CDDO regulates central and peripheral sensitization to attenuate post-herpetic neuralgia by targeting TRPV1/PKC-δ/p-Akt signals.

Postherpetic neuralgia (PHN) is a notorious neuropathic pain featuring persistent profound mechanical hyperalgesia with significant negative impact on patients' life quality. CDDO can regulate inflammatory response and programmed cell death. Its derivative also protects neurons from damages by modulating microglia activities. As a consequence of central and peripheral sensitization, applying neural blocks may benefit to minimize the risk of PHN. This study aimed to explore whether CDDO could generate analgesic action in a PHN-rats' model. The behavioural test was determined by calibrated forceps testing. The number of apoptotic neurons and degree of glial cell reaction were assessed by immunofluorescence assay. Activation of PKC-δ and the phosphorylation of Akt were measured by western blots. CDDO improved PHN by decreasing TRPV1-positive nociceptive neurons, the apoptotic neurons, and reversed glial cell reaction in adult rats. It also suppressed the enhanced PKC-δ and p-Akt signalling in the sciatic nerve, dorsal root ganglia (DRG) and spinal dorsal horn. Our research is the promising report demonstrating the analgesic and neuroprotective action of CDDO in a PHN-rat's model by regulating central and peripheral sensitization targeting TRPV1, PKC-δ and p-Akt. It also is the first study to elucidate the role of oligodendrocyte in PHN.

Linalyl Acetate Ameliorates Mechanical Hyperalgesia Through Suppressing Inflammation by TSLP/IL-33 Signaling.

Neuropathic pain is a debilitating chronic disorder, significantly causing personal and social burdens, in which activated neuroinflammation is one major contributor. Thymic stromal lymphopoietin (TSLP) and interleukin (IL)-33 is important for chronic inflammation. Linalyl acetate (LA) is main component of lavender oil with an anti-inflammatory property through TSLP signaling. The aim of the study is to investigate how LA regulates mechanical hyperalgesia after sciatic nerve injury (SNI). Adult Sprague-Dawley male rats were separated into 3 groups: control group, SNI group and SNI with LA group. LA was administrated intraperitoneally one day before SNI. Pain behavior test was evaluated through calibration forceps testing. Ipsilateral sciatic nerves (SNs), dorsal root ganglions (DRGs) and spinal cord were collected for immunofluorescence staining and Western blotting analyses. SNI rats were more sensitive to hyperalgesia response to mechanical stimulus since operation, which was accompanied by spinal cord glial cells reactions and DRG neuro-glial interaction. LA could relieve the pain sensation, proinflammatory cytokines and decrease the expression of TSLP/TSLPR complex. Also, LA could reduce inflammation through reducing IL-33 signaling. This study is the first to indicate that LA can modulate pain through TSLP/TSLPR and IL-33 signaling after nerve injury.

Impact of seborrheic dermatitis on osteoporosis risk: A population-based cohort study.

Osteoporosis is a systemic bone-resorbing disease that easily causes subsequent risk of fracture. Hence, the substantial physical burden of osteoporosis makes it an important public health issue. Seborrheic dermatitis (SD) is a chronic, recurrent, inflammatory skin disease. Despite the advances in medication for treating osteoporosis, identifying undiagnosed osteoporosis patients is still challenging. Since osteoporosis and SD share a similar pathobiology, e.g. inflammation and hormonal imbalance, we aimed to investigate whether the existence of SD increases osteoporosis risk by using the Taiwan National Health Insurance Research Database. A total of 7831 patients aged 18-50 years with SD and a control group of 31 324 patients without SD matched by age, gender, Charlson Comorbidity Index, and index date at a ratio of 1:4 during 1996-2010 were recruited in the study. To measure the cumulative incidence and compare the hazard ratios of osteoporosis between each group, the Kaplan-Meier method and Cox proportional hazard regression models were utilized. It was found that 0.98% of SD patients had osteoporosis. Compared to the non-SD group, the SD group had a 5.95-fold higher osteoporosis risk after adjustment for variables. The impact of SD on osteoporosis risk was largest in the female and young age groups. In addition, the presence of hyperlipidemia, hyperthyroidism, and epilepsy synergistically increased osteoporosis incidence in the SD group. This first large cohort study demonstrated an association between SD and osteoporosis. Since the effect on bone health in SD patients with concomitant diseases is largest in early life, diet or lifestyle recommendations as well as regular bone examinations are advised during follow-up of SD.

Direct End-to-End Neurorrhaphy for Wrist-Level Long Nerve Defect with Fixation of the Wrist in Flexion: Technique Note.

