Microtubular inclusions in normal skin of systemic lupus erythematosus patients

Biopsy specimens of clinically normal skin of 9 consecutive patients with SLE were examined ultrastructurally to determine the presence and frequency of microtubular inclusions. Ten blood vessels were examined in each specimen; every specimen contained at least two positive blood vessels, and some contained 80 to 100% positive vessels. No correlation was found between the frequency of the inclusions and either the disease duration or antinuclear factor titer. The inclusions tended to be more frequent in patients with more acute disease. The absence of inclusions in normal skin may mitigate a diagnosis of SLE.     

Thermally stable mesoporous tetragonal zirconia through surfactant-controlled synthesis and Si-stabilization

Thermally stable, highly mesoporous Si-stabilized ZrO₂ was prepared by sol–gel-synthesis. By utilizing the surfactant dodecylamine (DDA), large mesopores with a pore width of ∼9.4 nm are formed. Combined with an NH₃-treatment on the hydrogel, a high specific surface area of up to 225 m² g⁻¹ and pore volume up to 0.46 cm³ g⁻¹ are obtained after calcination at 973 K. The individual contributions of Si-addition, DDA surfactant and the NH₃-treatment on the resulting pore system were studied by inductively coupled plasma with optical emission spectrometry (ICP-OES), X-ray diffraction (XRD), N₂ sorption, and transmission electron microscopy (TEM). Electron tomography was applied to visualize and investigate the mesopore network in 3D space. While Si prevents the growth of ZrO₂ crystallites and stabilizes the t-ZrO₂ phase, DDA generates a homogeneous mesopore network within the zirconia. The NH₃-treatment unblocks inaccessible pores, thereby increasing specific surface area and pore volume while retaining the pore width distribution.

Schematic representation of ZrO₂ crystallites; (a) monoclinic ZrO₂, (b) tetragonal ZrO₂ following Si-stabilization, (c) mesoporous t-ZrO₂ following Si-stabilization and use of surfactant dodecylamine.     

Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment

Eicosapentaenoic acid (EPA), an omega-3 (ω-3) polyunsaturated fatty acid, is an essential nutrient that exhibits antiinflammatory, neuroprotective, and cardiovascular-protective activities. Although EPA is used as a nutrient-based pharmaceutical agent or dietary supplement, its molecular target(s) is debatable. Here, we showed that EPA and its metabolites strongly and reversibly inhibit vesicular nucleotide transporter (VNUT), a key molecule for vesicular storage and release of adenosine triphosphate (ATP) in purinergic chemical transmission. In vitro analysis showed that EPA inhibits human VNUT-mediated ATP uptake at a half-maximal inhibitory concentration (IC₅₀) of 67 nM, acting as an allosteric modulator through competition with Cl⁻. EPA impaired vesicular ATP release from neurons without affecting the vesicular release of other neurotransmitters. In vivo, VNUT^−/− mice showed a delay in the onset of neuropathic pain and resistance to both neuropathic and inflammatory pain. EPA potently attenuated neuropathic and inflammatory pain in wild-type mice but not in VNUT^−/− mice without affecting the basal nociception. The analgesic effect of EPA was canceled by the intrathecal injection of purinoceptor agonists and was stronger than that of existing drugs used for neuropathic pain treatment, with few side effects. Neuropathic pain impaired insulin sensitivity in previous studies, which was improved by EPA in the wild-type mice but not in the VNUT^−/− mice. Our results showed that VNUT is a molecular target of EPA that attenuates neuropathic and inflammatory pain and insulin resistance. EPA may represent a unique nutrient-based treatment and prevention strategy for neurological, immunological, and metabolic diseases by targeting purinergic chemical transmission.

Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are essential nutrients that contain multiple double bonds. PUFAs can be classified into ω-3 and ω-6 depending on the position of the bonds. As humans cannot produce PUFAs, they must be acquired from the diet to maintain homeostasis. Omega-3 PUFAs, such as eicosapentaenoic acid (EPA), are abundantly present in fish and linseed oil and exhibit antiinflammatory, neuroprotective, and cardiovascular-protective activities via the competitive inhibition of cyclooxygenase (COX)-2 in eicosanoid production (1–3). Danish and Greenland Inuit epidemiological studies have reported that EPA reduces the risk of death after myocardial infarction (4, 5), and other studies have reported its influence on analgesia, neuroinflammatory disease (Parkinson’s disease, Alzheimer’s disease, and depression) improvement, platelet aggregation inhibition, decrease in blood triglyceride and glucose levels, and improved insulin resistance (1, 6–11). Omega-3 fatty acid supplementation in COVID-19 patients showed a beneficial effect in managing the cytokine storm (12). Conversely, omega-6 fatty acids, such as arachidonic acid, produce inflammatory eicosanoids and play central roles in the initial stage of inflammatory responses (13). Although arachidonic acid has also been reported to produce antiinflammatory metabolites, omega-6 PUFA-derived linoleate diols have a harmful effect and are biomarkers for severe COVID-19 infection (14). An omega-6 PUFA-enriched Western-style diet, which abundantly contains linoleate, causes neuropathy and chronic pain, but an omega-3 PUFA-enriched diet attenuates these pathological conditions (15).All therapeutic effects of EPA cannot be explained by COX-2 inhibition alone (16). Typically, COX-2 inhibitors (nonsteroidal antiinflammatory druga [NSAIDs]) are effective for inflammatory pain but ineffective for neuropathic pain (16). However, EPA significantly attenuates both inflammatory and neuropathic pain, which strongly suggests another important molecular target of EPA related to neuropathy (7, 8). Although chronic pain is coincidentally caused by inflammation and neuropathy, there is no therapeutic drug with few side effects to attenuate both inflammatory and neuropathic pain (17–20). In this situation, EPA may affect the key signaling molecule(s) in neurological, metabolic, and immunological functions.Purinergic chemical transmission is involved in neurological, metabolic, and immunological disruptions and functions, including neuropathic and inflammatory pain, depression, inflammation, increase in blood triglyceride and glucose levels, insulin resistance, and blood coagulation (21, 22). The released adenosine triphosphate (ATP) and degraded adenosine diphosphate (ADP) or adenosine binds to many types of purinoceptors that are intricately involved in biological and pathological processes. In pain perception, ATP and ADP bind to P2X and P2Y receptors and thereby exacerbate neuropathic and inflammatory pain (23). Adenosine binds to P1 receptors and thereby attenuates neuropathic and inflammatory pain (24). However, a vesicular nucleotide transporter (VNUT/SLC17A9) is localized in the secretory vesicles of neuronal, endocrine, and immune cells. It plays an essential role in vesicular ATP storage in a Δψ- and Cl^–-dependent manner in the purinergic chemical transmission, which leads to vesicular ATP release (25, 26). Thus, VNUT is a key molecule in the initiation of purinergic signaling for neurological, metabolic, and immunological disruptions and functions. Interestingly, the observed effects of the VNUT inhibitor and phenotypes of VNUT^−/− mice were consistent with the above-mentioned therapeutic effects of EPA (27–31). Therefore, we hypothesized that VNUT serves as a molecular target of EPA to attenuate neuropathic and inflammatory pain.Here, we demonstrated that a low concentration of EPA and its metabolites, but not docosahexaenoic acid (DHA), are potent and selective physiological inhibitors of vesicular ATP release via the blockade of purinergic chemical transmission, which improved neuropathic and inflammatory pain and insulin resistance. Furthermore, EPA is more effective for neuropathic and inflammatory pain and has fewer side effects than existing drugs.     

Transplantation of bone marrow stromal cell-derived Schwann cells promotes axonal regeneration and functional recovery after complete transection of adult rat spinal cord

The aim of this study was to evaluate whether transplantation of Schwann cells derived from bone marrow stromal cells (BMSC-SCs) promotes axonal regeneration and functional recovery in completely transected spinal cord in adult rats. Bone marrow stromal cells (BMSCs) were induced to differentiate into Schwann cells in vitro. A 4-mm segment of rat spinal cord was removed completely at the T7 level. An ultra-filtration membrane tube, filled with a mixture of Matrigel (MG) and BMSC-SCs (BMSC-SC group) or Matrigel alone (MG group), was grafted into the gap. In the BMSC-SC group, the number of neurofilament- and tyrosine hydroxylase-immunoreactive nerve fibers was significantly higher compared to the MG group, although 5-hydroxytryptamine- or calcitonin gene-related peptide-immunoreactive fibers were rarely detectable in both groups. In the BMSC-SC group, significant recovery of the hindlimb function was recognized, which was abolished by retransection of the graft 6 weeks after transplantation. These results demonstrate that transplantation of BMSC-SCs promotes axonal regeneration of lesioned spinal cord, resulting in recovery of hindlimb function in rats. Transplantation of BMSC-SCs is a potentially useful treatment for spinal cord injury.     

