CYP7A1, NPC1L1, ABCB1, and CD36 Polymorphisms Are Associated with Increased Serum Coenzyme Q10 after Long-Term Supplementation in Women.

Coenzyme Q10 (CoQ10), an essential component for energy production that exhibits antioxidant activity, is considered a health-supporting and antiaging supplement. However, intervention-controlled studies have provided variable results on CoQ10 supplementation benefits, which may be attributed to individual CoQ10 bioavailability differences. This study aimed to investigate the relationship between genetic polymorphisms and CoQ10 serum levels after long-term supplementation. CoQ10 levels at baseline and after one year of supplementation (150 mg) were determined, and eight single nucleotide polymorphisms (SNPs) in cholesterol metabolism and CoQ10 absorption, efflux, and cellular uptake related genes were assessed. Rs2032582 (ABCB1) and rs1761667 (CD36) were significantly associated with a higher increase in CoQ10 levels in women. In addition, in women, rs3808607 (CYP7A1) and rs2072183 (NPC1L1) were significantly associated with a higher increase in CoQ10 per total cholesterol levels. Subgroup analyses showed that these four SNPs were useful for classifying high- or low-responder to CoQ10 bioavailability after long-term supplementation among women, but not in men. On the other hand, in men, no SNP was found to be significantly associated with increased serum CoQ10. These results collectively provide novel evidence on the relationship between genetics and CoQ10 bioavailability after long-term supplementation, which may help understand and assess CoQ10 supplementation effects, at least in women.

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.

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.

[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.

[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.

Miso Soup Consumption Enhances the Bioavailability of the Reduced Form of Supplemental Coenzyme Q10.

Coenzyme Q10 (CoQ10) is an essential compound that is involved in energy production and is a lipid-soluble antioxidant. Although it has been proposed as an antiaging and a health-supporting supplement, its low bioavailability remains a significant issue. Concurrent food intake enhances the absorption of orally administered CoQ10, but it has not been fully established whether specific food substances affect intestinal CoQ10 absorption. Therefore, to determine whether the bioavailability of supplemental CoQ10 is affected by diet, P30, a granulated and reduced form of CoQ10, was dispersed in four different foods, clear soup, miso soup, milk soup, and raw egg sauce. Those foods which contained CoQ10 were consumed on different occasions at intervals of 6-14 weeks by the same participants. Thirteen participants were recruited in the single-dose and repeated clinical study. When miso soup containing P30 was provided, the serum CoQ10 concentration increased faster than when participants consumed other P30-containing soups or a P30-containing raw egg sauce. The area under the curve for serum CoQ10 during the first 5 h after consumption of the P30-containing miso soup was approximately 1.5 times larger than those after the consumption of other P30-containing meals. These data imply that the absorption of CoQ10 supplements can be enhanced by consuming them with food and in particular with specific food substances, such as miso soup.

Guidelines for the management of dermatomycosis (2019).

The "Guidelines for the management of dermatomycosis" of the Japanese Dermatological Association were first published in Japanese in 2009 and the Guidelines Committee of the Japanese Dermatological Association revised it in 2019. The first guidelines was prepared according to the opinions of the Guidelines Committee members and it was of educational value. The revised version is composed of introductory descriptions of the disease concepts, diagnosis, medical mycology and recent advances in treatment, along with clinical questions (CQ), which is intended to help in general practice for dermatologists. The CQ are limited to those involved in therapy but include some of the recently launched antifungal agents. The level of evidence and the degree of recommendation for each item were reviewed by the committee based on clinical studies published by 2018. For rare dermatomycoses, recommendations by the committee are described in the guidelines. In this field, there are still few good quality studies on treatment. Periodic revision in line with new evidence is necessary.

[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.

[Current status of development for regenerative cell therapy, SB623].

SanBio Co., Ltd. is developing regenerative medicine, SB623. SB623 secretes neurotrophic and growth factors, and can possibly show benefit in repair of the damaged brain after stroke. An open-label, single-arm phase I/IIa clinical study was conducted with 18 chronic ischemic stroke patients in the United States to evaluate the safety and clinical outcomes of surgical transplantation of SB623. Clinical evaluation for a one year follow-up period showed significant improvements with all mean scores on the European Stroke Scale, the National Institute of Health Stroke Scale, and on the basis of fugl-Meyer Assessment. All patients experienced neither side effects nor serious treatment-emergent adverse events related to cell treatments. These results suggest that SB623 cell transplantation is safe and effective for treating chronic ischemic stroke. Currently we are conducting clinical studies in Japan and the US, and are accelerating clinical development to provide our cells to patients under new regulation of regenerative medical product in Japan.

