Acid-suppression Therapy Offers Varied Laryngopharyngeal and Esophageal Symptom Relief in Laryngopharyngeal Reflux Patients

It is widely accepted that laryngopharyngeal reflux requires more aggressive and prolonged therapy than gastro-esophageal reflux disease. Otolaryngologists often observe that laryngopharyngeal symptoms, such as throat clearing, hoarseness, cough, and globus pharyngeus, are slower to resolve than esophageal symptoms, such as heartburn and regurgitation. The aim of this was to provide empirical evidence to support this observation and to carry out a detailed investigation of the differences between these symptoms. Forty-five patients with laryngopharyngeal and esophageal symptoms received acid-suppression therapy that involved the continuous administration of a proton-pump inhibitor for up to 6 months. We investigated the differences in response to acid-suppression therapy between patients suffering from laryngopharyngeal and esophageal symptoms, respectively, who received upper gastrointestinal endoscopy and were assayed for serum Helicobacter pylori antibodies. The significance of the rate of symptom improvement was estimated by Kaplan-Meier analysis and the logrank test. Laryngopharyngeal symptoms improved significantly more slowly than esophageal symptoms following acid-suppression therapy (49.8 vs. 78.3%, 60 days after the start of acid suppression; P = 0.003). These differences were observed both in patients with erosive esophagitis (P = 0.008) and in H. pylori-seronegative patients (P = 0.001).     

GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes

Gasdermin-D (GsdmD) is a critical mediator of innate immune defense because its cleavage by the inflammatory caspases 1, 4, 5, and 11 yields an N-terminal p30 fragment that induces pyroptosis, a death program important for the elimination of intracellular bacteria. Precisely how GsdmD p30 triggers pyroptosis has not been established. Here we show that human GsdmD p30 forms functional pores within membranes. When liberated from the corresponding C-terminal GsdmD p20 fragment in the presence of liposomes, GsdmD p30 localized to the lipid bilayer, whereas p20 remained in the aqueous environment. Within liposomes, p30 existed as higher-order oligomers and formed ring-like structures that were visualized by negative stain electron microscopy. These structures appeared within minutes of GsdmD cleavage and released Ca²⁺ from preloaded liposomes. Consistent with GsdmD p30 favoring association with membranes, p30 was only detected in the membrane-containing fraction of immortalized macrophages after caspase-11 activation by lipopolysaccharide. We found that the mouse I105N/human I104N mutation, which has been shown to prevent macrophage pyroptosis, attenuated both cell killing by p30 in a 293T transient overexpression system and membrane permeabilization in vitro, suggesting that the mutants are actually hypomorphs, but must be above certain concentration to exhibit activity. Collectively, our data suggest that GsdmD p30 kills cells by forming pores that compromise the integrity of the cell membrane.Pyroptosis is an inflammatory form of programmed cell death that occurs in response to microbial products in the cytoplasm or to cellular perturbations caused by diverse stimuli, including crystalline substances, toxins, and extracellular ATP (1, 2). Pyroptosis plays a critical role in the clearance of intracellular bacteria (3), but may also contribute to autoinflammatory and autoimmune disease pathology. Mechanistically, pyroptosis occurs when cytosolic nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), including NLRP1, NLRP3, and NLRC4, or the pyrin domain-containing protein AIM2, nucleate a canonical inflammasome complex that activates the protease caspase-1 (2). Alternatively, intracellular lipopolysaccharide (LPS) from Gram-negative bacteria can trigger noncanonical activation of mouse caspase-11 and human caspases 4 and 5 (4–7). Caspases 1, 4, 5, and 11 can each cleave Gasdermin-D (GsdmD) to mediate pyroptotic cell death (8, 9). It is the N-terminal p30 fragment of GsdmD that is cytotoxic to cells, but precisely how it kills cells is unknown.Here we show that the human GsdmD p30 fragment liberated by active caspase-11 forms ring-like structures within membranes that function as pores. Therefore, we propose p30 kills cells by directly compromising the integrity of cellular membranes. We also show that the GsdmD I105N mutant that was unable to mediate macrophage pyroptosis (9) is hypomorphic at cell killing in a transient overexpression system and at liposome permeabilization in vitro—conditions where p30 concentration favors oligomerization.     

Exercise after heparin administration: new therapeutic program for patients with-option arteriosclerosis oblitrans.

