Prediction of ESBL-producing E coli for suspected urinary tract infection.

AIM: The widespread existence of extended-spectrum ß-lactamase (ESBL) producing Escherichia coli (E. coli) has become a critical threat in developed countries. Prediction rule for ESBL producing E. coli is relevant to see patients with suspected urinary tract infection. MATERIALS AND METHODS: We collected clinical and laboratory data and constructed multivariate logistic regression models to develop a clinical prediction rule in the derivation cohort with 1185 patients with urine cultures and validated the rule in the validation cohort with 516 patients. RESULTS: ESBL-producing E. coli was found in 185 patients (16%) in the derivation cohort. When assigning 14 points for being female (odds ratio (OR): 4.2), six points for CRP >5 mg/dl (OR: 1.87), and four points for a history of urinary tract infection (OR: 1.52), the area under the curve (AUC) had 0.67 (95% confidence interval (CI): 0.63-0.70) in the derivation cohort and 0.64 (95% CI: 0.59-0.69] in the validation cohort. CONCLUSIONS: The developed prediction rule had moderate accuracy to predict ESBL-producing E. coli in patients with suspected urinary tract infection.

Unexplained Abdominal Pain Caused by Fracture of the Thoracic Vertebra.

BACKGROUND It is important to identify the cause of chronic abdominal pain, especially in older adults. Thoracolumbar vertebral compression fractures are one potential cause, and can be difficult to identify. We report a case of an older man with severe unexplained abdominal pain and nausea due to an inadequately treated thoracolumbar vertebral compression fracture. CASE REPORT A 93-year-old man fell 89 days prior to visiting the hospital and was diagnosed with a compression fracture in the Th12 vertebra. He started wearing a corset on the day of the injury. Two days later, he developed abdominal pain, mild nausea, and a decreased appetite. He attributed the symptoms to wearing the corset; therefore, he stopped wearing it. The cause of his abdominal symptoms could not be determined by blood tests and computed tomography of the abdomen. A 45° upper body elevation induced marked right lower abdominal pain (consistent with the dominant region of Th12-L1), and decreased temperature sensation was observed in the same region. We concluded that the abdominal pain was caused by neuropathy owing to a ruptured Th12 vertebral fracture. The patient was treated conservatively, the abdominal pain and nausea resolved 7 weeks after admission, and the patient was discharged. CONCLUSIONS When assessing patients with unexplained abdominal pain, vertebral compression fractures should be included in the differential diagnosis and the necessary diagnostic assessments should be made as early as possible. Early diagnosis provides a wider range of treatment options and can contribute to minimizing functional decline.

Atypical, Levetiracetam-induced Hypersensitivity Syndrome Complicated by Fulminant Liver Failure in a Patient Undergoing Hemodialysis.

A 59-year-old man undergoing hemodialysis was administered levetiracetam, after which he developed a systemic rash, high fever, severe liver dysfunction, and leukocytopenia with reactivation of human herpes virus 6. Atypical drug-induced hypersensitivity (DIHS) was diagnosed, and prednisolone was administered at 60 mg/day. However, liver failure rapidly progressed, and the patient died 12 days following treatment. Despite the rarity of DIHS with concomitant fulminant liver failure from levetiracetam and sufficient clearance thereof by hemodialysis, our case suggests that this syndrome may still ensue, resulting in mortality, even in hemodialysis patients. Although no treatment has yet been established, strict monitoring and aggressive treatment may be required.

Anti-interferon-gamma autoantibody related disseminated nontuberculous mycobacteriosis with pathological features of immunoglobulin G4-related disease.

A 72-year-old man who was diagnosed as pulmonary mycobacterium avium complex (MAC) disease had suffered from antibiotics resistant fever with left renal enlargement surrounded by inflammatory change and multiple osteolytic lesions on computed tomography (CT). The renal biopsied samples pathologically showed immunoglobulin G4 (IgG4) positive plasma cell infiltration and many acid-fast bacilli without granuloma formation. Nucleic acid identification test for MAC from the samples of vertebral osteolytic lesion was positive. In the autopsy samples from left kidney, epithelioid cell granuloma and Langhans giant cell with many acid-fast bacilli were shown pathologically. In addition to osteolytic lesions on CT study, these pathological findings were not consistent with IgG4-related disease (IgG4-RD). The diagnosis of disseminated nontuberculous mycobacteriosis was made, and plasma anti-interferon-gamma (IFN-γ) autoantibody was found as the cause of underlying immunodeficiency. Disturbed function of IFN-γ resulted in impaired ability of phagocytic cells against pathogens and leading to spread of infection. T-helper type 2 dominant immune response was induced by prolonged antigenic stimulation of mycobacteria, which might have contributed to form the pathological features of IgG4-RD.

Lactoferrin Ameliorates Dry Eye Disease Potentially through Enhancement of Short-Chain Fatty Acid Production by Gut Microbiota in Mice.

