Complete Resolution of a Case of TAFRO Syndrome Accompanied by Mediastinal Panniculitis, Adrenal Lesion, and Liver Damage with Hyperbilirubinemia.

TAFRO syndrome is a systemic inflammatory, lymphoproliferative disorder, but the pathophysiology of the disease is unknown. It is typically characterized by thrombocytopenia, anasarca, a fever, reticulin fibrosis, renal dysfunction, and organomegaly. However, other manifestations have been also reported. We encountered a 43-year-old man with TAFRO syndrome who showed mediastinal panniculitis, liver damage, and adrenal lesions in addition to the core signs. He achieved complete remission with combination therapy of corticosteroids, tocilizumab, and cyclosporin, and remission was maintained even after drug discontinuation at 15 months. Atypical manifestations and complete remission of TAFRO syndrome were remarkable features of our case.

Plasma Level of von Willebrand Factor Propeptide at Diagnosis: A Marker of Subsequent Renal Dysfunction in Autoimmune Rheumatic Diseases.

INTRODUCTION: Patients with systemic autoimmune rheumatic diseases (SARDs) such as rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjögren syndrome, and systemic sclerosis, which are chronic inflammatory diseases, are prone to develop renal dysfunction, which is related to vascular endothelial cell damage. MATERIAL AND METHODS: We evaluated plasma levels of von Willebrand factor (VWF), VWF propeptide (VWF-pp), disintegrin-like and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and VWF multimer pattern in patients with SARDs at diagnosis and investigated whether they may serve as markers to identify patients destined to develop renal dysfunction within 1 year. Renal dysfunction was defined as subsequent reduced estimated glomerular filtration rate (eGFR) by >25% or the new appearance of abnormal urine findings such as proteinuria (protein > 30 mg/dL) or hematuria (red blood cells >20/HPF in urine sediments). Overall, 63 patients with SARDs were studied. RESULTS AND CONCLUSIONS: We observed a significant increase of VWF-pp and a significant decrease of ADAMTS13 in patients with SARDs compared with normal healthy controls. The highest level of VWF-pp was observed in patients with SLE among the groups. The levels of VWF and multimer pattern of VWF were not different compared with normal healthy controls. Von Willebrand factor propeptide predicted a subsequent decrease in eGFR at a cutoff point of 210% (sensitivity, 78.6%; specificity, 73.5%) and new urinary abnormal findings at a cutoff point of 232% (sensitivity, 77.8%; specificity, 77.8%) Using these cutoff points, multivariable analysis revealed that VWF-pp was a significant risk factor for renal dysfunction at an odds ratio of 8.78 and 22.8, respectively, and may lead to a new therapeutic approach to prevent vasculitis and renal dysfunction.

A Case of Idiopathic Orbital Inflammation with Shallow Anterior Chamber and Choroidal Detachment.

We report a case of idiopathic orbital inflammation with a shallow anterior chamber and choroidal detachments. This study involved an 87-year-old female patient who presented at our department after becoming aware of the progression of diplopia. Examination of the patient's right eye revealed proptosis, as well as conjunctival edema with dilated and tortuous blood vessels. The right-eye anterior chamber was shallow, and fundus examination revealed marked choroidal detachments. Magnetic resonance imaging revealed enlargement of the right-orbit extraocular muscles and a suspected compression of the right-orbit superior and inferior ophthalmic veins, yet no expansion of the cavernous sinus. We diagnosed the patient as having idiopathic orbital inflammation in her right orbit, and subsequently started corticosteroid therapy. One week after initiating treatment, the anterior chamber was found to be nearing a normal depth, and the choroidal detachments were found to have disappeared. Our findings revealed that the inflammatory swelling of the extraocular muscle due to idiopathic orbital inflammation resulted in compression of the right-orbit superior and inferior ophthalmic veins, thus leading to an apparent choroidal circulation disorder that presented with a shallow anterior chamber and marked choroidal detachments.

Spontaneous disappearance and recurrence of impending macular hole: a case report.