BACKGROUND: A prospective study examined whether a combination of an exercise program and heparin administration improves the clinical symptoms of patients with arteriosclerosis obliterans (ASO) without an indication for surgical revascularization because of the lack of distal target vessels or other reasons such as high surgical risk or lack of a vein conduit from previous coronary artery bypass surgery. METHODS AND RESULTS: A total of 19 consecutive patients with symptomatic non-option ASO diagnosed by angiography were randomly assigned to 3 groups: heparin + exercise (walking for 60 min after heparin injection [3,000 units/day IV for 14 days], n = 6), heparin administration only (n = 6), and exercise only (n = 7). Plasma levels of hepatocyte growth factor (HGF) were serially measured before and after intravenous administration of heparin. Ankle brachial pressure index was measured and treadmill exercise test (2.5 km/h, 12% slope) was performed before the 2-week treatment, just after finishing treatment, and 12 weeks after beginning the treatment. Ophthalmic examinations, including visual acuity test, ocular fundoscopy and fluorescein angiographic fundus photography, were performed before and 12 weeks after the treatment program. In all patients, HGF levels increased more than 4-fold of the basal level at 30 min after heparin injection. Maximum walking time was significantly higher in the heparin + exercise group than in the other 2 groups (p < 0.05). There were no patients who showed pathological retinal angiogenesis. CONCLUSION: The combination of an exercise program and heparin administration improves the clinical symptoms of patients with non-option ASO.     

Influence of contrast ultrasonography with perflutren lipid microspheres on microvessel injury.

Microbubbles have been reported to enhance ultrasound (US)-related side effects in animal systems. The present study investigated the influence of contrast ultrasonography (US) with perflutren lipid microspheres, a recently developed second-generation contrast agent, on microvessels. Rat mesentery was exposed to 1.8-MHz pulsed US with intravenous injection of perflutren (0.1 or 1.0 ml/kg) or Levovist (300 mg/kg), and the microvessel bleeding and endothelial cell injury was examined. Impaired endothelial cells were identified by the fluorescence of propidium iodide. Microvessel bleeding was examined also in the rat myocardium. The interaction between 0.1 ml/kg of perflutren and US exposure did not cause microvessel bleeding, and did not increase endothelial cell injury compared with the sham operation, unless frequent, strong US exposure occurred. When the dose was increased to 1.0 ml/kg, the combination of perflutren and US exposure resulted in capillary bleeding and increased endothelial cell injury in capillaries and venules (p<0.01). However, the incidence of microvessel bleeding and endothelial cell injury did not exceed that with Levovist microbubbles. In the myocardium, microvessel bleeding was not observed under any conditions. In conclusion, perflutren lipid microspheres enhanced US-related microvessel injury as with other contrast agents at the dose of 1.0 ml/kg, but not with 0.1 ml/kg and the appropriate US setting.     

Hyperthymic temperament and brightness preference in healthy subjects: Further evidence for involvement of left inferior orbitofrontal cortex in hyperthymic temperament

Background

Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Although several studies indicate that subjects with hyperthymic temperament receive more illuminance, our recent study suggests that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder. Therefore, at the next stage, it can be hypothesized that hyperthymic subjects may prefer brightness (i.e., heliotropism) and thereby seek illuminance, and that percent signal changes of left inferior orbitofrontal cortex during the preference task may be associated with hyperthymic temperament scores.

Methods

We compared brightness preference and un-preference between more and less hyperthymic subjects, and investigated percent signal changes of left inferior orbitofrontal cortex during brightness preference judgment, brightness un-preference judgment, and control task by using functional Magnetic Resonance Imaging (fMRI).

Results

There were significant differences in brightness preference judgment and un-preference judgment, showing that more hyperthymic subjects preferred brighter illuminace levels and un-preferred darker illuminance levels than less hyperthymic subjects. Moreover, fMRI signal changes of left inferior orbitofrontal cortex was significantly and negatively associated with hyperthymic temperament scores.

Limitations

It is unknown why left but not right inferior orbitofrontal cortex was associated with hyperthymic temperament scores.

Conclusions

The present findings suggest that more hyperthymic subjects may prefer brightness and un-prefer darkness than less hyperthymic subjects (i.e., heliotropism), and reconfirm that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which have been reported to be associated with bipolar disorders.     

