Partner-switching components PmgA and Ssr1600 regulate high-light acclimation in Synechocystis sp. PCC 6803.

Photomixotrophic growth A (PmgA) is a pleiotropic regulator essential for growth under photomixotrophic and prolonged high-light (HL) conditions in the cyanobacterium Synechocystis sp. PCC 6803. The overall similarity with the anti-sigma factor of the bacterial partner-switching system indicates that PmgA exerts a regulatory function via phosphorylation of its target proteins. In this study, we performed an in vitro phosphorylation assay and protein-protein interaction analysis and found that PmgA interacts with four anti-sigma antagonist homologs, Ssr1600, Slr1856, Slr1859, and Slr1912, but specifically phosphorylates Ssr1600. Phenotypic analyses using the set of gene disruption and overexpression strains of pmgA and ssr1600 revealed that phosphorylation by PmgA is essential for the accumulation of Ssr1600 protein in vivo. The ssr1600-disrupted mutant showed similar phenotypes as those previously reported for the pmgA-disrupted mutant, namely, no obvious phenotype just after the shift to HL, but higher chlorophyll content, 5-aminolevulinic acid synthesis activity, and psaAB transcript levels than those in the wild-type after 6 hours. These findings indicate that the phosphorylated form of Ssr1600 works as the output of the partner-switching system to coordinately repress chlorophyll biosynthesis and accumulation of photosystem I during HL acclimation.

Characterization of Actin-based Genotypes and Mycoplasma Endosymbionts of Trichomonas vaginalis Isolated in Sapporo, Japan.

PURPOSE: Trichomonas vaginalis is a causative agent of common non-viral sexually transmitted infections worldwide. However, the biological features, such as genotypes and endosymbionts, of T. vaginalis isolated in Japan remain unclear. The aim of this study was to characterize the actin-based genotypes and the endosymbionts of T. vaginalis isolated in Sapporo, Japan. METHODS: Three T. vaginalis clinical strains were isolated in Sapporo, Japan between 2019 and 2022. Actin-based genotyping was conducted by sequencing and phylogenetic analyses. The endosymbionts, such as Mycoplasma sp. and Trichomonasvirus, were detected using PCR and RT-PCR, respectively. Furthermore, the detected Mycoplasma spp. were identified using 16S rRNA gene sequencing. RESULTS: Of the three T. vaginalis strains, two belonged to genotype E, whereas one was genotype G as determined by actin-based genotyping. Two of the T. vaginalis strains harbored Mycoplasma spp. Using nearly full-length 16S rRNA gene sequencing, both were identified as Candidatus Mycoplasma girerdii. In contrast, the Trichomonasvirus was not found in the T. vaginalis strains. CONCLUSION: To our knowledge, this is the first report on the characterization of actin-based genotypes and the presence of endosymbiotic Ca. M. girerdii in T. vaginalis strains in Japan. Thus, this study will provide an important impetus for future research.

Heat acclimation improves exercise performance in hot conditions and increases heat shock protein 70 and 90 of skeletal muscles in Thoroughbred horses.

This study aimed to determine whether heat acclimation could induce adaptations in exercise performance, thermoregulation, and the expression of proteins associated with heat stress in the skeletal muscles of Thoroughbreds. Thirteen trained Thoroughbreds performed 3 weeks of training protocols, consisting of cantering at 90% maximal oxygen consumption (VO2max) for 2 min 2 days/week and cantering at 7 m/s for 3 min 1 day/week, followed by a 20-min walk in either a control group (CON; Wet Bulb Globe Temperature [WBGT] 12-13°C; n = 6) or a heat acclimation group (HA; WBGT 29-30°C; n = 7). Before and after heat acclimation, standardized exercise tests (SET) were conducted, cantering at 7 m/s for 90 s and at 115% VO2max until fatigue in hot conditions. Increases in run time (p = 0.0301), peak cardiac output (p = 0.0248), and peak stroke volume (p = 0.0113) were greater in HA than in CON. Pulmonary artery temperature at 7 m/s was lower in HA than in CON (p = 0.0332). The expression of heat shock protein 70 (p = 0.0201) and 90 (p = 0.0167) increased in HA, but not in CON. These results suggest that heat acclimation elicits improvements in exercise performance and thermoregulation under hot conditions, with a protective adaptation to heat stress in equine skeletal muscles.