BACKGROUND: There have been several reports of spontaneous closure and reopening of a macular hole, however, in most of those cases, it was observed in eyes post vitrectomy. Here, we report a case of multiple episodes of spontaneous disappearance and recurrence of impending macular hole (stage 1B macular hole) with no history of previous surgery. CASE PRESENTATION: A 76-year-old Japanese man presented with a primary complaint of reduced visual acuity in his right eye. On initial examination, the visual acuity in his right and left eye was 0.4 and 0.01, respectively. He had previously been diagnosed as having macular degeneration of unknown origin in his left eye. Optical coherence tomography imaging confirmed vitreomacular traction and impending macular hole in his right eye. After a 1-week follow-up period, posterior vitreous detachment was detected, and the impending macular hole appeared to be resolved. Two months later, the impending macular hole had completely disappeared and his visual acuity had improved to 0.9. Six months later, he again noticed decreased vision in his right eye. An examination revealed that his visual acuity had dropped to 0.4, and there was a recurrence of impending macular hole. An optical coherence tomography examination showed no definitive findings of vitreous traction, and, 1 month later, spontaneous disappearance was observed again and his visual acuity improved to 0.7. CONCLUSIONS: In this case, both the initial onset and the recurrence involved impending macular hole, however, the optical coherence tomography findings differed at each examination. These findings suggest that some causes other than vitreous traction were responsible for both the spontaneous disappearance and recurrence of the impending macular hole in this present case.

Importance Of Laboratory Detection Of Macro-Aspartate Aminotransferase.

The macroenzyme form of aspartate aminotransferase (macro-AST) is formed by the binding of AST with immunoglobulins. Macro-AST excretion from serum is prolonged because of its high molecular weight, leading to increased AST activities. Because of the difficulty in detecting macro-AST through routine laboratory tests, affected patients often undergo repeated examinations, with associated anxiety. We report a case in which macro-AST was detected by assaying the patient's serum after refrigeration at 4ºC for 3 days. The sample showed progressive loss of AST activity compared with that frozen in the refrigerator, indicating the presence of macro-AST, which was confirmed as a complex with IgG-κ. The cold storage method was validated using many samples obtained from several patients. Use of this simple method to detect macro-AST may avoid unnecessary examinations and patient anxiety even at primary care facilities.

A Case of a Newborn with Agenesis of the Corpus Callosum Complicated with Ocular Albinism.

PURPOSE: To report a case of ocular albinism found in a newborn infant in whom agenesis of the corpus callosum (ACC) was indicated in utero. CASE REPORT: This study involved a female newborn who was delivered after a gestational period of 41 weeks. The patient was referred to the Obstetrics Department at Takatsuki Hospital, Takatsuki City, Japan, after the indication of ACC by magnetic resonance imaging (MRI) at a nearby clinic during the fetal period. At birth, the baby's weight was 2,590 g, and ACC and ventricular enlargement were found by cranial sonography and cranial MRI. While initial ophthalmic findings noted partial loss of pigmentation of the iris and hypopigmentation of broad areas of the fundus in both eyes, nystagmus was not observed. The patient's hair pigment was slightly diluted, and the color of her skin was slightly off-white. At 2 years after birth, obvious mental retardation was observed. With regard to other systemic findings, no apparent heart, kidney, or immune system abnormalities were found. CONCLUSION: Although the patient in question is presently growing without any major systemic problems, it will be necessary in the future to pay attention to any changes in systemic and ophthalmic findings.

In vivo assessment of optical properties of basal cell carcinoma and differentiation of BCC subtypes by high-definition optical coherence tomography.

High-definition optical coherence tomography (HD-OCT) features of basal cell carcinoma (BCC) have recently been defined. We assessed in vivo optical properties (IV-OP) of BCC, by HD-OCT. Moreover their critical values for BCC subtype differentiation were determined. The technique of semi-log plot whereby an exponential function becomes linear has been implemented on HD-OCT signals. The relative attenuation factor (µraf ) at different skin layers could be assessed.. IV-OP of superficial BCC with high diagnostic accuracy (DA) and high negative predictive values (NPV) were (i) decreased µraf in lower part of epidermis and (ii) increased epidermal thickness (E-T). IV-OP of nodular BCC with good to high DA and NPV were (i) less negative µraf in papillary dermis compared to normal adjacent skin and (ii) significantly decreased E-T and papillary dermal thickness (PD-T). In infiltrative BCC (i) high µraf in reticular dermis compared to normal adjacent skin and (ii) presence of peaks and falls in reticular dermis had good DA and high NPV. HD-OCT seems to enable the combination of in vivo morphological analysis of cellular and 3-D micro-architectural structures with IV-OP analysis of BCC. This permits BCC sub-differentiation with higher accuracy than in vivo HD-OCT analysis of morphology alone.

