Comparison study of the Le Fort I osteotomy using 2- and 4-plate fixation.

This study was conducted to evaluate the postsurgical stability of Le Fort I osteotomy using zygomatic buttress internal fixation alone with no piriform aperture internal fixation. Patients with maxillary retrognathia and mandibular prognathism underwent the Le Fort I osteotomy with a bilateral sagittal split ramus osteotomy. In group I, fixation was accomplished using titanium plate and screws placed at the piriform aperture and the zygomatic buttress (4 plates). In group II, fixation was accomplished using titanium plate and screws placed at the zygomatic buttress (2 plates). Lateral cephalometric radiographs were taken preoperatively (T1), immediately after surgery (T2), and at 6 months to 1 year (T3) to evaluate skeletal movement. In total, 32 patients were included in this study. None of the patients had wound infection, dehiscence, bone fragment instability, and long-term malocclusion. Regarding point A and the posterior nasal spine (PNS), vertical and horizontal relapse in groups I and II did not differ significantly. In most hospitals, the maxilla was fixed using four plates (piriform aperture and zygomatic buttress); however, within the limitations of the study, the choice of the number of plates for osteosynthesis following Le Fort I osteotomy and repositioning of the maxilla can be left to the discretion of the surgeon without putting the patients at risk for increased relapse by careful intraoperative management.

Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model.

Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation.

Longitudinal Changes of Macular Curvature in Patients with Retinitis Pigmentosa.

Purpose: To investigate the longitudinal changes of the macular curvature in eyes with retinitis pigmentosa (RP) and to determine the factors associated with the changes. Methods: We reviewed the medical charts of 107 RP patients, for whom the axial length of their right eyes ranged from 21.5 to 26.0 mm and who had had been followed by spectral-domain optical coherence tomography (OCT). The OCT images at the initial and the most recent examinations were compared. The mean curvature of Bruch's membrane within 6 mm of the central macula obtained from the OCT images was evaluated as the mean macular curvature index (MMCI). Changes in the MMCI and their relationships with other clinical factors, including the ellipsoid zone (EZ) width, were assessed. Results: The MMCI decreased significantly in the vertical OCT images, from -15.47 × 10-5 µm-1 to -16.36 × 10-5 µm-1 (P = 0.008) during the mean observation period of 3.4 ± 1.4 years (mean ± SD). This indicated that the macular shape became more concave. The change to a steeper shape was more prominent in eyes with less photoreceptor degeneration and for which the EZ width was preserved at >2000 µm. In three eyes, the MMCI increased markedly by >5 × 10-5 µm-1, and this was accompanied by absorption of the macular edema. Conclusions: The macular curvature in RP eyes becomes more concave in eyes with preserved EZ width. Translational Relevance: Longitudinal changes of the macular curvature in RP should be considered in future therapies, such as the implantation of the retinal prosthesis.

Steeper Macular Curvature in Eyes With Non-Highly Myopic Retinitis Pigmentosa.

Purpose: A posterior staphyloma has been reported to be present in some eyes with retinitis pigmentosa (RP), and the purpose of this study was to determine the macular curvature of non-highly myopic RP eyes. Methods: This was a retrospective, observational study. The medical charts of the right eyes of 143 patients with RP and 60 controls whose axial length ranged from 21.5 mm to 26.0 mm were reviewed. The mean curvature of Bruch's membrane within 6 mm of the central macula obtained from the horizontal optical coherence tomographic images were evaluated as the mean macular curvature index (MMCI). The relationships between the MMCI and other clinical factors were assessed. Results: The mean MMCI of RP patients (-13.73 ± 9.63 × 10-5 µm-1) was significantly lower than that of the controls (-6.63 ± 5.63 × 10-5 µm-1). This indicated a deeper concave shape of the macula in RP eyes (P < 0.001). The MMCI was significantly correlated with the age (r = 0.20; P = 0.016) and the axial length (r = -0.24; P = 0.004). Further analysis suggested a nonlinear effect of the ellipsoid zone width on the macular curvature in the RP eyes. Conclusions: There is a high incidence of steeper macular curvatures even in non-highly myopic RP eyes, and the steepness was also affected by the degree of photoreceptor degeneration.

GPR34 in spinal microglia exacerbates neuropathic pain in mice.