Two-minute standing endurance test for axial postural abnormalities in patients with Parkinson's disease.

BACKGROUND: Photo-based measurement methods are used to assess axial postural abnormalities (PA) in Parkinson's disease (PD). However, they capture only moments in time. We developed the 2-minute standing endurance test (2 M-SET), which specifically captures temporal changes in posture, as a novel dynamic method for measuring axial PA in patients with PD. RESEARCH QUESTION: This study aimed to verify the effectiveness and validity of the 2 M-SET for capturing temporal changes in axial PA in patients with PD. METHODS: Twenty-eight patients with PD participated. The participants attempted to maintain an upright posture for 2 minutes during three tasks: standing, stepping in place, and walking. The rate of change in postural angle was recorded at 10-second intervals. Based on the results, the 2 M-SET was developed. Therapists evaluated the 2 M-SET using the NeuroPostureApp© to measure anterior trunk flexion (ATF) angles and lateral trunk flexion (LTF) angles at 0, 10, 30, 60, and 120 seconds. To assess reliability, the congruence between the measurements obtained by the therapists and those obtained using a three-dimensional motion-analysis system was examined. For validity, we assessed whether the ATF and LTF angles measured by the therapists could accurately capture postural changes at regular intervals over time. RESULTS: The average postural changes over 2 minutes for the standing, stepping in place, and gait tasks were 59.2±83.5%, 37.6±30.7%, and 45.4±50.6%, respectively. The intraclass correlation coefficients showed high reliability, with values of 0.985 and 0.970 for the ATF and LTF angles, respectively. SIGNIFICANCE: The results of our proposed 2 M-SET method, which uses temporal photo-based measurements to assess the patient's ability to maintain an upright standing position for 2 minutes, demonstrate the potential to capture temporal changes in axial PA. DATA AVAILABILITY STATEMENT: The data supporting the findings of this study are available upon reasonable request and approval from the local ethics committee.

Effects of mechanical insufflation-exsufflation on ventilator-free days in intensive care unit subjects with sputum retention; a randomized clinical trial.

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) facilitates extubation. However, its potential to reduce the duration of ventilator use remains unclear. Therefore, the present study investigated whether the use of MI-E shortened the duration of mechanical ventilation in patients with high sputum retention. METHODS: A randomized open-label trial was conducted at a single intensive care unit (ICU) in Japan between November 2017 and June 2019. Ventilated subjects requiring suctioning at least once every hour due to sputum retention were randomly assigned to the MI-E group or conventional care group. The primary endpoint was the number of ventilator-free days on day 28. Secondary endpoints were ventilator days in surviving subjects, the length of ICU stay, and mortality and tracheostomy rates among survivors. RESULTS: Forty-eight subjects (81% males) with a median age of 72 years (interquartile range [IQR], 65-85 years) were enrolled. There were 27 subjects in the MI-E group and 21 in the control group. The median number of ventilator-free days was 21 (IQR, 13-24) and 18, respectively (IQR, 0-23) (P = .38). No significant differences were observed in the ICU length of stay (median, 10 days (IQR, 7-12) vs 12 days (IQR, 6-15); P = .31), mortality rate (19% vs 15%; odds ratio [OR], 1.36 [0.28-6.50]; P = .69), or tracheostomy rate among survivors (14% vs 28%; OR, 0.40 [0.08-1.91]; P = .25). CONCLUSION: In ventilated subjects in the ICU with high sputum retention, the use of MI-E did not significantly increase the number of ventilator-free days over that with conventional care.

Field-training in young two-year-old thoroughbreds: investigating cardiorespiratory adaptations and the presence of exercise induced pulmonary hemorrhage.

