Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.

OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

A Patient with Cystic Granuloma Trichophyticum who Required Surgical Resection.

A 62-year-old male with numerous subcutaneous nodules in the lower extremities was referred to The University of Tokyo Hospital. The patient suffered from systemic lupus erythematosus (SLE), diabetes mellitus, and persisting hepatic dysfunction, and had been treated for SLE with oral prednisolone 20 mg/day and oral cyclosporine 3 mg/kg/day. The culture of scales collected from the patient's skin surface on Sabouraud's dextrose agar medium showed features of Trichophyton rubrum. Topically applied bifonazole cream was effective for tinea corporis, but oral griseofulvin 500 mg/day was discontinued after 2-month administration because of deteriorated liver function. All the nodules were resected surgically. Histologically, resected granulomas showed dermal abscesses that were tightly encapsulated by fibrous capsules. Grocott staining revealed numerous fungal elements within abscesses. The patient's condition indicated the need to perform histopathological examination of granuloma trichophyticum in order to determine whether it is tightly encapsulated. Namely, the presence of cystic granuloma trichophyticum with abscesses encapsulated by fibrous capsules suggested that the patient should be treated by surgical resection of the lesions.

[Anesthetic management of a patient with chronic spinal cord injury for laparoscopic cholecystectomy].

Spinal cord injury (SCI) is a rare disease that offers challenges to anesthesiologists, while laparoscopic cholecystectomy (LC) has become common in recent years. We report a case of adult patient with chronic high SCI who underwent LC. A 62-year-old man, a known case of cervical SCI, was presented for LC. Anesthetic problems included circulatory and respiratory complications because of both SCI and pneumoperitoneum. Anesthesia was induced with propofol and a standard endotracheal tube was inserted with vecuronium; and thereafter anesthesia was maintained with small bolus doses of fentanyl and sevoflurane inhalation in the absence of epidural block. The intra- and post-operative course was completely uneventful without any episode of autonomic hyperreflexia. Due to a lack of sensory and motor function, SCI patients will receive little benefit from minimally invasive laparoscopic procedures. In conclusion, compared to open laparotomy, LC will minimize surgical trauma and hospital stay, but may not always minimize complications in anesthetic management. To the best of our knowlegde this is the first report in the literature which describes anesthesia for laparoscopic surgery in a SCI patient.

Combined analysis of cell growth and apoptosis-regulating proteins in HPVs associated anogenital tumors.

BACKGROUND: The clinical course of human papillomavirus (HPV) associated with Bowenoid papulosis and condyloma acuminatum of anogenital tumors are still unknown. Here we evaluated molecules that are relevant to cellular proliferation and regulation of apoptosis in HPV associated anogenital tumors. METHODS: We investigated the levels of telomerase activity, and inhibitor of apoptosis proteins (IAPs) family (c-IAP1, c-IAP2, XIAP) and c-Myc mRNA expression levels in 20 specimens of Bowenoid papulosis and 36 specimens of condyloma acuminatum in anogenital areas. Overall, phosphorylated (p-) AKT, p-ribosomal protein S6 (S6) and p-4E-binding protein 1 (4EBP1) expression levels were examined by immunohistochemistry in anogenital tumors both with and without positive telomerase activity. RESULTS: Positive telomerase activity was detected in 41.7% of Bowenoid papulosis and 27.3% of condyloma acuminatum compared to normal skin (p < 0.001). In contrast, the expression levels of Bowenoid papulosis indicated that c-IAP1, c-IAP2 and XIAP mRNA were significantly upregulated compared to those in both condyloma acuminatum samples (p < 0.001, p < 0.001, p = 0.022, respectively) and normal skin (p < 0.001, p = 0.002, p = 0.034, respectively). Overall, 30% of Bowenoid papulosis with high risk HPV strongly promoted IAPs family and c-Myc but condyloma acuminatum did not significantly activate those genes. Immunohistochemically, p-Akt and p-S6 expressions were associated with positive telomerase activity but not with p-4EBP1 expression. CONCLUSION: Combined analysis of the IAPs family, c-Myc mRNA expression, telomerase activity levels and p-Akt/p-S6 expressions may provide clinically relevant molecular markers in HPV associated anogenital tumors.