Rapid-onset dystonia-parkinsonism with ATP1A3 mutation and left lower limb paroxysmal dystonia

BackgroundRapid-onset dystonia–parkinsonism (RDP) is a disease characterized by an abrupt onset of dystonia accompanied by signs of parkinsonism and prominent bulbar symptoms.Case reportWe describe a case of a female patient, born after normal delivery, but diagnosed with mild intellectual disability at age 7. She presented with an abrupt onset of upper limb dystonia and bradykinesia without tremor in parkinsonism, as well as dysarthria and dysphagia caused by prominent bulbar symptoms, at age 9. She had normal findings on brain magnetic resonance imaging, electroencephalography, and blood examination but was diagnosed with a psychogenic disorder. At age 10, she developed left lower limb paroxysmal stiffness with pain, and at 14, she was hospitalized due to lasting paroxysmal symptoms. Whole-exome sequencing was performed for this index case and her parents, and a de novo missense variant c.829G > A, p.Glu277Lys in ATP1A3 was identified.DiscussionThis RDP case highlights a rare clinical feature of paroxysmal dystonia that affects the lower left limb and develops after the abrupt onset of permanent dystonia. Currently, there are only three reported RDP cases associated with the same missense mutation, and we summarized the clinical features of all cases including ours, such as onset of age, time for stable, RDP score, relapse and exacerbation. Various symptoms owing to ATP1A3 mutation could develop as ATP1A3-related neurological disorders beyond classical phenotypes such as alternating hemiplegia of childhood (AHC) or RDP. Although RDP is extremely rare during childhood, it is important to understand its clinical characteristics in children.     

Transient hypoglycorrhachia with paroxysmal abnormal eye movement in early infancy

Paroxysmal abnormal eye movement in early infancy is one of the initial symptoms of glucose transporter 1 deficiency syndrome (GLUT1DS). We describe four early infants with transient hypoglycorrhachia presenting with abnormal eye movements. Their symptoms disappeared after the introduction of a ketogenic diet (KD), and their development was normal. Since no variants in SLC2A1 were detected, the CSF-to-blood glucose ratios (C/B) were re-examined, and within normal range. None of the four patients displayed recurrent symptoms after withdrawal from the KD. Because long-term KD has potential adverse effects and could affect the quality of life of patients and their families, re-examination of CSF glucose during late infancy should be considered in the case of absence of the SLC2A1 pathogenic variant.     

ARCO Consensus on the Pathogenesis of Non-traumatic Osteonecrosis of the Femoral Head

Osteonecrosis of the femoral head (ONFH) is a devastating disease frequently leading to femoral head collapse and hip arthritis. Specifically, non-traumatic ONFH primarily affects young and middle-aged adults. Although compromised local circulation of the femoral head seems to be pathognomonic for the disease, the pathogenesis is perplexing and continues to be an area of scrutiny and research. Comprehension of the pathogenesis is of crucial importance for developing and guiding treatments for the disease. Therefore, we provide an up-to-date consensus on the pathogenesis of non-traumatic ONFH.     

Multifocal and microscopic chromophobe renal cell carcinomatous lesions associated with ‘capsulomas’ without FCLN gene abnormality

Chromophobe renal cell carcinoma (RCC) accounts for approximately 5% of renal epithelial neoplasms. Multiple and/or bilateral chromophobe RCCs in an individual are generally rare but frequently occur in patients with Birt–Hogg–Dubé syndrome (BHDS) and in patients with tuberous sclerosis complex (TSC). The responsible genes in both BHDS and TSC act as tumor suppressors. Therefore, it seems that some genetic backgrounds are required for the generation and progression of multiple chromophobe RCCs. Here, we report a case of multiple and bilateral chromophobe RCCs along with several small‐sized capsular angiomyolipomas known as ‘capsulomas’ in a 39‐year‐old woman who had neither a particular medical history nor specific gene mutation. There has been no report of sporadic multiple chromophobe RCCs and ‘capsulomas’ developing in a patient without genetic features, having potential for novel genetic variation.     

Association of aging and tooth loss with masseter muscle characteristics: an ultrasonographic study

Clinical Oral Investigations - This study aimed to investigate the relationship between aging and tooth loss on masseter muscle quantity and quality. This cross-sectional study was conducted among...