Absence of Relationship between Oblique Muscle Size and Bielschowsky Head Tilt Phenomenon in Clinically Diagnosed Superior Oblique Palsy

PURPOSE. To study whether the variation in maximum oblique muscle size accounts for individual variation in the Bielschowsky head tilt phenomenon (BHTP) in clinically diagnosed superior oblique (SO) palsy. METHODS. Seventeen subjects with clinically diagnosed earlyonset or idiopathic SO palsy and 14 normal subjects were enrolled in the study. Magnetic resonance imaging (MRI) in coronal and sagittal planes was used for quantitative morphometry of inferior oblique (IO) and SO muscles. Maximum crosssectional area of the SO and IO cross section at the mid-inferior rectus crossing were determined in central gaze and compared with paretic eye hypertropia on ipsilesional versus contralesional head tilt. RESULTS. Mean (ϮSD) maximum SO cross section was 18.1 Ϯ 3.2 mm 2 in normal subjects, 14.2 Ϯ 6.8 mm 2 ipsilesional to SO palsy, and 19.2 Ϯ 4.5 mm 2 contralesional to SO palsy. The ipsilesional SO cross section was significantly smaller than the contralesional (P ϭ 0.004) and normal (P ϭ 0.01) ones. The mean IO cross section was 18.3 Ϯ 3.5 mm 2 in normal subjects, 21.3 Ϯ 7.9 mm 2 ipsilesional to SO palsy (P ϭ 0.43), and 22.0 Ϯ 6.7 mm 2 contralesional to SO palsy (P ϭ 0.26). Hyperdeviation varied with head tilt by 20.1 Ϯ 5.5°in subjects with SO atrophy, and 10.3 Ϯ 5.6°in subjects without SO atrophy (P ϭ 0.003). Although oblique muscle cross sections did not correlate with BHTP, subjects with clinically diagnosed SO palsy segregated into groups exhibiting normal versus atrophic SO size. CONCLUSIONS. SO size does not account for the variation in BHTP in clinically diagnosed SO palsy, supporting the proposition that the BHTP is nonspecific for SO function. (Invest Ophthalmol Vis Sci. 2009;50:175-179) DOI:10.1167/iovs.08-2393 P atients with early onset or idiopathic superior oblique (SO) palsy are heterogeneous. Only when orbital imaging shows a large asymmetry in cross-sectional areas of the SO muscles is actual muscle weakness 1-4 likely. SO palsy may not necessarily be neuropathic, because abnormalities of the SO tendon, 5-8 or of orbital pulleys may cause incomitant vertical strabismus mimicking SO palsy. 9,10 For this reason, the gold standard for the diagnosis of SO palsy is ultimately radiographic. Nevertheless, much clinical literature on SO palsy is based on clinical, not radiographic, criteria. If clinical criteria are nonspecific for SO palsy, then some beliefs about SO palsy may benefit from reexamination. The Bielschowsky head tilt phenomenon (BHTP) consists of a greater hypertropia during head tilt to the ipsilesional than contralesional shoulder in patients seated upright and is used as a clinical lateralizing test for SO palsy. The biomechanical basis of the BHTP is not fully understood, but probably includes loss of downward and intorsional torque of the palsied SO in compensatory ocular counterrolling (OCR). 11 The BHTP is considered by many clinicians to be the defining clinical criterion for SO palsy. Oblique muscles have both vertical and torsional actions. Contractility of the SO can be radiographically determined by evaluating the change in SO cross-sectional area during gaze shift from supraduction to infraduction. In patients with SO palsy, SO contractility is well correlated with maximum SO cross-sectional area in central gaze. 12 Further, MRI evidence of SO muscle contractile change in vertical gaze shift resembles similar MRI findings during ocular counterrolling. 13 During static ocular counterrolling, 13 the posterior SO cross section was found to be greater during head tilt to the ipsilateral than the contralateral side, reflecting SO contraction to implement ocular torsion. 2 Because changes in SO cross section due to vertical duction resemble changes associated with OCR, we sought to analyze whether variation in SO size accounts for variation in BHTP in SO palsy. Recognizing that maximum SO cross-sectional size in the central gaze is highly correlated with SO contractility, 12 we supposed that the BHTP would also correlate with SO size if this diagnostic test directly reflects SO function. METHODS Subjects Subjects with clinically diagnosed congenital or idiopathic SO palsy, including presumably decompensated cases, were recruited from a prospective study of extraocular muscle function at Okayama University Hospital. The subjects agreed to participate and gave written informed consent according to a protocol conforming to the tenets of the Declaration of Helsinki. Diagnosis of SO palsy was based on clinical criteria including: ipsilesional hypertropia greater in the contralesional than the ipsilesional version, and greater during head tilt to the ipsilateral than the contralateral shoulder when seated upright (Bielschowsky head tilt test); a deficit in infraduction when the ipsilesional eye was adducted; and results of Hess screen testing performed by strabismologists confirming greater hypertropia in deorsumversion and V pattern. All participants underwent complete ophthalmic examinations, including measurement of heterophorias with prism and cover testing. The BHTP was defined quantitatively to be the difference From th

