Selective regulation of ICAM-1 and major histocompatibility complex class I and II molecule expression on epidermal Langerhans cells by some of the cytokines released by keratinocytes and T cells

Epidermal Langerhans cells (LC) are major histocompatibility complex (MHC) class II (Ia)-positive dendritic cells that act as potent antigen-presenting or accessory cells for primary and secondary T cell-dependent immune responses. Recent studies have disclosed that the morphological, functional, and phenotypic characteristics of LC are variably and drastically modulated by external stimuli both in vivo and in vitro. However, little is known of the biological significance of diverse cytokines in regulating the surface molecules of LC. To determine the regulatory properties of ICAM-1, Ia, and MHC class I (H-2K) molecules in LC, we have examined the effects of interleukin (IL)-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the expression of these molecules. Among the cytokines examined, IFN-γ markedly and reproducibly up-regulates the expression of H-2K, but not ICAM-1, in Ia⁺ LC in a time- and dose-dependent manner. TNF-α consistently up-regulates the expression of ICAM-1, but not H-2K, in a time- and dose-dependent manner. IL-10 slightly but reproducibly inhibits the expression of ICAM-1, but not H-2K, in a time- and dose-dependent manner. IL-10 potently inhibits the TNF-α-induced ICAM-1 up-regulation, but not the IFN-γ-induced H-2K up-regulation. Moreover, no cytokine consistently affects the Ia expression of LC. In addition, slight enhancing effects have been observed on H-2K expression by IL-4, and on ICAM-1 expression by IL-1α, IL-1β, or GM-CSF. The present data suggest that the selective regulation is operative in a certain cell surface moiety of LC by various cytokines. These results further facilitate our understanding of immunobiology of LC.     

Anti-emetic effect and safety of consecutive use of ondansetron injection in cisplatin-induced nausea and emesis]

Anti-emetic effect, safety and clinical usefulness of Ondansetron injection given in the dose of 4 mg once daily by intravenous administration for 3-5 consecutive days were examined in patients receiving a high single dose (not less than 50 mg/m2 or over 75 mg/body) and lower multiple doses (over 15-20 mg/m2 once daily, for 3-5 consecutive days) of cisplatin. Efficacy rates of inhibitory effects on nausea and emesis in patients receiving the high single dose of cisplatin were 76% on the 1st day, 67% on the 2nd day and 78% on the 3rd day, the average being 71% (86/121 cases) for the 3 days. Those in patients receiving lower multiple doses of cisplatin were 83% on the 1st day, 78% on the 2nd day, 61% on the 3rd day, 65% on the 4th day and 57% on the 5th day, the average being 72% (13/18 cases) for the 3-5 days. Side effects were observed in 15 cases out of 207 (1st course, 182 cases; 2nd course, 21 cases; 3rd course, 4 cases), and major symptoms were headache and fever. Also, abnormalities in clinical laboratory findings attributable to Ondansetron were observed in 13 cases, mainly consisting of elevation of the hepatic function values. From the above, Ondansetron injection which showed sufficient anti-emetic effects on acute emesis and delayed emesis induced by a high single dose or lower multiple doses of cisplatin with its once daily intravenous dose given for 3-5 consecutive days, were considered a safe and clinically useful anti-emetic.     

Antiemetics and its clinical evaluations]

Nausea and vomiting induced by anticancer agents are common problems associated with chemotherapy for cancer. Recent trials have examined a variety of antiemetics, representing several different classes of drugs. High dose metoclopramide provided the impetus for many of the current studies because of its effect against cisplatin induced vomiting. However, current regimens are not yet entirely effective in many patients receiving cisplatin or other highly emetogenic anticancer agents. A promising new class of antiemetics, 5-hydroxytryptamine receptor antagonists are undergoing clinical evaluations. Members of this class are easily and safely administered to patients receiving cisplatin or other emetogenic anticancer agents. These are highly active antiemetics, both prophylactic and interventional treatment. Lack of extrapyramidal reaction and other adverse effects associated with its use makes the drug a very attractive one. However, studies of antiemetics require consideration of methodologic issues that may not be of concern in trials of anticancer agents. The results of these studies can be affected by the patient population, the sample size, pharmacologic variables, the trial design, the method of analysis, etc. Recently, developments both in new-antiemetics and better ways of using the existing ones, lead us to cautious thought that nausea and vomiting due to cancer chemotherapy can be controlled substantially with benefit to the patients.     