Lactoferrin is a glycoprotein found at high concentrations within exocrine secretions, including tears. Low levels of lactoferrin have been implicated in the loss of tear secretion and ageing. Furthermore, lactoferrin possesses a range of functionalities, including anti-inflammatory properties and the ability to modulate the gut microbiota. Expanding evidence demonstrates a crucial role of the gut microbiota in immune regulation and development. The specific composition of bacterial species of the gut has a profound influence on local and systemic inflammation, leading to a protective capacity against a number of inflammatory diseases, potentially by the induction of regulatory immune cells. In this study, we demonstrated that oral administration of lactoferrin maintains tear secretion in a restraint and desiccating stress induced mouse model of dry eye disease. Furthermore, we revealed that lactoferrin induces the reduction of inflammatory cytokines, modulates gut microbiota, and induces short-chain fatty acid production. Whereas, the antibiotic vancomycin abrogates the effects of lactoferrin on dry eye disease and significantly reduces short-chain fatty acid concentrations. Therefore, this protective effect of LF against a mice model of DED may be explained by our observations of an altered gut microbiota and an enhanced production of immunomodulatory short-chain fatty acids.

Acetylcholine and Royal Jelly Fatty Acid Combinations as Potential Dry Eye Treatment Components in Mice.

Dry eye is a multifactorial disease characterized by ocular discomfort and visual impairment. Our previous studies have shown that royal jelly (RJ) has restored the capacity for tear secretion by modulating muscarinic calcium signaling. RJ contains acetylcholine, which is a major cholinergic neurotransmitter, and a unique set of fatty acids with C 8 to 12 chains, which are expected to be associated with health benefits. The purpose of the present study was to investigate the active components involved in tear secretion capacity, focusing on acetylcholine and fatty acids in RJ. Using the stress-induced dry-eye model mice, it was confirmed that acetylcholine with three fatty acids (10-hydroxydecanoic acid, 8-hydroxyoctanoic acid, and (R)-3,10-dihydroxydecanoic acid) was essential for tear secretion. In ex vivo Ca2+ imaging, these three fatty acids suppressed the decrease in intracellular modulation of Ca2+ in the lacrimal gland by acetylcholine when treated with acetylcholinesterase, indicating that the specific type of RJ fatty acids contributed to the stability of acetylcholine. To our knowledge, this study is the first to confirm that a specific compound combination is important for the pharmacological activities of RJ. Our results elucidate the active molecules and efficacy mechanisms of RJ.

Clinical characteristics and factors related to antibiotic-associated diarrhea in elderly patients with pneumonia: a retrospective cohort study.

BACKGROUND: Antibiotic-associated diarrhea (AAD) is a common problem among elderly inpatients because many elderly patients are admitted for pneumonia or other conditions that necessitate antibiotic treatment. In the super aging population, more patients are suffering from pneumonia than before, but the incidence or risk factors for AAD among many elderly patients have not been well scrutinized. METHODS: We conducted a retrospective cohort study of elderly patients diagnosed with pneumonia from April 2014 to March 2019 who were admitted to the Department of General Medicine of a Tertiary Care Hospital in Japan. Patients (≥ 65 years of age) who were diagnosed with bacterial pneumonia or aspiration pneumonia and treated with antibiotics were included. We defined AAD by diarrhea with more than three loose or watery stools per day and included patients who had these symptoms for either one day or two or more consecutive days. We also assessed the length of hospital stay and in-hospital mortality. The potential risk factors for AAD included age, sex, body weight, body mass index, smoking, alcohol, activities of daily living (ADL),　comorbidities, vital signs, laboratories, the severity of pneumonia, antibiotic and other medication use. RESULTS: There were 1,067 patients, the mean age was 83 years, and men accounted for 59 %. ß-Lactamase inhibitors were frequently prescribed antibiotics in 703 patients (66 %), and proton pump inhibitors (PPIs) were also commonly administered (48 %). AAD developed in 322 patients (30 %). The multivariate logistic regression model showed that ß-lactamase inhibitors (OR 1.43, 95 % CI 1.05-1.95) and PPIs (OR 1.37, 95 % CI 1.03-1.83) were associated with AAD as well as age (OR 1.03 per year, 95 % CI 1.01-1.05). CONCLUSIONS: AAD was common among elderly inpatients with pneumonia, and ß-lactamase inhibitors and PPIs were associated with AAD. Strict use of such medication should be considered to decrease the risk of AAD.

Randomized, crossover clinical efficacy trial in humans and mice on tear secretion promotion and lacrimal gland protection by molecular hydrogen.