Oxaliplatin-induced neurotoxicity involves TRPM8 in the mechanism of acute hypersensitivity to cold sensation

Oxaliplatin-induced peripheral neurotoxicity (OPN) is commonly associated with peripheral hypersensitivity to cold sensations (CS) but the mechanism is unknown. We hypothesized that the transient receptor potential melastatin 8 (TRPM8), a putative cold and menthol receptor, contributes to oxaliplatin cold hypersensitivity. To determine whether the TRPM8 is involved in acute OPN, varying concentrations of menthol were topically applied to the tongues of healthy subjects (n = 40) and colorectal cancer patients (n = 36) before and after oxaliplatin administration. The minimum concentration of menthol to evoke CS at the menthol application site was determined as the CS detection threshold (CDT). In healthy subjects, the mean CDT was 0.068. Sex and age differences were not found in the CDT. In advanced colorectal cancer patients, the mean CDT significantly decreased from 0.067% to 0.028% (P = 0.0039) after the first course of oxaliplatin infusions, and this marked CS occurred in patients who had grade 1 or less neurotoxicity, and grade 2 neurotoxicity, but not in those with grade 3 neurotoxicity. Further, the mean baseline CDT in oxaliplatin-treated patients was significantly higher than that of chemotherapy-naïve patients and healthy subjects (0.151% vs. 0.066%, P = 0.0225), suggesting that acute sensory changes may be concealed by progressive abnormalities in sensory axons in severe neurotoxicity, and that TRPM8 is subject to desensitization on repeat stimulation. Our study demonstrates the feasibility of undertaking CDT test in a clinical setting to facilitate the identification of early neurotoxicity. Moreover, our results indicate potential TRPM8 involvement in acute OPN

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Efficacy of Goshajinkigan for Peripheral Neurotoxicity of Oxaliplatin in Patients with Advanced or Recurrent Colorectal Cancer

http://creativecommons.org/licenses/by/3.0/Peripheral neurotoxicity is the major limiting factor for oxaliplatin therapy. Goshajinkigan (GJG), a traditional Japanese herbal medicine, was recently shown to be effective in protecting against the neurotoxicity of taxanes in Japan. We retrospectively investigated the effect of GJG on peripheral neurotoxicity associated with oxaliplatin therapy. Ninety patients with metastatic colorectal cancer that received FOLFOX4 or modified FOLFOX6 therapy were assigned to receive one of the following adjuncts: oral GJG at 7.5 g day^ (Group A, n = 11), intravenous supplementation of calcium gluconate and magnesium sulfate (1 g each before and after FOLFOX) (Group B, n = 14), combined GJG and calcium gluconate and magnesium sulfate therapies (Group C, n = 21), or no concomitant therapy (Group D, n = 44). The incidence of peripheral neurotoxicity was investigated when the cumulative dose of oxaliplatin exceeded 500 mgm^.When the cumulative dose of oxaliplatin exceeded 500 mgm^, the incidence of neuropathy (all grades) in Groups A-Dwas 50.0%, 100%, 78.9%, and 91.7%, respectively. It was lowest in the group that received GJG alone. Concomitant administration of GJG reduced the neurotoxicity of oxaliplatin in patients that received chemotherapy for colorectal cancer