Clinical evaluation of ondansetron (injection of a single intravenous dose) against nausea and emesis associated with anti-cancer drugs--dose-finding study in patients receiving cisplatin]

We examined anti-emetic effects, safety and the optimal dose of Ondansetron Injection given in a single intravenous dose in patients receiving a single high dose of cisplatin in randomized controlled comparative study using telephone registration. Ondansetron was injected intravenously in a single dose of 4 mg, 8 mg or 12 mg, at 15 minutes before administration of cisplatin. Nausea and emesis were observed for 24 hours after administration of cisplatin. Efficacy rate of inhibitory effects on nausea and emesis were 76% (19/25 cases) in the 4 mg dose group, 57% (12/21 cases) in the 8 mg dose group and 83% (20/24 cases) in the 12 mg dose group, without a statistically significant difference among 3 dose groups. Hence, it was estimated that the low dose of 4 mg was adequate to exert satisfactory anti-emetic effects. No clear relationship between onset time of the initial emetic episode and plasma concentrations of Ondansetron was found in 16 cases of the 4 mg dose group, 11 cases in the 8 mg dose group and 15 cases in the 12 mg dose group. Side effects observed during this study period were headache and diarrhea in 1 case in the 12 mg dose group. Both symptoms were mild and resolved without treatment. No abnormal findings attributable to Ondansetron were observed in clinical laboratory test. From the above, it was considered that Ondansetron given by a single intravenous injection was highly effective to inhibit nausea and emesis induced by cisplatin, and was highly safe. As to the dose, 4 mg once daily was considered to be adequate for prophylaxis of cisplatin-induced nausea and emesis.     

Diagnostic value of computed tomography,magnetic resonance imaging,and scintigraphy in diagnosing actinomycosis of the mandible

Mandibular actinomycosis is an uncommon disease caused by Actinomyces israelii. Actinomycosis infection typically manifests as a chronic disease resulting in multiple abscesses, firm soft tissue mass, and presence of sulfur granules in exudates or tissues. A few reports have provided imaging findings of actinomycosis in the head and neck, but computed tomography (CT), magnetic resonance imaging (MRI), and scintigraphy of mandibular actinomycosis have not been fully described. Here, we report a case of mandibular actinomycosis with CT, MRI, and scintigraphy. The purpose of this article is to characterize the CT, MRI, and scintigraphy findings in cases of actinomycosis. Contrast-enhanced CT of the masticator space showed heterogeneous enhancement and a nonenhancing portion, suggestive of necrotic foci. Bone tissue algorithm CT showed an osteolytic lesion in the ramus of the left mandible only. On post-contrast T1-weighted images, the masticator space showed heterogeneous enhancement and nonenhancing portion, suggestive of necrotic foci. Bone scintigraphy revealed monostatic involvement of the mandible with a homogeneous intense uptake pattern. Gallium scintigraphy revealed significantly increased uptake in the left side of the face. These findings can be helpful for differentiating actinomycosis from other tumors of the mandible.     

Analysis of sebum lipid composition and the development of acneiform rash before and after administration of egfr inhibitor

Treatment with an epidermal growth factor receptor inhibitor (egfri) in patients having non-small-cell lung cancer can cause frequent and diverse skin toxicities, an acneiform rash being one of the commonest. Although the exact pathophysiology of this rash and its development mechanisms remain unknown, investigators have noted that egfri-induced skin toxicity might be partly associated with sebaceous gland function. Sebum is composed mainly of the lipids squalene (sq), wax ester (we), triglyceride, free fatty acid, and cholesterol, which are secreted mostly from the sebaceous glands and by keratinocytes. We therefore investigated the lipid composition of sebum before and after administration of egfri and whether sebum composition was associated with the development of acneiform rash. To investigate any associated changes in sebum gland activity, we focused especially on alterations in the amounts of sq and we, which are secreted solely from the sebaceous glands.In contrast to our expectations, we observed no substantial changes in the lipid composition of sebum before and after administration of egfri. Composition varies with the individual; however, the proportion of sq and we derived from the sebaceous glands was significantly lower in regions that did not develop acneiform rash than in regions that did. Our results suggest that development of an acneiform rash after administration of egfri could be related to sebaceous gland activity. Measurement of the lipid composition of sebum before therapy with egfri might predict which patients will be prone to acneiform rash.     