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.

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.

Rapid identification of Trichophyton tonsurans by specific PCR based on DNA sequences of nuclear ribosomal internal transcribed spacer (ITS) 1 region.

BACKGROUND: Trichophyton tonsurans, a dermatophyte implicated in an international epidemic of tinea capitis, was also found to be responsible for infecting wrestling and Judo athletes nationwide in Japan since 2001. OBJECTIVE: A rapid and highly accurate means of identifying this pathogen has been required to control the infection. We have developed a T. tonsurans-specific PCR method based on the DNA sequences of the nuclear ribosomal internal transcribed spacer 1 region. SUBJECTS: Eighteen species of six genera of standard strains and 75 strains of clinically isolated Trichophyton species were used in this study. METHODS: A T. tonsurans-specific PCR primer pair (tonsF1 and tonsR1) was designed on the nuclear ribosomal internal transcribed spacer 1 region, located between 18S and 5.8S rDNA. Fungal DNA was extracted from the colonies grown on culture plates, and the specificity of the PCR primers was tested. RESULTS: The specific PCR product was amplified from the standard strain of T. tonsurans and from five strains isolated from black dot ringworms, but there was no band from the 70 clinical isolates of other Trichophyton species. This T. tonsurans-specific PCR method was able to detect 10 pg of T. tonsurans genomic DNA with ethidium bromide staining. CONCLUSIONS: A PCR identification system specific for T. tonsurans is rapid, sensitive, and specific.

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.

Effects of habitual exercise and dietary restriction on intrahepatic and periepididymal fat accumulation in Zucker fatty rats.

BACKGROUND: Habitual exercise and dietary restriction are commonly recommended to prevent or ameliorate obesity and lifestyle-related diseases, including fatty liver. This study investigated the effects of habitual exercise and dietary restriction on hepatic triglyceride (TG) levels, serum leptin levels, and histological adipocyte size in periepididymal adipose tissue from Zucker fatty (ZF) rats. METHODS: Six-week-old male ZF rats were randomly assigned to one of three groups: sedentary (Sed), sedentary and dietary restriction (Sed + DR), and training and dietary restriction (Tr + DR). Male Zucker lean (L) rats were used as control animals. All rats had access to water and the allowed quantity of food ad libitum. The rats in the Sed + DR and Tr + DR groups were fed a 30% restricted diet, while those in the Tr + DR group exercised voluntarily on a wheel ergometer. After 12 weeks, the rats were sacrificed for a histological examination of their liver and periepididymal adipose tissue. Hepatic and serum TG, serum total cholesterol, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, free fatty acid, and leptin levels were also measured. RESULTS: The hepatic TG levels were significantly higher in the Sed + DR group than in the L (P < 0.001) and Sed (P < 0.05) groups. By contrast, the hepatic TG levels in the Tr + DR group were significantly lower than those in the Sed (P < 0.05) and Sed + DR (P < 0.001) groups, but not significantly different from the L group values. The periepididymal adipocytes were significantly larger in the Sed, Sed + DR, and Tr + DR groups than in the L group (P < 0.001) and were significantly smaller in the Tr + DR group compared to the Sed and Sed + DR groups (P < 0.001). CONCLUSIONS: Our results suggest a relationship between lipid metabolism and the size of adipose cells in ZF rats. Exercising plays an important role in decreasing hepatic TG levels, serum leptin levels, and the size of adipose cells.

Interferon-gamma, a strong suppressor of cell proliferation, induces upregulation of keratin K6, one of the inflammatory- and proliferation-associated keratins.