Risk Factors for Complications Associated with Peripherally Inserted Central Catheters During Induction Chemotherapy for Acute Myeloid Leukemia

Objective Peripherally inserted central catheters (PICCs) are widely used in patients with hematologic malignancies. However, the risks of PICC-related complications during chemotherapy for acute myeloid leukemia (AML) are not fully understood. Methods We conducted a retrospective review of 128 adult patients with AML who received induction therapy by way of PICC insertion between 2012 and 2019. Results The median duration of PICC insertion was 30 days. The incidence rate of catheter-related bloodstream infection (CRBSI) was 2.4% at 30 days, and women were more likely to suffer from CRBSI than men. Local reactions at the insertion site were observed in 56 patients; however, these events did not predict CRBSI. The incidence rates of catheter-related thrombosis (CRT) were 1.6% at 30 days. Obesity put patients at an increased risk for CRT. Unexpected PICC removal occurred in 59 patients, and women were at a higher risk of catheter removal than men. Conclusion Low PICC-related complication rates, possibly associated with high rates of catheter removal, were observed during intensive chemotherapy for AML. Women and obese patients require careful monitoring of their PICC. Procedures to achieve appropriate PICC removal without increasing the complication rate need to be considered.     

Vertebral derotation in adolescent idiopathic scoliosis causes hypokyphosis of the thoracic spine

The underlying purpose of this commentary and position paper is to achieve evidence-based recommendations on prevention of work-related musculoskeletal disorders (MSDs). Such prevention can take different forms (primary, secondary and tertiary), occur at different levels (i.e. in a clinical setting, at the workplace, at national level) and involve several types of activities. Members of the Scientific Committee (SC) on MSDs of the International Commission on Occupational Health (ICOH) and other interested scientists and members of the public recently discussed the scientific and clinical future of prevention of (work-related) MSDs during five round-table sessions at two ICOH conferences (in Cape Town, South Africa, in 2009, and in Angers, France, in 2010). Approximately 50 researchers participated in each of the sessions. More specifically, the sessions aimed to discuss new developments since 1996 in measures and classification systems used both in research and in practice, and agree on future needs in the field. The discussion focused on three questions: At what degree of severity does musculoskeletal ill health, and do health problems related to MSDs, in an individual worker or in a group of workers justify preventive action in occupational health? What reliable and valid instruments do we have in research to distinguish ??normal musculoskeletal symptoms?? from ??serious musculoskeletal symptoms?? in workers? What measures or classification system of musculoskeletal health will we need in the near future to address musculoskeletal health and related work ability? Four new, agreed-upon statements were extrapolated from the discussions: 1. Musculoskeletal discomfort that is at risk of worsening with work activities, and that affects work ability or quality of life, needs to be identified. 2. We need to know our options of actions before identifying workers at risk (providing evidence-based medicine and applying the principle of best practice). 3. Classification systems and measures must include aspects such as the severity, frequency, and intensity of pain, as well as measures of impairment of functioning, which can help in prevention, treatment and prognosis. 4. We need to be aware of economic and/or socio-cultural consequences of classification systems and measures.     

Late recurrence after resection of mass-forming intrahepatic cholangiocarcinoma: report of a case

The outcome after surgical resection for intrahepatic cholangiocarcinoma has not been satisfactorily evaluated due to its malignant behavior. Surgical resection, however, has the potential to improve the prognosis and may allow surgeons to experience rare cases with long survival. This report presents the case of a patient who developed recurrence 9?years after resection of intrahepatic cholangiocarcinoma. A 76-year-old female was diagnosed to have intrahepatic cholangiocarcinoma and underwent an extended right posterior subsegmentectomy. The gross appearance showed a mass-forming type tumor. The histopathological examination revealed well to moderately differentiated adenocarcinoma associated with portal vein invasion. Subcutaneous metastasis in the head as the first sign of relapse was diagnosed 9?years after hepatectomy. The histopathological findings of the subcutaneous tumor were similar to those of the intrahepatic cholangiocarcinoma, thus suggesting metastasis from intrahepatic cholangiocarcinoma. Positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-d-glucose was useful for detecting multiple metastases. Long-term follow-up for more than 5?years is recommended because the present case shows that late recurrence of intrahepatic cholangiocarcinoma occurs even 5?years after resection.