[Respiratory management for a patient with a giant bulla and pulmonary dysfunction during off-pump coronary artery bypass grafting].

This case report describes a successful anesthetic management of a 74-year-old patient with a giant bulla and pulmonary dysfunction during off-pump coronary artery bypass grafting (OPCAB). BiPAP Vision with a laryngeal mask airway (LMA) was used for intraoperative respiratory management. General anesthesia was induced with propofol. After insertion of a LMA anesthesia was maintained with propofol and dexmedetomidine under spontaneous breathing with bilevel positive airway pressure. Epidural analgesia was used in combination with general anesthesia. The LMA was removed without coughing and bucking soon after the end of the surgery. There was no complication during and after anesthesia. This respiratory management may be beneficial for patients with a giant bulla and pulmonary dysfunction during OPCAB.

[Novel echogenic needle for ultrasound-guided peripheral nerve block "Hakko type CCR"].

A novel echogenic insulated nerve block needle (CCR-needle: Echogenic Needle Type CCR; Hakko, Japan) is commercially available since 2006 in Japan. This needle has three echogenic dimples, namely corner cube reflectors (CCR) on its tip. The CCR-needle will potentially provide a significant advantage for detecting the needle tip. In this report, we firstly evaluated this new disposable echogenic needle in simulation phantom, and demonstrated improved visibility of the needle tip. Afterwards, an interscalene brachial plexus block was performed on a male patient undergoing shoulder surgery. The needle insertion procedure was the "out of plane" ultrasound-guided technique using simultaneous electrical nerve stimulation. The surgery was successfully conducted without any complications.

Bowen's disease with high telomerase activity.

We describe an 81-year-old Japanese woman who had a palm-sized, erythematous plaque with a nodular lesion on the lateral abdomen. The biopsy specimens taken from the erythematous plaque and reddish nodule show that bowenoid changes were present in the epidermis and epidermis to dermis, respectively. A sentinel lymph node biopsy (SNB) was performed with blue dye and radioisotope in her right groin region and two lymph nodes were found to be occupied by many atypical cells. The erythematous plaque with nodular lesion was completely removed with a 3-cm margin under general anesthesia, and complete regional lymph node dissection was also performed. In addition, high telomerase activity was seen in the erythema plaque while using a telomeric repeat amplification protocol assay. In conclusion, some instances of Bowen's disease might have high telomerase activity in the atypical cells and can progress to Bowen's carcinoma. The SNB was regarded as a useful method to detect early lymph node metastases in this case.

[New method for accurate ECG trigger of intraaortic balloon counterpulsation during off-pump coronary artery bypass surgery].

BACKGROUND: Retractions of the heart required for exposure and construction of distal anastomoses often decrease R-wave amplitude of ECG and interfere with intraaortic balloon pump (IABP) trigger during off-pump coronary artery bypass (OPCAB). Missing R wave trigger results in asynchronous work of IABP and probably produces hemodynamic instability. We report our early experience with a new interface BPI 202 (Osypka Medical, Inc., USA) for sensing accurate ECG trigger for IABP during OPCAB procedure. CASES: Six high-risk patients undergoing multivessel OPCAB using BPI 202 are described. RESULTS: With the new interface BPI 202, simulated R wave signal could be processed from an external dual chamber pacemaker sensing surface R wave. The simulated R wave was successfully used for controlling IABP and secured a synchronous work between the heart and IABP during heart retraction maneuver. BPI 202, an interface for IABP appeared to facilitate the intraoperative management of our series of patients. CONCLUSIONS: We believe BPI 202 can produce a synchronous work of IABP during OPCAB procedures to high-risk patients and avoid dangerous hemodynamic instability.

AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats.