BACKGROUND: Comparatively little is known regarding the initial cardiorespiratory response of young racehorses to training. The objectives were to compare physiological parameters before and after introductory training and determine whether young Thoroughbreds show endoscopic signs of exercise-induced pulmonary hemorrhage (EIPH). Ten Thoroughbreds (20-23 months) underwent 12-weeks of introductory training, including weekly speed sessions. Two 600 m high-speed exercise tests (HSET) were performed following weeks 4 and 12 while wearing a validated ergospirometry facemask. Peak oxygen consumption (V̇O2pk) and ventilatory parameters (tidal volume, VT; peak inspiratory and expiratory flow, PkV̇I, PkV̇E; respiratory frequency, Rf; minute ventilation, V̇E) were measured. The ventilatory equivalent of oxygen (V̇E/V̇O2) and the aerobic and anaerobic contributions to energy production were calculated. Maximal heart rate (HRmax) and HR at maximal speed (HRVmax) were determined. Post-exercise hematocrit, plasma ammonia and blood lactate were measured. Evidence of EIPH was investigated via tracheobronchoscopy post-exercise. Results were compared (paired t-test, P < 0.05). RESULTS: Horses were faster following training (P < 0.001) and V̇O2pk increased 28 ml/(kg total mass.min) (28 ± 16%; P < 0.001). Ventilatory (V̇E, P = 0.0015; Rf, P < 0.001; PkV̇I, P < 0.001; PkV̇E, P < 0.001) and cardiovascular parameters (HRmax, P = 0.03; HRVmax, P = 0.04) increased. The increase in V̇E was due to greater Rf, but not VT. V̇E/V̇O2 was lower (26 ± 3.6 vs 23 ± 3.7; P = 0.02), indicating improved ventilatory efficiency. Anaerobic contribution to total energy production increased from 15.6 ± 6.1% to 18.5 ± 6.3% (P = 0.02). Post-exercise hematocrit (P < 0.001), plasma ammonia (P = 0.03) and blood lactate (P = 0.001) increased following training. Horses showed no signs of EIPH. CONCLUSIONS: Young two-year-old Thoroughbreds responded well to introductory training without developing tracheobronchoscopic evidence of EIPH.

Detailed Lipid Profiles and Lipid-related Residual Risk after 12-week 10 mg Rosuvastatin Treatment for Acute Myocardial Infarction.

Objective We aimed to reveal detailed on-treatment lipid profiles, lipid-related surrogate markers, and factors predicting failure to achieve the guideline-recommended lipid management goal following guideline-recommended statin treatment in Japanese patients with acute myocardial infarction (AMI). Methods and Results Sixty AMI patients who underwent coronary intervention and had received rosuvastatin 10 mg/day since the start of their hospitalization were assessed for on-treatment lipid-related profiles, including high-sensitivity C-reactive protein, small dense low-density lipoprotein cholesterol (sd LDL-C), and lipoprotein (a), at the 12-week follow-up. Patients who failed to achieve the guideline-recommended lipid management at 12 weeks were defined as the "unachieved group." Univariate and multivariate logistic regression analyses were performed to evaluate the predictors of inclusion in the unachieved group after high-dose statin treatment. Despite the use of high-dose rosuvastatin, 61.7% of the enrolled AMI patients were included in the unachieved group. In addition, the unachieved group had higher sd LDL-C and lipoprotein (a) levels than the achieved group. Logistic regression analyses demonstrated that low baseline high-density lipoprotein cholesterol (HDL-C) levels and the absence of diabetes were predictors of inclusion in the unachieved group. Conclusion More than half of the Japanese AMI patients treated with rosuvastatin 10 mg/day did not achieve the guideline-recommended goal of lipid management and still had lipid-related residual risk at 12 weeks. Particular attention should be paid to patients with low baseline HDL-C levels and those without diabetes with regard to their on-treatment lipid profiles.

Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases.

Eomesodermin-expressing (Eomes+) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes+ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes+ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes+ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes+ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093-1098.

Nescient helix-loop-helix 1 (Nhlh1) is a novel activating transcription factor 5 (ATF5) target gene in olfactory and vomeronasal sensory neurons in mice.