Background For a nerve gap, end-to-end neurorrhaphy would either be difficult or would include tension. The use of a nerve graft or conduit could be a solution, but it might compromise the reinnervation. We describe a method for wrist-level ulnar and/or median long nerve injury by fixing the wrist in the flexion position with K-wire (s) to make possible an end-to-end and tension-free neurorrhaphy. Patients and Methods Two patients had wrist-level ulnar nerve injury for 2 and 3 months and nerve gaps of 2.5 cm and 3.5 cm, respectively, after the neuroma excision. K-wires were used to transfix from the radius to carpal bones, in order to keep their wrists in flexion of 45 and 65 degrees, respectively, with which the tension-free end-to-end neurorrhaphy could be achieved. The K-wires were removed in 6 weeks after surgery, and their wrists were kept in the splint for a progressive extension program. Results Both patients were noted to have an improved claw hand deformity 4 months after the surgery. The ulnar nerve motor and sensory function could be recovered mostly in the 12-month follow-up. The wrist flexion and extension motion arc both achieved, at least, 150 degree in the 12-month follow-up. There were no complications related to the K-wire fixation. Conclusion With the wrist fixed in a flexed position, maintaining a longer nerve gap to achieve a direct end-to-end and tension-free neurorrhaphy would be more likely and safer. Without the use of nerve graft, innervation of the injured nerve would be faster.

The Contribution of TSLP Activation to Hyperalgesia in Dorsal Root Ganglia Neurons of a Rat.

Peripheral nerve injury involves divergent alterations within dorsal root ganglia (DRG) neurons sensitized by persistent inflammation. Thymic stromal lymphopoietin (TSLP) production is crucial in the development of chronic inflammatory responses. Herein, we investigate the changes of TSLP expression in rats' DRG neurons between injured and uninjured sides in the same rat. Linalyl acetate (LA) was served as a TSLP inhibitor and given intraperitoneally. Rats were assigned to be group of chronic constriction injury (CCI) of the sciatic nerve and the group of CCI of the sciatic nerve administrated with LA. Over 14 days, the rats were measured for paw withdrawal thresholds. DRGs were collected to assess morphological changes via immunofluorescence study. After receiving CCI, the rats rapidly developed mechanical hyperalgesia. TSLP expression at DRG, on the ipsilateral injured side, was consistent with changes in pain behaviors. TSLP appeared in nerve fibers with both small diameters and large diameters. Additionally, TSLP was expressed mostly in transient receptor potential vanilloid-1 (TRPV1)-positive nociceptive neurons. Administration with LA can attenuate the pain behaviors and expression of TSLP in DRG neurons, and in apoptotic neurons at the injured side, but not in the contra-lateral uninjured side. Overall, these results imply that altered expressions of TSLP in nociceptive DRG neurons contributed to mechanical hyperalgesia in a CCI rat model.

Migraines and keloids: a 15-year Taiwan claim database analysis.

BACKGROUND: Fibroproliferative lesions with intractable pruritus, pain and hyperesthesia that cause uncontrolled scar growth are known as keloids. Migraines are common upsetting headache disorders characterised by frequent recurrence and attacks aggravated by physical activity. Both keloids and migraines can cause physical exhaustion and discomfort in patients; they have similar pathophysiological pathways, that is, the transforming growth factor-ß1 gene and neurogenic inflammation. OBJECTIVE: To investigate subsequent development of migraines in patients with keloids. Methods Data were retrieved from the Taiwan National Health Insurance Research Database. The keloids group included patients aged 20 years and older with a recent diagnosis of keloids(n=9864). The non-keloids group included patients without keloids matched for gender and age at 1-4 ratio (n=39 456). Migraine risk between groups was measured by Cox proportional hazards regression models. Incidence rates and hazard ratios were calculated. RESULTS: During the study period, 103 keloids patients and 323 non-keloids patients developed migraines. The keloids patients had a 2.29-fold greater risk of developing migraines compared with the non-keloids group after adjustment for covariates (1.81 vs 0.55 per 1000 person-years, respectively). In the keloids group, female or patients younger than 50 years were prone to developing migraines. CONCLUSION: The higher tendency to develop migraines in the keloids group in comparison with the non-keloids group suggests that keloids could be a predisposing risk factor for migraine development in adults. Keloids patients who complain of headaches should be examined for migraines.

Increased Expression of Thymic Stromal Lymphopoietin in Chronic Constriction Injury of Rat Nerve.