Validation of a diagnostic algorithm for the discrimination of actinic keratosis from normal skin and squamous cell carcinoma by means of high-definition optical coherence tomography.

Actinic keratoses (AKs) commonly arise on sun-damaged skin. Visible lesions are often associated with subclinical lesions on surrounding skin, giving rise to field cancerization. To avoid multiple biopsies to diagnose subclinical/early invasive lesions, there is an increasing interest in non-invasive diagnostic tools, such as high-definition optical coherence tomography (HD-OCT). We previously developed a HD-OCT-based diagnostic algorithm for the discrimination of AK from squamous cell carcinoma (SCC) and normal skin. The aim of this study was to test the applicability of HD-OCT for non-invasive discrimination of AK from SCC and normal skin using this algorithm. Three-dimensional (3D) HD-OCT images of histopathologically proven AKs and SCCs and images of normal skin were collected. All images were shown in a random sequence to three independent observers with different experience in HD-OCT, blinded to the clinical and histopathological data and with different experience with HD-OCT. Observers classified each image as AK, SCC or normal skin based on the diagnostic algorithm. A total of 106 (38 AKs, 16 SCCs and 52 normal skin sites) HD-OCT images from 71 patients were included. Sensitivity and specificity for the most experienced observer were 81.6% and 92.6% for AK diagnosis and 93.8% and 98.9% for SCC diagnosis. A moderate interobserver agreement was demonstrated. HD-OCT represents a promising technology for the non-invasive diagnosis of AKs. Thanks to its high potential in discriminating SCC from AK, HD-OCT could be used as a relevant tool for second-level examination, increasing diagnostic confidence and sparing patients unnecessary excisions.

Optical Coherence Tomography in an Infant with Walker-Warburg Syndrome.

PURPOSE: Walker-Warburg syndrome (WWS) is a type of congenital muscular dystrophy (CMD) characterised by severe brain malformation, lissencephaly, and congenital eye abnormalities. Despite the coexistence of various eye abnormalities, results from optical coherence tomography (OCT) in WWS have not previously been reported. We herein report specific OCT findings in an infant with WWS. PATIENTS AND METHODS: The patient was a 14-day-old boy delivered by caesarean section at 38 weeks and 4 days of gestation and with a birth weight of 2,543 g. A cranial MRI showed lissencephaly, hydrocephalus, an encephalocele, and cerebellar hypoplasia, consistent with the diagnosis of WWS. RESULTS: A bilateral ocular examination showed no abnormalities of the anterior eye segment. A fundus examination showed a persistent hyaloid artery in the vitreous cavity, a widespread loss of fundus pigmentation, transparent choroidal vessels (some choroidal vessel sections were visible), and the absence of a distinct macular reflex. OCT showed no foveal pit and an indistinct laminar structure of the retina. The infant subsequently developed congenital glaucoma and he then died of respiratory failure at the age of 8 months. CONCLUSIONS: WWS is associated with a high incidence of congenital eye abnormalities, and this infant showed findings consistent with WWS. OCT revealed a marked retinal dysplasia.

Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain.

Pregabalin is effective in treating many neuropathic pain conditions. However, the mechanisms of its analgesic effects remain poorly understood. The aim of the present study was to determine whether pregabalin suppresses facial mechanical hypersensitivity and evoked glutamate release in the medullary dorsal horn (MDH) in a rodent model of trigeminal neuropathic pain. Nociceptive mechanical sensitivity was assessed pre-operatively, and then post-operatively 1h following pregabalin or vehicle (saline) treatment on post-operative days 2 and 5 following infraorbital nerve transection (IONX). In addition, an in vivo microdialysis probe was inserted into the exposed medulla post-operatively and dialysate samples were collected. Glutamate release was then evoked by mustard oil (MO) application to the tooth pulp, and the effects of pregabalin or vehicle were examined on the MDH glutamate release. Glutamate concentrations in the dialysated samples were determined by HPLC, and data analyzed by ANOVA. IONX animals (but not control animals) showed facial mechanical hypersensitivity for several days post-operatively. In addition, tooth pulp stimulation with MO evoked a transient release of glutamate in the MDH of IONX animals. Compared to vehicle, administration of pregabalin significantly attenuated the facial mechanical hypersensitivity as well as the MO-evoked glutamate release in MDH. This study provides evidence in support of recent findings pointing to the usefulness of pregabalin in the treatment of orofacial neuropathic pain.