BACKGROUND: Previous work with metformin has shown that this antidiabetic agent improves nonalcoholic fatty liver in ob/ob mice. AMP-activated protein kinase (AMPK) is one of the major cellular regulators of lipid and glucose metabolism, and reportedly mediates the beneficial metabolic effects of metformin. In this study, we examined the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an AMPK activator, on an experimental model of ethanol-induced hepatic steatosis. METHODS: Rats were randomly divided into three groups: (A) rats fed ethanol-containing liquid diet for six weeks; (B) rats pair-fed ethanol-containing liquid diet for six weeks, during the last three weeks of which they were subcutaneously injected with 0.5 mg AICAR/g body weight per day; (C) rats pair-fed isocaloric liquid diet without ethanol for six weeks. At the end of the six-week period, the animals were sacrificed. Serum and liver specimens were analyzed using biochemical and histologic methods, as well as real-time PCR. RESULTS: Chronic ethanol feeding resulted in fatty liver both histologically and biochemically, whereas AICAR administration attenuated the degree of change in the liver. AICAR also decreased the hepatic sterol regulatory factor binding protein-1c (SREBP-1c) and reduced fatty acid synthase (FAS) expression; these changes led to reduced triglyceride synthesis in rat livers. Furthermore, detection of 4-hydroxy-2-nonenal (4-HNE)-protein adducts showed that the AICAR treatment also decreased the products of lipid peroxidation. CONCLUSION: In this preclinical rat model, AICAR, an AMPK activator, appears to protect the liver from fatty changes associated with chronic alcohol use. As such, AICAR may have a role in the treatment and prevention of alcohol-induced fatty liver.

Herbal cardiotonic pills prevent gut ischemia/reperfusion-induced hepatic microvascular dysfunction in rats fed ethanol chronically.

AIM: Cardiotonic Pill (CP), an oral herbal medicine that includes Danshen (Salviae Miltiorrhizae), Panax notoginseny and Dyroblanops aromatica gaertn, has been clinically used for vascular diseases such as occlusive vasculitis, coronary diseases, atherosclerosis, and cerebral infarction. The main component, Salviae Miltiorrhizae, has been reported to prevent cerebral and intestinal reperfusion injury. However, little is known about the effect of CP on hepatic microcirculation. Thus, this study aimed to determine whether CP could affect hepatic microvascular dysfunction elicited by gut ischemia/reperfusion (I/R) in rats fed ethanol chronically. METHODS: Male Wistar rats were pair-fed with a liquid diet containing ethanol or isocaloric control diet for 6 wk. After laparotomy, one lobe of the liver was examined through an inverted intravital microscope. The rats were exposed to 30 min of gut ischemia followed by 60 min of reperfusion. Rhodamine-6G-labeled leukocytes in the sinusoids were observed 90 min after the onset of superior mesenteric artery occlusion. Plasma tumor necrosis factor (TNF)-alpha and endotoxin levels were measured 1 h after the onset of reperfusion. Plasma alanine aminotransferase (ALT) activities were measured 6 h after the onset of reperfusion. In another set of experiments, CP (0.8 g/kg, intragastrically) was administered 1 and 24 h before the onset of ischemia. RESULTS: In control rats, gut I/R elicited increases in the number of stationary leukocytes, and plasma TNF-alpha and endotoxin levels and plasma ALT activities. These changes were mitigated by pretreatment with CP. In ethanol-fed rats, the gut I/R-induced increases in the number of stationary leukocytes, plasma endotoxin levels and ALT activities were enhanced. Pretreatment with CP attenuated the enhancement of gut I/R-induced responses by chronic ethanol consumption. CONCLUSION: These results suggest that CP prevents the gut I/R-induced hepatic microvascular dysfunction and hepatocellular injury. A reduction of inflammatory responses such as TNF-alpha production via reduction of blood endotoxin levels appears to be involved in the mechanisms. Chronic ethanol consumption enhances gut I/R-induced hepatic microvascular and hepatocellular injury. CP also attenuates an enhancement of gut I/R-induced responses by chronic ethanol consumption via the reduction of blood endotoxin levels.