Activating transcription factor 5 (ATF5) is a transcription factor that belongs to the cAMP-response element-binding protein/ATF family and is essential for the differentiation and survival of sensory neurons in mouse olfactory organs. However, transcriptional target genes for ATF5 have yet to be identified. In the present study, chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) experiments were performed to verify ATF5 target genes in the main olfactory epithelium and vomeronasal organ in the postnatal pups. ChIP-qPCR was conducted using hemagglutinin (HA)-tagged ATF5 knock-in olfactory organs. The results obtained demonstrated that ATF5-HA fusion proteins bound to the CCAAT/enhancer-binding protein-ATF response element (CARE) site in the enhancer region of nescient helix-loop-helix 1 (Nhlh1), a transcription factor expressed in differentiating olfactory and vomeronasal sensory neurons. Nhlh1 mRNA expression was downregulated in ATF5-deficient (ATF5-/-) olfactory organs. The LIM/homeobox protein transcription factor Lhx2 co-localized with ATF5 in the nuclei of olfactory and vomeronasal sensory neurons and bound to the homeodomain site proximal to the CARE site in the Nhlh1 gene. The CARE region of the Nhlh1 gene was enriched by the active enhancer marker, acetyl-histone H3 (Lys27). The present study identified Nhlh1 as a novel target gene for ATF5 in murine olfactory organs. ATF5 may upregulate Nhlh1 expression in concert with Lhx2, thereby promoting the differentiation of olfactory and vomeronasal sensory neurons.

SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. METHODS: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants. RESULTS: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction. INTERPRETATION: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.

Influence of microarchitecture on stressed volume and mechanical fatigue behaviour of equine subchondral bone.

Fractures of the equine metacarpophalangeal (MCP) joint are among the most common and fatal injuries experienced by racehorses. These bone injuries are a direct result of repetitive, high intensity loading of the skeleton during racing and training and there is consensus that they represent a mechanical fatigue phenomenon. Existing work has found the fatigue life of bone to be strongly determined by bone microarchitecture and the resulting stressed volume (i.e., the volume of bone stressed above assumed yield). The purpose of this study was to quantify the influence of bone microarchitecture on the mechanical fatigue behaviour of equine subchondral bone from the MCP joint across a wide variety of sample types. Forty-eight subchondral bone samples were prepared from the third metacarpal (MC3) and proximal phalanx (P1) of 8 horses and subsequently imaged using high resolution micro-computed tomography (µCT) to quantify microarchitectural features of interest, including bone volume fraction, tissue mineral density, pore size, pore spacing, and pore number. Samples were cyclically loaded in compression to a stress of 70 MPa, and fatigue life was defined as the number of cycles until failure. Finite element models were created from the µCT images and used to quantify stressed volume. Based on the expected log point-wise predictive density, stressed volume was a strong predictor of fatigue life in both the MC3 and P1. A regional analysis indicated fatigue life was more strongly associated with bone volume fraction in the superficial (r2 = 0.32, p < 0.001) and middle (r2 = 0.70, p < 0.001) regions of the subchondral bone, indicating the prominent role that the cortical plate played in the fatigue resistance of equine subchondral bone. By improving our understanding of the variance in fatigue life measurements, this research helps clarify the underlying mechanisms of the mechanical fatigue process and provides a basic understanding of subchondral bone injuries in the equine fetlock joint.

Combined home and clinic-based therapy versus home-based exercise programme after distal radial fracture: a randomized controlled study.

We investigated outcomes of clinic-based hand therapy combined with a home-based exercise programme after anterior plating for distal radial fractures. A total of 102 patients were randomly assigned to one of three groups: a home-based exercise programme alone; a home-based exercise programme combined with four hand therapy sessions in the clinic; and a home-based exercise programme with seven sessions in the clinic. Mean Patient-Rated Wrist Evaluation scores at 6 weeks were significantly better for the group of patients with seven sessions in the clinic than in those with only home exercises (12 vs. 30), but the difference was no longer significant at 12 weeks. Grip strength was significantly better at 6 and 12 weeks. Combined home- and clinic-based hand therapy may facilitate an earlier return of function after anterior plating for distal radius fractures.Level of evidence: II.

Monitoring ventral tail base surface temperature for fever detection in calves.

In this study, we investigated whether monitoring the ventral tail base surface temperature (ST) using a wearable wireless sensor could be effective for fever detection in calves with experimentally induced pneumonia after inoculation with Histophilus somni strain 2336. We found a significant difference in the changes in ST values between the control and H. somni-inoculated groups after 24 h of inoculation and detected fever; however, the rectal temperature showed a significant difference between the groups after 12 h of inoculation. When a significant difference in the ST between the two groups was observed, serum haptoglobin concentration and exacerbation of clinical score increased in the H. somni-inoculated group compared with those in the control group. Pneumonia was observed in the H. somni-inoculated group at necropsy, indicating that the changes in ST may reflect fever with inflammation caused by H. somni infection. Our results demonstrated that monitoring ST using a sensor attached to the ventral tail base can detect fever in calves and may be a useful and labor-saving tool for the health management of calves.