Predictive validity of weekly monitoring of wound status using DESIGN‐R score change for pressure ulcer healing: A multicenter prospective cohort study

There are few studies on predictive validity of methods to monitor the healing process of pressure ulcers. We evaluated whether the change of DESIGN‐R (rating) score could predict subsequent healing, and determined the optimal cutoff points. In a multicenter prospective cohort study, patients were followed until wound healing or censoring. Wound severity was evaluated by the DESIGN‐R tool every week, and the score change was calculated over 1–4 weeks (n = 411, 286, 224, and 170, respectively). In the multivariate analyses stratified by depth, a one‐point improvement in DESIGN‐R score over any period was positively associated with healing within the next 30 days independent of initial wound severity (hazard ratios over each 1–4 weeks ranging from 1.16 to 1.33 for superficial ulcers and from 1.21 to 1.27 for deep ulcers; all p < 0.05). The optimal cutoff points over 1–4 weeks were set as negative change for superficial ulcers and as positive change of ≥two points for deep ulcers. Nonhealing rate was higher for ulcers with DESIGN‐R score change below the cutoff points than that aforementioned for both depths. Weekly monitoring by the DESIGN‐R tool will be advantageous for evaluating prognosis of pressure ulcers independent of initial wound severity and depth.     

A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior

A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP⁺) and show that specific ablation or silencing of AAV-NpyP⁺ SDH interneurons converted touch-sensing Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP⁺ neurons received excitatory inputs from Aβ fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP⁺ neurons exhibited deeper resting membrane potentials, and their excitation by Aβ fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP⁺ neurons in nerve-injured rats reversed Aβ fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing Aβ fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.

Damage to the nervous system by cancer, diabetes, chemotherapy, infection, or traumatic injury causes neuropathic pain, a highly debilitating chronic pain condition (1). A cardinal symptom of neuropathic pain is mechanical allodynia, pain that is produced by innocuous mechanical stimulus, such as light touch. The mechanisms underlying mechanical allodynia are poorly understood. Currently available treatments including opioids are largely ineffective.Light mechanical information from the skin is conveyed to the spinal dorsal horn (SDH) via primary afferent low-threshold mechanoreceptors (LTMRs), such as Aβ fibers. These LTMRs are considered to mediate mechanical allodynia (2–7). A major question is where and how touch signals are pathologically converted to pain in the context of nerve damage. One potential region could be the SDH where Aβ fibers and nociceptors interact through interneurons (6, 8–10), as depicted in the gate control theory of pain (11). Over the last 5 y, studies using multiple lines of transgenic mice have identified several subsets of excitatory and inhibitory interneurons in the SDH that are genetically defined (12–18) and shown that these subsets are involved in peripheral nerve injury (PNI)-induced mechanical hypersensitivity (assessed using von Frey filaments). However, the behavioral hypersensitivity by these filaments involves activation not only of LTMRs but also of nociceptors (19–24) and is effectively suppressed by treatment with morphine (18, 25). Thus, the mechanisms underlying LTMR-derived and morphine-resistant neuropathic allodynia are still poorly understood.Using a transgenic rat line W-TChR2V4 in which channelrhodopsin-2 (ChR2) was expressed at nerve endings associated with Merkel cells and lamellar cells to form Meissner’s corpuscle-like structures in the skin (26), we recently reported that following PNI, stimulation of touch-sensing Aβ fibers by illuminating the rats with blue light elicited morphine-resistant mechanical allodynia-like responses (27). Furthermore, Aβ fiber stimulation after PNI causes activation of lamina I neurons, which are normally silent in response to this stimulation. This raises the possibility that alterations in SDH circuits after PNI underscore the conversion of Aβ fiber-derived signals to morphine-resistant pain, but the underlying mechanisms remain to be determined. Considering previous findings (6, 8–11), a possible mechanism for the conversion might involve a loss or reduction of the activity of inhibitory interneurons in the SDH. A single-cell RNA sequencing study has shown that SDH inhibitory interneurons are genetically divided into over 10 subsets, some of which express mRNA encoding neuropeptide Y (NPY) (28). In immunohistochemistry, NPY has been shown to be expressed in inhibitory interneurons (29, 30). Furthermore, previous studies have demonstrated that spinal NPY has inhibitory effects on chronic pain, including PNI-induced mechanical hypersensitivity (31, 32). Thus, to identify a subset of inhibitory SDH interneurons that contributes to the behavioral symptom evoked by optical stimulation of the primary afferent Aβ fibers in the W-TChR2V4 rats after PNI, we focused on the role of inhibitory SDH interneurons operated by an adeno-associated viral (AAV) vector including a Npy promoter (AAV-NpyP). Using the optogenetic approach for neuropathic allodynia (27) combined with chemogenetics, electrophysiology, and transsynaptic tracing, this study reveals that diminished inhibitory tone of these SDH neurons operated by AAV-NpyP contributes to Aβ fiber-derived neuropathic pain-like behavioral responses. Our findings suggest that this subset of neurons could be a therapeutic target for treating neuropathic mechanical allodynia.