The incidence of dry eye disease is increasing worldwide because of the aging population and increasing use of information technology. Dry eye disease manifests as tear-layer instability and inflammation caused by osmotic hypersensitization in tear fluids; however, to our knowledge, no agent that treats both pathologies simultaneously is available. Molecular hydrogen (H2) is known to be effective against various diseases; therefore, we aimed to elucidate the effects of H2 on tear dynamics and the treatment of dry eye disease. We revealed that administering a persistent H2-generating supplement increased the human exhaled H2 concentration (p < 0.01) and improved tear stability (p < 0.01) and dry eye symptoms (p < 0.05) significantly. Furthermore, H2 significantly increased tear secretion in healthy mice (p < 0.05) and significantly suppressed tear reduction in a murine dry eye model (p = 0.007). H2 significantly and safely improved tear stability and dry eye symptoms in a small exploratory group of 10 human subjects, a subset of whom reported dry eye symptoms prior to treatment. Furthermore, it increased tear secretion rapidly in normal mice. Therefore, H2 may be a safe and effective new treatment for dry eye disease and thus larger trials are warranted.

Identification of Lacrimal Gland Postganglionic Innervation and Its Regulation of Tear Secretion.

Tear fluid secreted from the exocrine lacrimal gland (LG) has an essential role in maintaining a homeostatic environment for a healthy ocular surface. Tear secretion is regulated by the sympathetic and parasympathetic components of the autonomic nervous system, although the contribution of each component is not fully understood. To investigate LG innervation, we identified sympathetic and parasympathetic postganglionic nerves, specifically innervating the mouse LG, by injecting a retrograde neuronal tracer into the LG. Interruption of neural stimuli to the LG by the denervation of these postganglionic nerves immediately and chronically decreased tear secretion, leading to LG atrophy along with destruction of the lobular structure. This investigation also found that parasympathetic, but not sympathetic, innervation was involved in these alterations.

Severe fever with thrombocytopenia syndrome complicated with subdural hematoma: A rare case and literature review.

A 79-year-old woman presented with fever and general malaise. Examination revealed hepatic injury, thrombocytopenia, skin lesions, and regional lymphadenopathy; severe fever with thrombocytopenia syndrome (SFTS) was diagnosed using polymerase chain reaction. The patient developed impaired consciousness that worsened after 4 days. Magnetic resonance imaging of the head revealed a subdural hematoma in the occipital region with an uncertain onset time. As SFTS rarely causes intracranial hemorrhage, the associated risk factors are unknown. Clinicians may overlook potential intracranial hemorrhage in stuporous SFTS patients.

Corneal Sensory Experience via Transient Receptor Potential Vanilloid 1 Accelerates the Maturation of Neonatal Tearing.

Tearing maturates rapidly after birth, and external environmental challenges play a key role in promoting lacrimal functional maturation. However, little is known about the facilitative factors underlying this developmental process or the potential of application of these factors to treat hypofunction of the lacrimal gland. In this study, eye opening and the subsequent ocular surface sensory experience, which is thought to be involved in postnatal maturation of lacrimal function, were investigated. Our results demonstrated that eye opening after birth is essential for the maturation of neonatal tearing. The maturation process of lacrimal function is dependent on the ocular surface sensory experience via transient receptor potential cation channel subfamily member 1 after birth. This study provides, for the first time, important evidence of the sensory experience of the ocular surface in relation to the maturation of functional tear secretion during the postnatal period.

Enriched environment alleviates stress-induced dry-eye through the BDNF axis.

The number of patients with dry eye disease (DED) is increasing, and DED has become an urgent public health problem. A comorbidity of mental disorders has been reported in DED patients. We hypothesized that physical and psychological stressors impair tear secretion. To examine the relationship between stress loading and decreased tear secretion, we established a stress-induced DED mouse model, which permitted us to address the underlying mechanism of pathogenesis and resilience. Enriched environment (EE) was an effective intervention to prevent and alleviate stress-induced decreased tear secretion. Because stress loading resulted in decreased brain-derived neurotrophic factor (BDNF) expression while EE resulted in increased expression, we focused on the role of BDNF in tear secretion. Using two distinct Bdnf gene knockdown mice, we evaluated whether BDNF was a deterministic factor in regulating tear secretion in healthy and stressed conditions. Bdnf knockdown mice showed decreased basal tear secretion and loss of stress tolerance by EE for tear secretion. These results suggest that BDNF expression is related to tear secretion and to the pathology of DED.

Intravital Two-photon Imaging of Ca2+ signaling in Secretory Organs of Yellow Cameleon Transgenic Mice.