BACKGROUND: Neuropathic pain is caused by sensory nerve injury, but effective treatments are currently lacking. Microglia are activated in the spinal dorsal horn after sensory nerve injury and contribute to neuropathic pain. Accordingly, molecules expressed by these cells are considered potential targets for therapeutic strategies. Our previous gene screening study using a mouse model of motor nerve injury showed that the G-protein-coupled receptor 34 gene (GPR34) is induced by nerve injury. Because GPR34 is now considered a microglia-enriched gene, we explored the possibility that it might be involved in microglial activation in the dorsal horn in a mouse model of neuropathic pain. METHODS: mRNA expression of GPR34 and pro-inflammatory molecules was determined by quantitative real-time PCR in wild-type and GPR34-deficient mice with L4 spinal nerve injury. In situ hybridization was used to identify GPR34 expression in microglia, and immunohistochemistry with the microglial marker Iba1 was performed to examine microglial numbers and morphology. Mechanical sensitivity was evaluated by the von Frey hair test. Liquid chromatography-tandem mass spectrometry quantified expression of the ligand for GPR34, lysophosphatidylserine (LysoPS), in the dorsal horn, and a GPR34 antagonist was intrathecally administrated to examine the effect of inhibiting LysoPS-GPR34 signaling on mechanical sensitivity. RESULTS: GPR34 was predominantly expressed by microglia in the dorsal horn after L4 nerve injury. There were no histological differences in microglial numbers or morphology between WT and GPR34-deficient mice. However, nerve injury-induced pro-inflammatory cytokine expression levels in microglia and pain behaviors were significantly attenuated in GPR34-deficient mice. Furthermore, the intrathecal administration of the GPR34 antagonist reduced neuropathic pain. CONCLUSIONS: Inhibition of GPR34-mediated signal by GPR34 gene deletion reduced nerve injury-induced neuropathic pain by suppressing pro-inflammatory responses of microglia without affecting their morphology. Therefore, the suppression of GPR34 activity may have therapeutic potential for alleviating neuropathic pain.

CLINICAL COURSE OF PARANEOPLASTIC RETINOPATHY WITH ANTI-TRPM1 AUTOANTIBODY IN JAPANESE COHORT.

PURPOSE: To report the clinical course of eyes with paraneoplastic retinopathy caused by an autoantibody against transient receptor potential cation channel, subfamily M, member 1 (TRPM1). METHODS: Ten paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction, including six melanoma-associated retinopathy, from eight institutions in Japan were evaluated for the presence of an anti-TRPM1 antibody. The results of ophthalmic examinations and the presence of anti-TRPM1 antibody were analyzed. RESULTS: Five patients were positive for the anti-TRPM1 antibody. These patients had similar clinical findings in both eyes at the time of diagnosis; relatively preserved best-corrected visual acuity, absence of fundus and optical coherence tomography abnormalities, and specific abnormalities of the electroretinography (ERG); and negative-type ERGs with bright stimulus flashes. One patient whose retinal ON-bipolar cells remained dysfunctional for the entire testing period, although the anti-TRPM1 antibody had disappeared. On the other hand, the ERGs recovered in 2 cases within 2 years after the onset. One case progressed to additional impairment of the photoreceptors with deterioration of ERGs. One case died and the clinical course was unavailable. CONCLUSION: Paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction possess autoantibodies against TRPM1 at the onset of the disease process; however, the clinical course of these eyes can be different.

Significant Relationship of Visual Field Sensitivity in Central 10° to Thickness of Retinal Layers in Retinitis Pigmentosa.

Purpose: To determine the relationship between the sensitivity of the retina in the central 10° and the thickness of the retinal layers in patients with retinitis pigmentosa (RP). Methods: Fifty-two RP patients were studied. All of the patients had been examined by the Humphrey Field Analyzer 10-2 program (HFA10-2) and spectral-domain optical coherence tomography (SD-OCT). The thicknesses of the photoreceptor outer segment (OS), outer nuclear layer (ONL), inner nuclear layer (INL), and the retinal nerve fiber layer (RNFL) were measured at 1°, 3°, 5°, 7°, and 9° from the fovea. The same measurements were made on the SD-OCT images of 40 healthy subjects and used as controls. The relationships between the retinal sensitivities and retinal layer thicknesses were determined. Results: The thicknesses of the OS and ONL and their product were significantly and positively correlated with the retinal sensitivities. The thickness of the INL was significantly and negatively correlated with the sensitivity. The strongest correlation with the sensitivity was with the OS thickness (marginal R2 [mR2] = 0.525, P < 0.001), followed by the product of the OS and ONL thicknesses (mR2 = 0.420, P < 0.001), ONL thickness (mR2 = 0.416, P < 0.001), and the INL thickness (mR2 = 0.014, P = 0.044). The thickness of the RNFL was not correlated with the sensitivity (mR2 = 0.005, P = 0.331). Conclusions: In contrast to previous reports, the thickness of the OS reflected the retinal sensitivity better than the product of OS and ONL.

Quantification of Macular Microvascular Changes in Patients With Retinitis Pigmentosa Using Optical Coherence Tomography Angiography.

