Treatment of Vernal Keratoconjunctivitis Using Upadacitinib.

This case report presents a case of improvement of vernal keratoconjunctivitis associated with initiation of an oral Janus kinase inhibitor upadacitinib.

Staphylococcus aureus-derived virulent phenol-soluble modulin α triggers alarmin release to drive IL-36-dependent corneal inflammation.

Methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients with keratitis produces substantial amounts of phenol-soluble modulin α (PSMα). However, the role of PSMα in S. aureus keratitis remains unclear. We observed that PSMα-producing and PSMα-deficient strains could infect the cornea in our experimental mouse keratitis model; however, only the PSMα-producing strain delayed epithelial wound healing and induced stromal inflammation. PSMα induced damage to the epithelium, the release of alarmins IL-1α and IL-36α, and the expression of inflammatory chemokines by resident corneal cells in the mouse corneal organ culture. The IL-36 (but not IL-1) receptor antagonist attenuated mouse keratitis induced by PSMα-containing bacterial culture supernatants, as well as by infection with PSMα-producing S. aureus, suggesting that the corneal inflammations were dependent on IL-36. Recombinant PSMα elicited IL-36-dependent corneal inflammation in mice. Thus, PSMα and the subsequently released IL-36 are critical factors triggering inflammation during S. aureus keratitis.

Single-Nucleotide Polymorphisms of the PAR2 and IL-17A Genes Are Significantly Associated with Chronic Pain.

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.

Clinical Application of Inferior Alveolar Nerve Block Device for Safe and Secure IANB by Any Operator.

The inferior alveolar nerve block (IANB) is an established technique with a success rate of 60-80%; however, large errors have been reported among operators. Some dentists do not prefer to use IANB because of the risk of complications. Nevertheless, it is a useful technique for pain control, and a secure IANB offers significant benefits to operators and patients. This case series study aimed to investigate the efficacy of the "IANB Device," a nerve block guide for IANB, and the adverse events associated with its use in clinical practice. IANB was performed using the device on five patients who had undergone detailed computed tomography examination for chronic orofacial pain in the third division of the trigeminal nerve. Lidocaine 1% (1 mL, no adrenaline added) was used as the local anesthetic. IANB was performed by three dentists with 2, 5, and 11 years of experience in orofacial pain treatment. Thus, the data were collected in triplicate for each patient. The primary endpoints were whether adjustment of the IANB device was required, changes in the sensation threshold of the lower lip, the time to disappearance of pain, the presence or absence of tongue sensation ("Do you have numbness in your tongue?": "Yes/No"), and discomfort (visual analog scale). The incidence of any other adverse events was recorded. The procedure was judged to be successful if the pain disappeared and an elevation in the sensation threshold of the lower lip was observed. Adjustment of the IANB device was not required in any patient. A significant elevation in the sensation threshold of the lower lip and the disappearance of pain were observed in all patients. Three of the five patients reported experiencing tongue numbness. Discomfort with the use of the IANB device was less than 30 mm on the visual analog scale. No notable complications were observed. The appropriate type, concentration, and dosage of the local anesthetic must be considered during general dental treatment and oral surgical procedures. Our findings suggest that the IANB device is useful for eliminating errors between operators, enhancing safety, and improving the success rate.

The rs216009 single-nucleotide polymorphism of the CACNA1C gene is associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.

Improvement in persistent idiopathic facial pain with comorbid ADHD using the combination of a dopamine system stabilizer and psychostimulant: A case report.

Key Clinical Message: Persistent idiopathic facial pain (PIFP) and attention-deficit/hyperactivity disorder (ADHD) may coexist and can be improved with ADHD medications. Thus, clinicians should screen for ADHD by a multidisciplinary approach when treating PIFP and differentiate between other odontogenic disorders. Abstract: We report a case of a woman with persistent idiopathic facial pain (PIFP) and attention-deficit/hyperactivity disorder (ADHD) that markedly improved with the administration of a combination of aripiprazole (APZ) and methylphenidate (MP) treatment. Screening for ADHD and administration of APZ and/or MP may be considered in treating PIFP.

Effects of Myostatin on Nuclear Morphology at the Myotendinous Junction.

Myostatin (Myo) is known to suppress skeletal muscle growth, and was recently reported to control tendon homeostasis. The purpose of the present study was to investigate the regulatory involvement of Myo in the myotendinous junction (MTJ) in vivo and in vitro. After Achilles tendon injury in mice, we identified unexpected cell accumulation on the tendon side of the MTJ. At postoperative day 7 (POD7), the nuclei had an egg-like profile, whereas at POD28 they were spindle-shaped. The aspect ratio of nuclei on the tendon side of the MTJ differed significantly between POD7 and POD28 (p = 4.67 × 10-34). We then investigated Myo expression in the injured Achilles tendon. At the MTJ, Myo expression was significantly increased at POD28 relative to POD7 (p = 0.0309). To investigate the action of Myo in vitro, we then prepared laminated sheets of myoblasts (C2C12) and fibroblasts (NIH3T3) (a pseudo MTJ model). Myo did not affect the expression of Pax7 and desmin (markers of muscle development), scleraxis and temonodulin (markers of tendon development), or Sox9 (a common marker of muscle and tendon development) in the cell sheets. However, Myo changed the nuclear morphology of scleraxis-positive cells arrayed at the boundary between the myoblast sheet and the fibroblast sheet (aspect ratio of the cell nuclei, myostatin(+) vs. myostatin(-): p = 0.000134). Myo may strengthen the connection at the MTJ in the initial stages of growth and wound healing.