Keratin K6 is known as an inflammatory and hyperproliferative keratin, and is induced by an inflammatory and hyperproliferative agent. In this study, we demonstrated that interferon-gamma, an antiproliferative agent, also induces keratin K6. We used normal human ex vivo skin, normal human cultured keratinocytes, HaCaT keratinocytes, and DJM cells to examine the induction of K6 by interferon-gamma, by immunohistochemical staining, Western blot analysis, promoter chloramphenicol acetyl transferase assay, and reverse transcriptase polymerase chain reaction of mRNA. We succeeded in demonstrating the induction of keratin K6 by interferon-gamma in ex vivo human skin and HaCaT keratinocytes at the protein and message level, and in cultured normal human keratinocytes at the promoter level. The inhibition of the signal transducing activator of transcription 1 pathway by a dominant-negative transfer gene caused the inhibition of K6 induction by interferon-gamma, and the blocking of nuclear factor kappaB using antisense oligonucleotides also inhibited the K6 induction. We also blocked the released interleukin-1alpha from keratinocytes after stimulation with interferon-gamma by neutralizing antibodies, which showed a decrease in the K6 induction. Our results suggest that a small amount of interleukin-1alpha, which cannot induce K6 by itself, is secreted upon stimulation by interferon-gamma, and that the induction of K6 occurs through the synergistic effect of the interferon-gamma/signal transducing activator of transcription 1 and interleukin-1alpha/nuclear factor kappaB pathways. This is the first report to describe K6 induction in epidermal keratinocytes by interferon-gamma and indicate a probable signal transduction pathway, and demonstrates that K6 is a possible partner of K17 in the inflammatory process.

Specificity in stress response: epidermal keratinocytes exhibit specialized UV-responsive signal transduction pathways.

UV light, a paradigmatic initiator of cell stress, invokes responses that include signal transduction, activation of transcription factors, and changes in gene expression. Consequently, in epidermal keratinocytes, its principal and frequent natural target, UV regulates transcription of a distinctive set of genes. Hypothesizing that UV activates distinctive epidermal signal transduction pathways, we compared the UV-responsive activation of the JNK and NFkappaB pathways in keratinocytes, with the activation of the same pathways by other agents and in other cell types. Using of inhibitors and antisense oligonucleotides, we found that in keratinocytes only UVB/UVC activate JNK, while in other cell types UVA, heat shock, and oxidative stress do as well. Keratinocytes express JNK-1 and JNK-3, which is unexpected because JNK-3 expression is considered brain-specific. In keratinocytes, ERK1, ERK2, and p38 are activated by growth factors, but not by UV. UVB/UVC in keratinocytes activates Elk1 and AP1 exclusively through the JNK pathway. JNKK1 is essential for UVB/UVC activation of JNK in keratinocytes in vitro and in human skin in vivo. In contrast, in HeLa cells, used as a control, crosstalk among signal transduction pathways allows considerable laxity. In parallel, UVB/UVC and TNFalpha activate the NFkappaB pathway via distinct mechanisms, as shown using antisense oligonucleotides targeted against IKKbeta, the active subunit of IKK. This implies a specific UVB/UVC responsive signal transduction pathway independent from other pathways. Our results suggest that in epidermal keratinocytes specific signal transduction pathways respond to UV light. Based on these findings, we propose that the UV light is not a genetic stress response inducer in these cells, but a specific agent to which epidermis developed highly specialized responses.

[A trouble in air conditioning in the operating area].

We experienced malfunction of air conditioning system in the operating area. Rust inside the circulating pipe to the operating area was an obstacle to inflow of cold and hot water. Installing an additional air conditioning system and treatment with chemicals to remove the dust made it possible to adjust room temperature appropriately. Anesthesiologists should be interested and understand equipments used in the operation area such as air conditioning system.

Histopathological evaluation of the efficacy of antifungals for experimental Trichosporon bloodstream infection.

The efficacy of polyene macrolides to treat experimental Trichosporon bloodstream infection was evaluated by histopathological examination and viable cell counts in the kidneys of infected mice. Viable cell counts on the 5th day after infection confirmed that liposomal amphotericin B (L-AMB) is a more effective treatment than fluconazole (FLC) for mice infected with an azole-resistant strain of Trichosporon. Histological examination revealed that the administration of L-AMB induced a transformation from acute purulent inflammation caused by both azole-susceptible and -resistant strain infections to a chronic and subsiding form, whereas FLC failed to convert the acute inflammation induced by the azole-resistant strain to a subsiding form. Our results demonstrate that polyene macrolides can be used as an alternative therapy for infection of azole-resistant strains of Trichosporon and that histopathological evaluation is useful for elucidating the pathophysiology of an experimental Trichosporon infection.