Structural Validity of the Mini-Balance Evaluation Systems Test in Individuals With Spinocerebellar Ataxia: A Rasch Analysis Study.

OBJECTIVE: To examine the structural validity of the Mini-Balance Evaluation Systems Test (Mini-BESTest) in individuals with spinocerebellar ataxia (SCA). DESIGN: Methodological research on data gathered in a cross-sectional study. A Rasch analysis was conducted (partial credit model). SETTING: Inpatients in a hospital rehabilitation setting. PARTICIPANTS: A pooled sample of patients with SCA (N=65 [total 110 data]; 23 women, 42 men; mean±SD age 63.1±9.9y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We evaluated the Mini-BESTest's category structure, unidimensionality, and measurement accuracy (0: unable to perform or requiring help to 2: normal performance). RESULTS: The Mini-BESTest rating scale fulfilled the category functioning criteria. The analysis of the standardized Rasch residuals showed the scale's unidimensionality, but there were 7 item pairs indicating local dependence. All of the items fit the underlying scale construct (dynamic balance), with the exception of item #1, "Sit to stand," which was an underfit. The Mini-BESTest demonstrated adequate reliability (person separation reliability=.87) and separated the patients into 5 strata. The item-difficulty measures ranged from -4.49 to 2.02 logits, and the person ability-item difficulty matching was very good (the mean of person ability=-.07 logits and the mean of item difficulty=.00). No floor or ceiling effects were detected. The keyform identified items with small (#11, "Walk with head turns, horizontal") and large (#3, "Stand on 1 leg") item thresholds. CONCLUSIONS: The Mini-BESTest has a unidimensional balance assessment scale with good category structure and reliability even for individuals with SCA. However, it also has some inherent shortcomings such as fit statistics, local item dependencies, and item thresholds. The results obtained when the Mini-BESTest is administered to patients with cerebellar ataxia should, thus, be interpreted cautiously.

Nationwide survey of patients with multisystem proteinopathy in Japan.

OBJECTIVE: Multisystem proteinopathy (MSP) is an inherited disorder in which protein aggregates with TAR DNA-binding protein of 43 kDa form in multiple organs. Mutations in VCP, HNRNPA2B1, HNRNPA1, SQSTM1, MATR3, and ANXA11 are causative for MSP. This study aimed to conduct a nationwide epidemiological survey based on the diagnostic criteria established by the Japan MSP study group. METHODS: We conducted a nationwide epidemiological survey by administering primary and secondary questionnaires among 6235 specialists of the Japanese Society of Neurology. RESULTS: In the primary survey, 47 patients with MSP were identified. In the secondary survey of 27 patients, inclusion body myopathy was the most common initial symptom (74.1%), followed by motor neuron disease (11.1%), frontotemporal dementia (FTD, 7.4%), and Paget's disease of bone (PDB, 7.4%), with no cases of parkinsonism. Inclusion body myopathy occurred most frequently during the entire course of the disease (81.5%), followed by motor neuron disease (25.9%), PDB (18.5%), FTD (14.8%), and parkinsonism (3.7%). Laboratory findings showed a high frequency of elevated serum creatine kinase levels and abnormalities on needle electromyography, muscle histology, brain magnetic resonance imaging, and perfusion single-photon emission computed tomography. INTERPRETATION: The low frequency of FTD and PDB may suggest that FTD and PDB may be widely underdiagnosed and undertreated in clinical practice.

Metabolomic responses to high-intensity interval exercise in equine skeletal muscle: effects of rest interval duration.