Thymic stromal lymphopoietin (TSLP) is a well-known cytokine for T helper 2 inflammatory responses. A nerve injury activates the neuroinflammation cascade and neuron-glia interaction in dorsal root ganglions (DRG)s, leading to neuropathic pain. Therefore, this study was to investigate the role of TSLP after nerve injury. Male Sprague-Dawley rats were divided as an experimental group with chronic constriction injury (CCI) to the sciatic nerve and a control group. The mechanical pain threshold response was determined by calibration forceps. After assessment of mechanical allodynia, the ipsilateral spinal cord, DRG, sciatic nerve and skin were harvested. Immunofluorescence staining was performed to identify cell types with various markers. Western blot analyses were performed to evaluate protein expressions. Mechanical allodynia developed after CCI and persisted for the next 14 days. Astrocyte reactions occurred and continued until day 14, too. After CCI, DRG and the sciatic nerve also had significantly increased expressions of TSLP/TSLP-R/STAT5. The TSLPR was localized to sensory neuronal endings innervating the skin. This study is the first to demonstrate that the TSLP complex and the STAT5 pathway in nerve are potential therapeutic targets because of their roles in pain regulation after nerve injury.

Impact of Hepatoma-Derived Growth Factor Blockade on Resiniferatoxin-Induced Neuropathy.

Resiniferatoxin is an ultrapotent capsaicin analog that mediates nociceptive processing; treatment with resiniferatoxin can cause an inflammatory response and, ultimately, neuropathic pain. Hepatoma-derived growth factor, a growth factor related to normal development, is associated with neurotransmitters surrounding neurons and glial cells. Therefore, the study aims to investigate how blocking hepatoma-derived growth factor affects the inflammatory response in neuropathic pain. Serum hepatoma-derived growth factor protein expression was measured via ELISA. Resiniferatoxin was administrated intraperitoneally to induce neuropathic pain in 36 male Sprague-Dawley rats which were divided into three groups (resiniferatoxin+recombinant hepatoma-derived growth factor antibody group, resiniferatoxin group, and control group) (n = 12/group). The mechanical threshold response was tested with calibration forceps. Cell apoptosis was measured by TUNEL assay. Immunofluorescence staining was performed to detect apoptosis of neuron cells and proliferation of astrocytes in the spinal cord dorsal horn. RT-PCR technique and western blot were used to measure detect inflammatory factors and protein expressions. Serum hepatoma-derived growth factor protein expression was higher in the patients with sciatica compared to controls. In resiniferatoxin-group rats, protein expression of hepatoma-derived growth factor was higher than controls. Blocking hepatoma-derived growth factor improved the mechanical threshold response in rats. In dorsal root ganglion, blocking hepatoma-derived growth factor inhibited inflammatory cytokines. In the spinal cord dorsal horn, blocking hepatoma-derived growth factor inhibited proliferation of astrocyte, apoptosis of neuron cells, and attenuated expressions of pain-associated proteins. The experiment showed that blocking hepatoma-derived growth factor can prevent neuropathic pain and may be a useful alternative to conventional analgesics.

The association between keloid and osteoporosis: real-world evidence.

BACKGROUND: Keloids are characterized by disturbance of fibroblast proliferation and apoptosis, deposition of collagen, and upregulation of dermal inflammation cells. This benign dermal fibro-proliferative scarring condition is a recognized skin inflammation disorder. Chronic inflammation is a well-known contributor to bone loss and its sequelae, osteoporosis. They both shared a similar pathogenesis through chronic inflammation. We assessed whether keloids increase osteoporosis risk through using National Health Insurance Research Database. METHODS: The 42,985 enrolled patients included 8597 patients with keloids but no history of osteoporosis; 34,388 controls without keloids were identified from the general population and matched at a one-to-four ratio by age, gender. Kaplan-Meier method was applied to determine cumulative incidence of osteoporosis. Cox proportional hazard regression analysis was performed after adjustment of covariates to estimate the effect of keloids on osteoporosis risk. RESULTS: Of the 8597 patients with keloids, 178 (2.07%) patients were diagnosed with osteoporosis while in the 34,388 controls, 587 (1.71%) were diagnosed with osteoporosis. That is, the keloids patients had 2.64-fold higher risk of osteoporosis compared to controls after adjustment for age, gender, Charlson Comorbidity Index and related comorbidities. The association between keloids and osteoporosis was strongest in patients younger than 50 years (hazard ratio = 7.06%) and in patients without comorbidities (hazard ratio = 4.98%). In the keloids patients, a high incidence of osteoporosis was also associated with advanced age, high Charlson Comorbidity Index score, hyperlipidemia, chronic liver disease, stroke, and depression. CONCLUSIONS: Osteoporosis risk was higher in patients with keloids compared to controls, especially in young subjects and subjects without comorbidities.

Keloid risk in patients with atopic dermatitis: a nationwide retrospective cohort study in Taiwan.

