Autologous stem cell transplantation in the treatment of refractory rheumatoid arthritis

The concept of using high-dose immunosuppressive treatment (HDIT) with autologous stem cell transplantation (ASCT) to treat patients with refractory rheumatoid arthritis has been provided by animal studies and anecdotal case reports. Over the past five years, an increasing number of patients with refractory rheumatoid arthritis have received HDIT with ASCT as an adjunct to intense immunosuppression. Here, we present a case of refractory rheumatoid arthritis in a 54-yr-old woman using HDIT with ASCT. Peripheral blood stem cells were mobilized with cyclophosphamide (4 g/m(2)) followed by G-CSF (5 microg/kg/day). Leukapheresis continued daily until the number of harvested progenitor cells reached 2 x 10(6) CD34+ cells/kg after CliniMax CD34+ positive selection. For HDIT, high-dose cyclophosphamide (total dose 200 mg/kg) and antithymocyte globulin (total dose 90 mg/kg) were administered and CD34+ cells were infused 24 hr after HDIT. The patient tolerated the treatment well but experienced an episode of neutropenic fever. She achieved an early dramatic improvement of joint symptoms during therapy. Fifty percent of improvement of rheumatoid arthritis by the American College of Rheumatology (ACR 50) preliminary definition was fulfilled during the 6 months following ASCT. Although further long-term follow-up is required, the patient's activity of arthritis has been stable since receiving HDIT with ASCT.     

Applications of the pulsatile flow versatile ECLS: in vivo studies

INTRODUCTION: T-PLS (Twin-Pulse Life Support) is the first commercial pulsatile ECLS (Extra Corporeal Life Support) device (1). The dual sac structure of T-PLS can effectively reduce high membrane oxygenator inlet pressure and hemolysis. To verify both the use of T-PLS for ECLS and the advantages of T-PLS, we tested various models. METHOD AND RESULTS: In the partial CPB (cardio pulmonary bypass) model (swine), T-PLS (N = 6), and Biopump (N = 2), a single pulsatile pump (N = 2), were compared. In the case of single pulsatile flow, during pump systole, pressure increased to 700 - 800 mmHg at the inlet port of the membrane oxygenator. fHb, a hemolysis measurement value, was about 80 mg/dL at 3 hours. On the contrary, because of T-PLS's dual sac system, the pressure of T-PLS had a maximum value of about 250 mmHg and fHb was similar to that of the commercial centrifugal pumps. In the total CPB model (bovine, N = 6), the heart was stopped via cardioplegia (Kcl). T-PLS flow was maintained at 3.0-4.5 L/min. T-PLS functioned like a natural heart, having a pulse pressure of 26-43 mmHg and a pulse rate of 40-60 bpm (beats per minute). In the emergency case model (canine, N = 6), T-PLS was started 10 minutes after cardiac arrest from electronic shock. In spite of cardiac arrest for a period of 40 minutes, the heart was recovered after defibrillation. In the ARDS (Acute Respiratory Distress Syndrome) model (canine, N = 6), minimal ventilator parameters were set: tidal volume 130 ml, respiration rate = bpm, FiO2 = 10%. Three hours after starting T-PLS, PO2 of the carotid artery blood (after 2 hours: 195 +/- 89.4; after 3 hours: 258 +/- 99.3 mmHg) was above half the value of the femoral artery but was within normal range. CONCLUSION: It is suggested that a portable pulsatile ECLS like T-PLS may be used as a CPB device and as an alternative CPR (cardiopulmonary resuscitation) device in the case of cardiac arrest. Due to the pulsatile flow, oxygenated blood is delivered to the patient without overloading the ARDS patients heart.     

A rat model for radiation-induced proctitis

Radiation proctitis is a frequent acute complication encountered with pelvic irradiation. This study was aimed at establishing the optimal radiation dose for radiation-induced proctitis in rats. Female Wistar rats were used. The rectal specimens were examined morphologically at 5th and 10th day following 10-30 Gy irradiation in single fraction. With increasing dose, mucosal damage became worse, and there was a prominent reaction after > or =15 Gy. We selected 17.5 Gy as an optimal dose for radiation proctitis and examined specimens at day 1-14 and at week 4, 6, 8, and 12 after 17.5 Gy. The rectal mucosa revealed characteristic histological changes with time. An edema in lamina propria started as early as 1-2 days after irradiation and progressed into acute inflammation. On day 7 and 8, regeneration was observed with or without ulcer. Four weeks later, all regeneration processes have been completed with end result of either fibrosis or normal appearing mucosa. This study showed that the radiation injury of the rectum in rat develops in dose-dependent manner as it has reported in previous studies and suggested that 17.5 Gy in single fraction is the optimum dose to evaluate the protective effect of various medications for radiation proctitis in face of the clinical situation.     

Colorectal adenocarcinoma as a second malignant neoplasm following rhabdomyosarcoma of the urinary bladder: a case report

Following improvements in therapy for childhood malignancies, the striking increase in survival rate over the past 30 years has led to the increase risk of developing second malignant neoplasms (SMNs). We report a case of colorectal carcinoma as a SMN, following treatment for rhabdomyosarcoma. The patient was diagnosed with rhabdomyosarcoma of the urinary bladder at his age of three years, and developed adenocarcinoma in the colon 13 years later. Histologic examination of the surgical specimen revealed adenocarcinoma involving the rectosigmoid area with radiation colitis in its background. The tumor cells showed strong immunoreactivity for p53 protein, suggesting the role of irradiation and p53 mutation in carcinogenesis. This case emphasizes the need for dose observation in survivors of early childhood malignancies treated with radiation and multiagent chemotherapy.     

PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted,but Functional in Patients with COVID-19

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Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress

The activation of eukaryotic heat shock protein (Hsp) gene expression occurs in response to a wide variety of cellular stresses including heat shock, hydrogen peroxide, uncoupled oxidative phosphorylation, infection, and inflammation. Biochemical and genetic studies have clearly demonstrated critical roles for mammalian heat shock factor 1 (HSF1) in stress-inducible Hsp gene expression, resistance to stress-induced programmed cell death, extra-embryonic development, and other biological functions. Activation of mammalian Hsp gene expression involves the stress-inducible conversion of HSF1 from the inactive monomer to the DNA-binding competent homotrimer. Although Hsp activation is a central conserved process in biology, the precise mechanisms for stress sensing and signaling to activate HSF1, and the mechanisms by which many distinct stresses activate HSF1, are poorly understood. In this report we demonstrate that recombinant mammalian HSF1 directly senses both heat and hydrogen peroxide to assemble into a homotrimer in a reversible and redox-regulated manner. The sensing of both stresses requires two cysteine residues within the HSF1 DNA-binding domain that are engaged in redox-sensitive disulfide bonds. HSF1 derivatives in which either or both cysteines were mutated are defective in stress-inducible trimerization and DNA binding, stress-inducible nuclear translocation and Hsp gene trans-activation, and in the protection of mouse cells from stress-induced apoptosis. This redox-dependent activation of HSF1 by heat and hydrogen peroxide establishes a common mechanism in the stress activation of Hsp gene expression by mammalian HSF1.     

Clinical prognostic values of vascular endothelial growth factor, microvessel density,and p53 expression in esophageal carcinomas

Vascular endothelial growth factor (VEGF) is known to play a key role in tumor angiogenesis. The tumor-suppressor gene p53 has been thought to regulate VEGF. We investigated the effect of VEGF on esophageal carcinoma and the correlation between VEGF and p53. Tissue samples were taken from 81 patients with esophageal carcinoma after surgery. VEGF and p53 expressions were examined by immunohistochemical staining. Microvessels in the tumor stained for CD34 antigen were also counted. VEGF and p53 expressions were observed in 51.3% (41/80) and 51.9% (41/79), respectively. The microvessel density was 70.9+/-6.7 (mean+/-SE) in VEGF-positive group and 68.7+/-5.1 in VEGF-negative group. However, no correlation was noted between VEGF and p53 expression. Whereas the tumor size, nodal status, depth of invasions, and tumor stage were associated with poor overall survival, VEGF expression or p53 expression was not. These results indicate that VEGF and p53 are highly expressed in esophageal carcinomas. Since the VEGF expression is not correlated with the p53 expression, microvessel density or clinicopathological findings, further studies with other angiogenic molecules are needed to determine the role in esophageal carcinomas.     

Pharmacokinetics of theophylline and caffeine after intravenous administration of aminophylline to premature neonates in Korea

Theophylline has been widely used to treat apnea of premature neonates. The purpose of this study was to compare the pharmacokinetic parameters of theophylline and caffeine after intravenous administration of aminophylline to seven Korean low-birthweight neonates with apnea to those in other countries. The serum concentrations of theophylline and caffeine were measured simultaneously by high-performance liquid-chromatography (HPLC). The mean (+/- S.E.M.) birth weight and gestational period were 1190 +/- 253 g and 31.5 +/- 1.99 weeks, respectively. The mean (+/- S.E.M.) theophylline maintenance dosage was 1.28 +/- 0.15 mg/kg (given as equivalent aminophylline solution) every six hours. The mean (+/- S.E.M.) volume of distribution, 0.937 +/- 0.232 l/kg, elimination rate constant, 0.0249 +/- 0.0095/h, elimination half-life, 32.1 +/- 12.1 h, and total body clearance, 21.7 +/- 6.18 ml/h/kg, of theophylline in Korean premature neonates were comparable to the values of neonates in other countries. For caffeine, the mean (+/- S.E.M.) elimination half-life was 95.1 +/- 25.4 h and the elimination rate constant was 0.0079 +/- 0.0024/h. The mean (+/- S.E.M.) serum concentrations of theophylline and caffeine on the sixth day after aminophylline infusion were 10.4 +/- 2.28 microg/ml (range, 6.38-13.4 microg/ml) and 2.94 +/- 0.98 microg/ml (range, 1.80-4.44 microg/ml), respectively. The mean (+/- S.E.M.) caffeine to theophylline concentration ratio on the day after discontinuation of aminophylline infusion was 0.71 +/- 0.23 (range, 0.39-1.03).     

A case of multiple schwannomas of the trigeminal nerves, acoustic nerves, lower cranial nerves, brachial plexuses and spinal canal: schwannomatosis or neurofibromatosis?

In most cases, while schwannoma is sporadically manifested as a single benign neoplasm, the presence of multiple schwannomas in one patient is usually indicative of neurofibromatosis 2. However, several recent reports have suggested that schwannomatosis itself may also be a distinct clinical entity. This study examines an extremely rare case of probable schwannomatosis associated with intracranial, intraspinal and peripheral involvements. A 63-year-old woman presented with a seven-year history of palpable lumps on both sides of the supraclavicular area and hearing impairment in both ears. On physical examination, no skin manifestations were evident. Facial sensory change, deafness in the left ear and decreased gag reflex were revealed by neurological examination. Magnetic resonance imaging revealed multiple lesions of the trigeminal nerves, acoustic nerves, lower cranial nerves, spinal accessory nerve, brachial plexuses, and spinal nerves. Pathological examination of tumors from the bilateral brachial plexuses, the spinal nerve in the T8 spinal position and the neck mass revealed benign schwannomas. Following is this patient case report of multiple schwannomas presenting with no skin manifestations of neurofibromatosis.