High-intensity interval training has attracted considerable attention as a time-efficient strategy for inducing physiological adaptations, but the underlying mechanisms have yet to be elucidated. By using metabolomics techniques, we investigated changes in the metabolic network responses in Thoroughbred horses to high-intensity interval exercise performed with two distinct (15 min or 2 min) rest intervals. The peak plasma lactate level was higher during high-intensity exercise with a 2 min rest duration than that with a 15 min rest duration (24.5±6.8 versus 13.3±2.7 mmol l-1). The arterial oxygen saturation was lower at the end of all exercise sessions with a 2 min rest duration than that with a 15 min rest duration. Metabolomic analysis of skeletal muscle revealed marked changes in metabolite concentrations in the first and third bouts of the 15 min rest interval conditions. In contrast, there were no metabolite concentrations or pathways that significantly changed during the third bout of exercise performed with a 2 min rest interval. Our findings suggest that the activity of each energy production system is not necessarily reflected by apparent changes in metabolite concentrations, potentially due in part to a better match between metabolite flux into and out of the pathway and cycle, as well as between metabolite production and disposal. This study provides evidence that changes in metabolite concentrations vary greatly depending on the number of repetitions and the length of rest periods between exercises, even if the exercises themselves are identical.

[Spinocerebellar ataxia 2 develop lower motor neuron involvement as an initial symptom: a case report].

A 36-year-old man has developed weakness of left thumb and atrophy of left thenar muscle and left first dorsal interosseous muscle without sensory disturbance for a year. A nerve conduction study revealed decreases in the amplitude of compound muscle action potentials and occurrence of F-waves on left medial nerve. Needle electromyography examination revealed positive sharp waves and later recruited motor units on left abductor pollicis brevis muscle. Brain MRI showed atrophy of bilateral cerebellar hemisphere. His grandmother and his two uncles have been diagnosed as spinocerebellar degeneration. After discharge, he developed bilateral lower limb ataxia. Genetic analysis showed heterozygous CAG repeat expansion (19/39) in ATXN2 gene, being diagnosed as spinocerebellar ataxia 2 (SCA2). A previous report has shown that motor neuron involvement is recognized as part of SCA2 in the same pedigree with full CAG repeat expansions in ATXN2 gene. We here report the patient with lower motor neuron involvement as an initial symptom of SCA2.

Inhibition of Heat Shock Protein 90 Lowered Intraocular Pressure without Affecting the Production of Aqueous Humor in Rabbits.

INTRODUCTION: Heat shock protein (Hsp) 90 is one of the most abundant proteins in unstressed cells and regulates stability and functional maintenance of client proteins. In ocular tissue, Hsp90 is widely expressed in the cornea and retina and has multiple roles in these tissues. The expression of HSPs was induced in the retinas of glaucomatous patients and laser-induced glaucoma in monkey while their mechanisms remain to be elucidated. For this reason, we tried to elucidate the role of Hsp90 in intraocular pressure (IOP) regulation in rabbits. METHODS: IOP was measured by a pneumatonometer before and after intracameral injection of Hsp90 inhibitors. The aqueous flow rate was measured by fluorophotometry. Trans-epithelial electrical resistance was measured in primary human trabecular meshwork cells. RESULTS: 17-AAG, a specific Hsp90 inhibitor, significantly lowered IOP at concentrations of more than 30 µm in normotensive rabbits. Other Hsp90 inhibitors also significantly lowered IOP in normotensive rabbits at a dose of 100 µm. No reduction of aqueous humor production was observed by injection of 17-AAG in rabbits. Topical administration of pilocarpine tended to attenuate the IOP-lowering effects induced by the Hsp90 inhibitor. No reduction of trans-epithelial electrical resistance was observed by inhibition of Hsp90 in culture cells. CONCLUSIONS: These results indicated that intraocular Hsp90 regulates IOP, and the inhibition of Hsp90 by Hsp90 inhibitor decreases IOP without affecting aqueous humor production in rabbits. Further research in elucidating the mechanism of Hsp90 inhibitors will result in a better understanding of the role of Hsp90 in the regulation of IOP.

Writer's Cramps as an Initial Symptom of Spinocerebellar Ataxia Type 14: A Case Report.

Spinocerebellar ataxia type 14 (SCA14) is a rare form of autosomal dominant cerebellar ataxia caused by mutations in PRKCG. We herein report a case of SCA14 presenting with writer's cramp that predated the onset of progressive ataxia by four years. A 47-year-old Japanese woman had an 11-year history of writer's cramps, followed by unsteadiness. Whole-exome sequencing revealed a heterozygous mutation in PRKCG (p.C142S), leading to an SCA14 diagnosis. Therefore, writer's cramp might be a characteristic extracerebellar sign of SCA14 and can precede the onset of cerebellar ataxia.