Genetic Polymorphisms of ENPP2 Are Possibly Associated with Pain Severity and Opioid Dose Requirements in Patients with Inflammatory Pain Conditions: Clinical Observation Study.

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.

Rs11726196 Single-Nucleotide Polymorphism of the Transient Receptor Potential Canonical 3 (TRPC3) Gene Is Associated with Chronic Pain.

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.

Diagnosis and treatment of intractable idiopathic orofacial pain with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP.

Biologics for allergy: therapeutic potential for ocular allergic diseases and adverse effects on the eye.

Biologics applying antibodies against IgE, IL-5, IL-5 receptor α, IL-4 receptor α, and IL-13 have dramatically improved recent treatment outcomes in allergic diseases including asthma, rhinitis, and atopic dermatitis. However, these drugs have not been approved for ocular allergic diseases such as allergic conjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis. Although the putative mechanisms suggest that these drugs should have beneficial effects in patients with ocular allergies and some studies have reported such beneficial effects, various adverse ocular symptoms have also been observed in clinical trials and off-label use studies. Since ocular allergic diseases have distinct pathogeneses, each biologic drug must be examined regarding specific effects on each ocular allergy. For example, IgE-mediated type 1 hypersensitivity plays a critical role in allergic conjunctivitis. By contrast, T cells and eosinophilic and non-IgE-mediated type 2 inflammation play important roles in vernal keratoconjunctivitis. Allergists must fully understand the effects of each drug on the eye. This review outlines both potential therapeutic and adverse effects of various biologics on allergic diseases of the eye.

Minimally Invasive Surgery for Colorectal Cancer During the COVID-19 Pandemic in a Tertiary Medical Facility in Japan.

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) pandemic has reduced hospital visits due to concerns regarding infection and also resulted in cancer screening delays. These changes may have had an impact on the progression of colorectal cancer (CRC). Therefore, the present study investigated the effects of the COVID-19 pandemic on minimally invasive surgery (MIS) for CRC using a correlation analysis of clinical outcomes before and during the COVID-19 pandemic. PATIENTS AND METHODS: The present study targeted CRC patients who underwent MIS between January 2018 and December 2019 (pre-COVID-19) and between April 2020 and March 2021 (COVID-19). A comparison analysis of clinical, surgical, and pathological findings between the pre-COVID-19 and COVID-19 groups was performed. RESULTS: Ninety-one patients underwent MIS for CRC pre-COVID-19 and 67 during COVID-19. The number of CRC cases detected by fecal occult blood tests was slightly higher in the pre-COVID-19 group than that in the COVID-19 group. Re-evaluations of laparoscopic videos revealed that the number of cases of surgical T4 CRC resected with the combined resection of the adjacent organs was significantly higher in the COVID-19 group than that in the pre-COVID-19 group (16.4 vs. 4.4%, p=0.010). Furthermore, surgical times were significantly longer in the COVID-19 group than those in the pre-COVID-19 group (p<0.001). Pathological findings showed that the number of pT4 cases was significantly higher in the COVID-19 group than that in the pre-COVID-19 group (p=0.026). CONCLUSION: The number of T4 CRC cases was higher during than before the COVID-19 pandemic, with increases in the surgical difficulty of MIS.

Executive summary: Japanese guidelines for allergic conjunctival diseases 2021.

Allergic conjunctival disease (ACD) is an inflammatory disease of the conjunctiva that is mainly caused by type I hypersensitivity response to allergens and accompanied by subjective symptoms and other findings induced by antigens. ACD is classified as allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. This article summarizes the third edition of the Japanese guidelines for allergic conjunctival diseases published in 2021 and outlines the diagnosis, pathogenesis, and treatment of ACD. Since the introduction of immunosuppressive eye drops, the treatment strategies for severe ACDs have significantly changed. To clarify the recommended standard treatment protocols for ACD, the advantages and disadvantages of these treatments were assessed using clinical questions, with a focus on the use of steroids and immunosuppressive drugs. This knowledge will assist healthcare providers and patients in taking an active role in medical decision making.

Neurometabolite Levels and Relevance to Central Sensitization in Chronic Orofacial Pain Patients: A Magnetic Resonance Spectroscopy Study.

Background: Refractory chronic pain in the orofacial region involves central sensitization (CS). However, not all chronic pain patients exhibit CS. An objective assessment of CS may be useful for pain management. Changes in the balance of excitatory and inhibitory neural activity or excessive activity of nerves and glial cells may cause CS and contribute to pain chronification. Patients and Methods: 1H-magnetic resonance spectra were acquired from the anterior cingulate cortex (ACC) and thalamus in 20 patients with chronic orofacial pain and suspected CS, and 21 healthy volunteers, using a single-voxel point-resolved spectroscopy sequence. The patients were assessed using the Central Sensitization Inventory. Results: Aspartate/total creatine (tCr) and glutathione in the ACC were significantly higher in the patient group. However, no significant difference was observed between groups in the neurometabolites measured in the thalamus. Patients also exhibited a tendency for increased gamma-aminobutyric acid (GABA)/tCr in the ACC. There were positive relationships between Central Sensitization Inventory scores and glutamate + glutamine (Glx) in the thalamus, a positive trend for Glx in the ACC and a negative relationship for GABA/tCr in the ACC. Conclusion: The high levels of aspartate/tCr and glutathione in the patient group suggest excitatory neuronal activity and hyperactivity of neurons and glial cells. The correlation analysis results suggest that excitatory and inhibitory neurometabolites are involved in the chronification of orofacial pain, including CS.