85% denatured ethanol (cold stress test) was applied onto the required scan areas. It was found that cold stress testing was able to bring out distinct differences in LDI perfusion images before and during menstruation. Results were best captured when perfusion images were taken approximately after 85% denatured ethanol had been applied in two layers for 30 s, allowed to evaporate over the next 5 min (approximately the time taken to obtain one image), reapplied for another 30 s and then finally over the next 30 s allowed to evaporate further. However, it was impossible to deduce conclusively any correlation regarding migraine and skin blood flow since all the patients for this work had menstrual cramps only.     

Radioprotective Effect of Whey Hydrolysate Peptides against γ-Radiation-Induced Oxidative Stress in BALB/c Mice

Radiation therapy is widely used in the treatment of tumor diseases, but it can also cause serious damage to the body, so it is necessary to find effective nutritional supplements. The main purpose of this study is to evaluate the protective effect of whey hydrolysate peptides (WHPs) against ⁶⁰Coγ radiation damage in mice and explore the mechanism. BALB/c mice were given WHPs by oral gavage administration for 14 days. Then, some mice underwent a 30-day survival test after 8 Gy radiation, and other mice received 3.5 Gy radiation to analyze the changes in body weight, hematology and bone marrow DNA after three and 14 days. In addition, through further analysis of the level of oxidative stress and intestinal barrier function, the possible mechanism of the radioprotective effect of WHPs was explored. The study found WHPs can prolong survival time, restore body weight, and increase the number of peripheral blood white blood cells and bone marrow DNA content in irradiated mice. In addition, WHPs can significantly improve the antioxidant capacity, inhibit pro-inflammatory cytokines and protect the intestinal barrier. These results indicate that WHPs have a certain radioprotective effect in mice, and the main mechanism is related to reducing oxidative damage.     

Machine Learning Algorithms to Predict Mortality and Allocate Palliative Care for Older Patients With Hip Fracture

ObjectivesTo evaluate a machine learning model designed to predict mortality for Medicare beneficiaries aged >65 years treated for hip fracture in Inpatient Rehabilitation Facilities (IRFs).DesignRetrospective design/cohort analysis of Centers for Medicare & Medicaid Services Inpatient Rehabilitation Facility–Patient Assessment Instrument data.Setting and ParticipantsA total of 17,140 persons admitted to Medicare-certified IRFs in 2015 following hospitalization for hip fracture.MeasuresPatient characteristics include sociodemographic (age, gender, race, and social support) and clinical factors (functional status at admission, chronic conditions) and IRF length of stay. Outcomes were 30-day and 1-year all-cause mortality. We trained and evaluated 2 classification models, logistic regression and a multilayer perceptron (MLP), to predict the probability of 30-day and 1-year mortality and evaluated the calibration, discrimination, and precision of the models.ResultsFor 30-day mortality, MLP performed well [acc = 0.74, area under the receiver operating characteristic curve (AUROC) = 0.76, avg prec = 0.10, slope = 1.14] as did logistic regression (acc = 0.78, AUROC = 0.76, avg prec = 0.09, slope = 1.20). For 1-year mortality, the performances were similar for both MLP (acc = 0.68, AUROC = 0.75, avg prec = 0.32, slope = 0.96) and logistic regression (acc = 0.68, AUROC = 0.75, avg prec = 0.32, slope = 0.95).Conclusion and ImplicationsA scoring system based on logistic regression may be more feasible to run in current electronic medical records. But MLP models may reduce cognitive burden and increase ability to calibrate to local data, yielding clinical specificity in mortality prediction so that palliative care resources may be allocated more effectively.