Purpose: To evaluate the microvascular changes in eyes with RP quantitatively using optical coherence tomography angiography (OCTA) and to determine whether the correlations between these indices and the severity of RP are significant. Methods: This was a retrospective, observational study. The medical records of 53 RP patients and 46 controls were reviewed. The OCTA images were obtained with the Cirrus 5000 with Angioplex, and an automated program was used to analyze the microvascular patterns. The perfusion density (PD) and vessel length density (VLD) were used as indices of the microvascular density, whereas the vessel diameter index (VDI) was used as a measure of the caliber of the vessels. The width of the ellipsoid zone (EZ) in the OCT images and the mean deviation (MD) of the Humphry Field Analyzer (HFA) were used to determine the severity of the RP. Student's t-tests and Spearman's correlation tests were used. Results: Both the PD and VLD in the superficial and deep plexuses and the whole retina were significantly reduced, and the VDI was significantly increased in RP patients compared with the corresponding values of the controls (P < 0.001). Spearman's rank tests indicated the RP severity was significantly correlated with the PD and VLD in all three layers (P < 0.001, r ranging from 0.50 to 0.87) and significantly correlated with VDI in the deep and the whole retina (P < 0.001, ranging from -0.64 to -0.73). Conclusions: Quantitative changes in the microvascular density might be useful for examining the pathophysiology of RP.

Longitudinal study of visual field changes determined by Humphrey Field Analyzer 10-2 in patients with Retinitis Pigmentosa.

The aim of this study is to determine the progress of the visual field defects obtained by the Humphrey Field Analyzer 10-2 program (HFA 10-2) in patients with retinitis pigmentosa (RP). The medical records of 45 eyes of 45 RP patients who had at least 3 visual field tests were reviewed. Linear mixed models were used to follow the changes of the mean deviation and the average sensitivity of 4, 12, and 20 points in three concentric squares, designated as S4, S12, and S20. The median follow-up time was 3.86 years [range: 1.93 to 9.86, IQR (Interquartile range): 3.01 to 4.93]. The median number of the visual field tests was 3 (range: 3 to 15, IQR: 3 to 4). The mean change of the MD was -0.46 dB/year (-5.80%/year). When the patients were grouped by the average initial MD, the less advanced group had slower progressions than the more advanced group in S4, S12, and S20. These results should be useful in understanding the pathological changes of RP in the central visual field.

Temporal Properties of Flicker ERGs in Rabbit Model of Retinitis Pigmentosa.

Purpose: We determined the effects of a remodeled inner retina on the flicker electroretinograms (ERGs) in a rabbit eye at an advanced stage of inherited retinal degeneration. Methods: Six wild-type (WT) and four rhodopsin P347L transgenic (Tg) rabbits were studied at 18 months of age. Flicker ERGs were elicited by sinusoidal stimuli at frequencies of 3.906 to 50.781 Hz. To block the ON and OFF retinal pathways, 2-amino-4-phosphonobutyric acid (APB), and 6-cyano-7-nitroquinoxaline-2, 3(1H, 4H)-dione (CNQX), respectively, were injected intravitreally. The amplitudes and phases of the fundamental components of the pre- and postdrug ERGs were analyzed. The postsynaptic APB (ON-) and CNQX (OFF-) sensitive components were determined by examining the phases and amplitude vectors. Results: The temporal properties of the Tg rabbits were different from those of the WT rabbits and had unique features; at 3.906 Hz, the amplitude was depressed but it increased by more than 3.5-fold at 15.625 Hz. The reduction of the amplitude at 3.906 Hz in Tg rabbits was caused by a cancelation of the ON and OFF components by a phase difference of 180°. On the other hand, an increase in the amplitude at 15.625 Hz in Tg rabbits was caused by the summation of the ON and OFF components, which had an approximate 120° phase difference. Conclusions: The temporal properties of the flicker ERGs of Tg rabbits were affected markedly by the remodeling of the retinal neurons. Evaluations of the flicker ERGs in RP eyes must be done with careful considerations of the current findings.

Siglec-H is a microglia-specific marker that discriminates microglia from CNS-associated macrophages and CNS-infiltrating monocytes.

Several types of myeloid cell are resident in the CNS. In the steady state, microglia are present in the CNS parenchyma, whereas macrophages reside in boundary regions of the CNS, such as perivascular spaces, the meninges and choroid plexus. In addition, monocytes infiltrate into the CNS parenchyma from circulation upon blood-brain barrier breakdown after CNS injury and inflammation. Although several markers, such as CD11b and ionized calcium-binding adapter molecule 1 (Iba1), are frequently used as microglial markers, they are also expressed by other types of myeloid cell and microglia-specific markers were not defined until recently. Previous transcriptome analyses of isolated microglia identified a transmembrane lectin, sialic acid-binding immunoglobulin-like lectin H (Siglec-H), as a molecular signature for microglia; however, this was not confirmed by histological studies in the nervous system and the reliability of Siglec-H as a microglial marker remained unclear. Here, we demonstrate that Siglec-H is an authentic marker for microglia in mice by immunohistochemistry using a Siglec-H-specific antibody. Siglec-H was expressed by parenchymal microglia from developmental stages to adulthood, and the expression was maintained in activated microglia under injury or inflammatory condition. However, Siglec-H expression was absent from CNS-associated macrophages and CNS-infiltrating monocytes, except for a minor subset of cells. We also show that the Siglech gene locus is a feasible site for specific targeting of microglia in the nervous system. In conclusion, Siglec-H is a reliable marker for microglia that will allow histological identification of microglia and microglia-specific gene manipulation in the nervous system.