OBJECTIVE: The pathogenesis of keloid is largely unknown. Because keloid and atopic dermatitis have overlapping pathophysiological mechanisms, we aimed to evaluate keloid risk in patients with atopic dermatitis. STUDY DESIGN: Population-based retrospective cohort study. SETTING: The Taiwan National Health Insurance Research Database was used to analyse data for people who had been diagnosed with atopic dermatitis. PARTICIPANTS: We identified 8371 patients with newly diagnosed atopic dermatitis during 1996-2010. An additional 33 484 controls without atopic dermatitis were randomly identified and frequency matched at a one-to-four ratio. PRIMARY AND SECONDARY OUTCOME MEASURE: The association between atopic dermatitis and keloid risk was estimated using Cox proportional hazard regression models. RESULTS: After adjustment for covariates, the atopic dermatitis patients have a 3.19-fold greater risk of developing keloid compared with the non-atopic dermatitis group (3.19vs1.07 per 1000 person-years, respectively). During the study period, 163 patients with atopic dermatitis and 532 patients without atopic dermatitis developed keloid. Notably, keloid risk increased with severity of atopic dermatitis, particularly in patients with moderate to severe atopic dermatitis. CONCLUSIONS: Our results indicate that patients with atopic dermatitis had a higher than normal risk of developing keloid and suggest that atopic dermatitis may be an independent risk factor for keloid.

Hyperpigmentation as a peculiar presentation of mycosis fungoides.

Hyperpigmented mycosis fungoides is an extremely rare subtype of mycosis fungoides. It presents as multiple pigmented macules and patches without poikilodermatous changes and characterized by a CD8+ phenotype on immunohistochemistry. This report describes a typical case of hyperpigmented mycosis fungoides in a 62-year-old woman, who presented with a 7-year history of multiple hyperpigmented macules and patches on the trunk and right leg with progression over this half a year. Histology and immunohistochemical staining of skin samples confirmed the diagnosis of mycosis fungoides. She received psoralen plus ultraviolet A (PUVA) therapy. After an 8-week treatment, the erythematous changes cleared without recurrence during a 6-month follow-up period. An intractable hyperpigmented patch should raise the clinical suspicion of mycosis fungoides with sequential skin biopsy.

Osteoporosis in adult patients with atopic dermatitis: A nationwide population-based study.

The aim of this study was to investigate osteoporosis risk in atopic dermatitis (AD) patients. This study included patients in the Taiwan National Health Insurance Research dataset. The population-based study included all patients aged 20-49 years who had been diagnosed with AD during 1996-2010. In total, 35,229 age and gender-matched patients without AD in a 1:1 ratio were randomly selected as the non-AD group. Cox proportional-hazards regression and Kaplan-Meier analyses were used to measure the hazard ratios and the cumulative incidences of osteoporosis, respectively. During the follow-up period, 360(1.02%) AD patients and 127(0.36%) non-AD patients developed osteoporosis. The overall incidence of osteoporosis was4.72-fold greater in the AD patients compared to the non-AD patients (1.82 vs. 0.24 per 1,000 person-years, respectively) after adjusting for potential confounding factors. Osteoporosis risk factors included female gender, age, advanced Charlson Comorbidity Index, depression and use of corticosteroids. The dataset analysis showed that AD was significantly associated with subsequent risk of osteoporosis.

Hyperpigmentation as a peculiar presentation of mycosis fungoides

Abstract Hyperpigmented mycosis fungoides is an extremely rare subtype of mycosis fungoides. It presents as multiple pigmented macules and patches without poikilodermatous changes and characterized by a CD8+ phenotype on immunohistochemistry. This report describes a typical case of hyperpigmented mycosis fungoides in a 62-year-old woman, who presented with a 7-year history of multiple hyperpigmented macules and patches on the trunk and right leg with progression over this half a year. Histology and immunohistochemical staining of skin samples confirmed the diagnosis of mycosis fungoides. She received psoralen plus ultraviolet A (PUVA) therapy. After an 8-week treatment, the erythematous changes cleared without recurrence during a 6-month follow-up period. An intractable hyperpigmented patch should raise the clinical suspicion of mycosis fungoides with sequential skin biopsy.

Familial angiokeratoma corporis diffusum without identified enzyme defect.

Angiokeratoma corporis diffusum is the cutaneous hallmark of several rare inherited lysosomal diseases associated with specific enzyme deficiencies in the metabolism of glycoproteins, most notably Fabry disease. These defects result in many systemic manifestations. Here, we report a rare familial case of angiokeratoma corporis diffusum that developed at puberty with no major systemic manifestations and no underlying enzyme defect or gene mutation. Familial angiokeratoma corporis diffusum without identified enzyme defect appears to be a distinct clinical entity with a benign course.