Sarcopenia accompanied by systemic inflammation can predict clinical outcomes in patients with head and neck cancer undergoing curative therapy

ObjectivesEvaluation of sarcopenia accompanied by systemic inflammation status is a more beneficial prognostic marker than sarcopenia alone in various cancers. However, few studies have focused on this combination in patients with head and neck squamous cell cancer (HNSCC). In this study, we investigated how the combination of sarcopenia and systemic inflammation could affect survival in patients with HNSCC. Moreover, we explored which systemic inflammation markers could be better prognostic indicators when accompanied by sarcopenia.Materials and methodsWe retrospectively reviewed the medical records of patients with HNSCC treated between 2012 and 2016. Sarcopenia was defined by the skeletal muscle area measured on a computed tomography image slice at the level of the third cervical vertebra. The neutrophil/lymphocyte, platelet/lymphocyte, and lymphocyte/monocyte ratios (NLR, PLR, and LMR, respectively) were used as systemic inflammation markers that were combined with sarcopenia to evaluate prognosis.ResultsA total of 100 patients were enrolled, and 71 patients were considered sarcopenia. Patients with sarcopenia had significantly lower LMR and higher NLR and PLR. They also showed worse overall survival (OS) and progression-free survival (PFS). The comparative assessment of multiple combination patterns of sarcopenia and systemic inflammation indices proved that sarcopenia plus LMR considered as most reliable indicator for prognosis in HNSCC patients. Sarcopenia plus low LMR was a significantly poor prognostic factor both for OS and PFS with greater HR values than sarcopenia alone.ConclusionsThe combination of sarcopenia and LMR was considered the most sensitive prognostic factor in patients with HNSCC, suggesting it might be beneficial for identifying poor outcome risks

Pre-donation BMI and preserved kidney volume can predict the cohort with unfavorable renal functional compensation at 1-year after kidney donation

Abstract Background The magnitude of renal function recovery after kidney donation differs in donors with a heterogeneous background. Preoperative assessment of candidates with potentially unfavorable renal functional compensation is critical when baseline kidney function is marginal. We explored the significance of preserved kidney volume (PKV) and known preoperative risk factors for the prediction of unfavorable renal function compensation. Methods We enrolled 101 living donors for whom a 1-mm sliced enhanced computed tomography scan was performed preoperatively and clinical data could be collected up to 1 year after donation. The donors whose estimated glomerular filtration rate (eGFR) at 1 year after donation was 70% or higher of baseline eGFR were assigned to the “favorable renal compensation” group and the others to the “unfavorable renal compensation” group. Results Age, sex, and preoperative serum uric acid level were not significant predictors for “unfavorable renal compensation.” Multivariable logistic regression analysis revealed that body mass index (BMI) and body surface area (BSA)-adjusted PKV were independent preoperative risk factors for “unfavorable renal compensation” (adjusted odds ratio, 1.342 and 0.929, respectively). Hypertension and preoperative eGFR were not independent predictors when adjusted with BMI and BSA-adjusted PKV. Receiver operative characteristic analysis revealed that the predictive equation with the two independent predictors yielded a good accuracy to detect donor candidates with unfavorable renal functional compensation (area under the curve = 0.803), and the optimal cut-off values were identified as 23.4 kg/m2 for BMI and 107.3 cm3/m2 for BSA-adjusted PKV. Conclusions BMI and BSA-adjusted PKV may be useful to select candidates with potentially unfavorable renal function compensation before kidney donation