Involvement of AMPA receptor GluR2 and GluR3 trafficking in trigeminal spinal subnucleus caudalis and C1/C2 neurons in acute-facial inflammatory pain.

To evaluate the involvement of trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluR2 and GluR3 subunits in an acute inflammatory orofacial pain, we analyzed nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) and Fos expression in Vi/Vc, Vc and C1/C2 in GluR2 delta7 knock-in (KI), GluR3 delta7 KI mice and wild-type mice. We also studied Vc neuronal activity to address the hypothesis that trafficking of GluR2 and GluR3 subunits plays an important role in Vi/Vc, Vc and C1/C2 neuronal activity associated with orofacial inflammation in these mice. Late nocifensive behavior was significantly depressed in GluR2 delta7 KI and GluR3 delta7 KI mice. In addition, the number of pERK-immunoreactive (IR) cells was significantly decreased bilaterally in the Vi/Vc, Vc and C1/C2 in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice at 40 min after formalin injection, and was also significantly smaller in GluR3 delta7 KI compared to GluR2 delta7 KI mice. The number of Fos protein-IR cells in the ipsilateral Vi/Vc, Vc and C1/C2 was also significantly smaller in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice 40 min after formalin injection. Nociceptive neurons functionally identified as wide dynamic range neurons in the Vc, where pERK- and Fos protein-IR cell expression was prominent, showed significantly lower spontaneous activity in GluR2 delta7 KI and GluR3 delta7 KI mice than wild-type mice following formalin injection. These findings suggest that GluR2 and GluR3 trafficking is involved in the enhancement of Vi/Vc, Vc and C1/C2 nociceptive neuronal excitabilities at 16-60 min following formalin injection, resulting in orofacial inflammatory pain.

Involvement of peripheral ionotropic glutamate receptors in orofacial thermal hyperalgesia in rats.

BACKGROUND: The purpose of the present study was to elucidate the mechanisms that may underlie the sensitization of trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) neurons to heat or cold stimulation of the orofacial region following glutamate (Glu) injection. RESULTS: Glu application to the tongue or whisker pad skin caused an enhancement of head-withdrawal reflex and extracellular signal-regulated kinase (ERK) phosphorylation in Vc-C2 neurons. Head-withdrawal reflex and ERK phosphorylation were also enhanced following cold stimulation of the tongue but not whisker pad skin in Glu-injected rats, and the head-withdrawal reflex and ERK phosphorylation were enhanced following heat stimulation of the tongue or whisker pad skin. The enhanced head-withdrawal reflex and ERK phosphorylation after heat stimulation of the tongue or whisker pad skin, and those following cold stimulation of the tongue but not whisker pad skin were suppressed following ionotropic glutamate receptor antagonists administration into the tongue or whisker pad skin. Furthermore, intrathecal administration of MEK1/2 inhibitor PD98059 caused significant suppression of enhanced head-withdrawal reflex in Glu-injected rats, heat head-withdrawal reflex in the rats with Glu injection into the tongue or whisker pad skin and cold head-withdrawal reflex in the rats with Glu injection into the tongue. CONCLUSIONS: The present findings suggest that peripheral Glu receptor mechanisms may contribute to cold hyperalgesia in the tongue but not in the facial skin, and also contribute to heat hyperalgesia in the tongue and facial skin, and that the mitogen-activated protein kinase cascade in Vc-C2 neurons may be involved in these Glu-evoked hyperalgesic effects.

Involvement of GluR2 and GluR3 subunit C-termini in the trigeminal spinal subnucleus caudalis and C1-C2 neurons in trigeminal neuropathic pain.

To clarify the involvement of GluR2 and GluR3 subunits of AMPA receptor in orofacial neuropathic pain, we studied changes in nocifensive behavior and extracellular-signal regulated kinase (ERK) phosphorylation followed by infraorbital nerve (ION)-partial transection model applied to GluR2 or GluR3 delta7 knock-in (KI) mice. In these animals, last seven amino acids of GluR2 or GluR3 subunit, the binding sites of interacting protein, are deleted in vivo. Head-withdrawal threshold to mechanical stimulation of the whisker pad skin ipsilateral to ION-partial transection was significantly reduced at 1, 3, 5, 7, 11 and 14 days after transection compared with that before transection in wild-type mice. In the GluR2 and GluR3 delta7 KI mice, the head-withdrawal threshold did not change following ION-partial transection. The number of pERK-LI cells examined in Vc and C1-C2 in wild-type mice after the non-noxious stimulation was larger than that of GluR2 and GluR3 delta7 KI mice. The present findings suggest that GluR2 and GluR3 subunits of AMPA receptor play roles in the trigeminal nerve injury-mediated enhancement of Vc and C1-C2 neuronal excitability, and hyperalgesia.