Differences in ocular findings in two siblings: one with complete and other with incomplete achromatopsia.

PURPOSE: Patients with complete achromatopsia (ACHM) lack cone function, and patients with incomplete ACHM have relatively good visual acuity with residual color vision. The pathological mechanism(s) underlying incomplete ACHM has not been determined. The purpose of this study was to determine the pathophysiology of ACHM in two siblings: one with complete ACHM and the other with incomplete ACHM. METHODS: The medical charts of the two siblings were reviewed. RESULTS: The sibling with incomplete ACHM had decimal visual acuities that ranged from 0.4 to 0.6 and had moderate color blindness in both eyes. Her younger brother was diagnosed with complete ACHM and was not able to hold fixation, had severe pendular nystagmus, visual acuity that ranged from 0.08 to 0.1, and severe color vision abnormalities in both eyes. Optical coherence tomography (OCT) showed that the ellipsoid zone (EZ) was disruptive in the macular region in both patients. However, careful examination of the OCT images in the incomplete ACHM patient showed a high-density EZ in the central fovea. Adaptive optics (AO) fundus imaging of the sibling with incomplete ACHM revealed sparse cone mosaics remaining within 1° of the foveal center with no mosaics visible outside the central fovea. AO fundus imaging could not be performed in Case 2 because of the severe nystagmus. CONCLUSION: Our results showed that cone mosaics were present in the central fovea in the sibling with incomplete ACHM patient. This may explain the better visual acuity and color vision in this sibling.

TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain.

Neuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain. Nerve injury-induced proinflammatory cytokine expression in microglia and pain behaviors were significantly suppressed in Dap12-deficient mice. Furthermore, intrathecal administration of TREM2 agonistic antibody induced proinflammatory cytokine expression, as well as neuropathic pain, in mice without nerve injury. The agonistic antibody induced proinflammatory responses and neuropathic pain was not observed in Dap12-deficient mice. Together, these results suggest that TREM2/DAP12-mediated signals in microglia exacerbate nerve injury-induced neuropathic pain by inducing proinflammatory cytokine secretion from microglia. Suppression of DAP12-mediated signals could be a therapeutic target for neuropathic pain. SIGNIFICANCE STATEMENT: Recent studies have revealed that activated microglia in the spinal dorsal horn exacerbate neuropathic pain, which has suggested that suppression of microglial activity should be considered as a therapeutic target. However, only a few molecules have been identified as regulators of microglial activity. In this study, we focused on a receptor complex of TREM2 and DAP12, both of which are expressed by microglia and have been implicated in the pathogenesis of Alzheimer's disease, and demonstrated that TREM2/DAP12 signaling promoted proinflammatory responses in microglia and exacerbates neuropathic pain. The present results revealed the functional significance of TREM2/DAP12 signaling in microglial activation after neuronal injury, and could help in the development of treatments for neuropathic pain and neurodegenerative diseases.

Pseudo Gitelman Syndrome Associated With Pregnancy.

BACKGROUND: Gitelman syndrome is a rare inherited renal tubulopathy associated with metabolic alkalosis and electrolyte disorders. Pseudo Gitelman syndrome presents with the same clinical characteristics as Gitelman syndrome, yet without genetic mutations in SLC12A3. CASE: A 32-year-old woman with no remarkable medical and family history developed hypokalemia at 32 weeks of gestation. Laboratory findings were consistent with Gitelman syndrome and potassium supplementation was initiated. The patient delivered a healthy neonate at 40 weeks of gestation and the electrolyte disorders drastically improved. After delivery, genomic analysis revealed no evidence of mutations in SLC12A3, and pseudo Gitelman syndrome was finally diagnosed. CONCLUSION: Pseudo Gitelman syndrome, presenting with Gitelman syndrome-like renal tubulopathy without mutations in SLC12A3, can cause a temporary electrolyte imbalance based on the physiologic changes of pregnancy. Although pregnant women with isolated hypokalemia need not be evaluated for Gitelman or pseudo Gitelman syndrome, if it is accompanied by metabolic alkalosis, hypocalciuria, hypomagnesia, and activation of the renin-angiotensin-aldosterone system without hypertension, this evaluation should be considered.