Purinergic receptors are involved in tooth-pulp evoked nocifensive behavior and brainstem neuronal activity.

BACKGROUND: To evaluate whether P2X receptors are involved in responses to noxious pulp stimulation, the P2X3 and P2X2/3 receptor agonist α,ß-methyleneATP (α,ß-meATP) was applied to the molar tooth pulp and nocifensive behavior and extracellular-signal regulated kinase (ERK) phosphorylation in trigeminal spinal subnucleus caudalis (Vc), trigeminal spinal subnucleus interpolaris (Vi), upper cervical spinal cord (C1/C2) and paratrigeminal nucleus (Pa5) neurons were analyzed in rats. RESULTS: Genioglossus (GG) muscle activity was evoked by pulpal application of 100 mM α,ß-meATP and was significantly larger than GG activity following vehicle (phosphate-buffered saline PBS) application (p < 0.01). The enhanced GG muscle activity following 100 mM α,ß-meATP was significantly reduced (p < 0.05) by co-application of 1 mM TNP-ATP (P2X1, P2X3 and, P2X2/3 antagonist). A large number of pERK-LI cells were expressed in the Vc, Vi/Vc, C1/C2 and Pa5 at 5 min following pulpal application of 100 mM α,ß-meATP compared to PBS application to the pulp (p < 0.05). The pERK-LI cell expression and GG muscle activity induced by 100 mM α,ß-meATP pulpal application were significantly reduced after intrathecal injection of the MAPK/ERK kinase (MEK) inhibitor PD 98059 and by pulpal co-application of 1 mM TNP-ATP (p < 0.05). CONCLUSIONS: The present findings suggest that activation of P2X3 and P2X2/3 receptors in the tooth pulp is sufficient to elicit nociceptive behavioral responses and trigeminal brainstem neuronal activity.

Increased phosphorylation of extracellular signal-regulated kinase in trigeminal nociceptive neurons following propofol administration in rats.

UNLABELLED: Although propofol (PRO) is widely used in clinic as a hypnotic agent, the underlying mechanisms of its action on pain pathways is still unknown. Sprague-Dawley rats were assigned to receive PRO or pentobarbital (PEN) and were divided into 2 groups as LIGHT and DEEP hypnotic levels based on the EEG analysis. Rats in each hypnotic level received capsaicin injection into the face and phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry was performed in subnucleus caudalis (Vc) and upper cervical spinal cord. In the rats with PEN or PRO administration, a large number of pERK-like immunoreactive (LI) cells was observed in the trigeminal spinal subnuclei interpolaris and caudalis transition zone (Vi/Vc), middle Vc, and transition zone between Vc and upper cervical spinal cord (Vc/C2) following capsaicin injection into the whisker-pad region. The number of pERK-LI cells in Vi/Vc, middle Vc, and Vc/C2 was significantly larger in rats with PRO infusion than those with PEN infusion. The number of pERK-LI cells was increased following an increase in the dose of PRO but not in PEN. The pERK-LI cells were mainly distributed in the Vi/Vc, middle Vc, and Vc/C2 after the bolus infusion of PRO. The expression of pERK-LI cells was depressed after the intravenous lidocaine application before bolus PRO infusion. The present findings suggest that PRO induced an enhancement of the activity of trigeminal nociceptive pathways through nociceptors innervating the venous structure, as indicated by a lidocaine-sensitive increase in pERK. This may explain deep pain around the injection regions during intravenous bolus infusion of PRO. PERSPECTIVE: The effect of propofol administration on ERK phosphorylation in the subregions of the spinal trigeminal complex and upper cervical spinal cord neurons were precisely analyzed in rats with PRO infusion. A large number of pERK-LI cells was observed following intravenous PRO administration, suggesting an enhancement of trigeminal nociceptive activity and that PRO may produce pain through nociceptors innervating the venous structures during infusion.