Intracellular calcium ([Ca2+]i) signaling regulates physiological functions in most cells. In secretory organs, such as the pancreas, salivary gland, and lacrimal gland (LG), [Ca2+]i elevation in acinar cells triggers fluid secretion, which plays vital roles in the maintenance of functional health across the life-course. It is important to understand the secretory mechanism of secretory organs, but lack of analytic systems available for living animals limits the scope of research to gain deeper insights into the precise mechanism of secretion. We established an intravital imaging system for specific cell types of secretory organs to monitor the [Ca2+]i changes using mouse line expressing Yellow Cameleon 3.60, a genetically encoded Ca2+ indicator. Elevation of [Ca2+]i in specific cell types of secretory organs could be monitored after cholinergic stimulation ex vivo and intravitally. We found that a marked attenuation of LG [Ca2+]i response to cholinergic stimulation was induced under pathological conditions by postganglionic denervation. Intravital Ca2+ imaging in secretory organs will broaden our understanding of the cellular mechanisms in animal models of secretory diseases.

Ketone body 3-hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina.

Calorie restriction (CR) being the most robust dietary intervention provides various health benefits. D-3-hydroxybutyrate (3HB), a major physiological ketone, has been proposed as an important endogenous molecule for CR. To investigate the role of 3HB in CR, we investigated potential shared mechanisms underlying increased retinal 3HB induced by CR and exogenously applied 3HB without CR to protect against ischemic retinal degeneration. The repeated elevation of retinal 3HB, with or without CR, suppressed retinal degeneration. Metabolomic analysis showed that the antioxidant pentose phosphate pathway and its limiting enzyme, glucose-6-phosphate dehydrogenase (G6PD), were concomitantly preserved. Importantly, the upregulation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a regulator of G6PD, and elevation of the tricarboxylic acid cycle's Nrf2 activator, fumarate, were also shared. Together, our findings suggest that CR provides retinal antioxidative defense by 3HB through the antioxidant Nrf2 pathway via modification of a tricarboxylic acid cycle intermediate during 3HB metabolism.

Serotonin hormonally regulates lacrimal gland secretory function via the serotonin type 3a receptor.

Tears are extracellular fluid secreted from the lacrimal gland (LG). Tears consist of a dynamic tri-layered film composed of secretions from the LG, Meibomian gland, and conjunctival goblet cells. The LG secretes the aqueous component of the tear, the Meibomian gland secretes the lipid component, and conjunctival goblet cells secrete mucin. The regulation of LG activity via the autonomic nervous system has been recognized as fundamental to maintaining aqueous tear flow. Here, we describe the role of a hormone, peripheral serotonin, in tear secretion. We found that blood serotonin concentration, changed by feeding a diet deprived of the serotonin precursor tryptophan, correlated with tear secretion, and that a sustained decrease in serotonin resulted in LG atrophy and autophagy. The combination of a decrease in serotonin with the interruption of autonomic neural stimuli to the LG preceded these alterations. Furthermore, we found that the serotonin type 3a receptor expressed in LG acinar cells is involved in tear secretion via intracellular calcium mobilization. Our findings demonstrate that hormonal regulation by serotonin, in cooperation with the autonomic nervous system, regulates tear secretion.

Restoration of Tear Secretion in a Murine Dry Eye Model by Oral Administration of Palmitoleic Acid.

Sea buckthorn (Hippophae rhamnoides)-derived products have traditionally been used as food and medicinal ingredients in Eastern countries. The purpose of this study was to investigate the effect of oral intake of sea buckthorn oil products on tear secretion using a murine dry eye model. Orally administered sea buckthorn pulp oil (not seed oil) restored aqueous tear secretion to its normal value under a dry eye condition. Palmitoleate (C16:1), a fatty acid present in sea buckthorn pulp oil, preserved tear secretion and suppressed inflammatory cytokines in the lacrimal gland to the same extent as that by pulp oil. These results suggest that an oral intake of sea buckthorn pulp oil has a potency to preserve tear secretion capacity in the dry eye state and palmitoleate, its main constituent fatty acid, is an active component of the oil. This effect may enable a potent diet-based treatment for the prevention of dry eye.

Heavy Chain-Hyaluronan/Pentraxin 3 from Amniotic Membrane Suppresses Inflammation and Scarring in Murine Lacrimal Gland and Conjunctiva of Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) is a major complication of hematopoietic stem cell transplantation. Dry eye disease is the prominent ocular sequel of cGVHD and is caused by excessive inflammation and fibrosis in the lacrimal glands. Heavy chain-Hyaluronan/Pentraxin 3 (HC-HA/PTX3) is a complex purified from human amniotic membrane (AM) and known to exert anti-inflammatory and anti-scarring actions. In this study, we utilized a mouse model of cGVHD to examine whether HC-HA/PTX3 could attenuate dry eye disease elicited by cGVHD. Our results indicated that subconjunctival and subcutaneous injection of HC-HA/PTX3 preserved tear secretion and conjunctival goblet cell density and mitigated inflammation and scarring of the conjunctiva. Such therapeutic benefits were associated with suppression of scarring and infiltration of inflammatory/immune cells in the lacrimal glands. Furthermore, HC-HA/PTX3 significantly reduced the extent of infiltration of CD45+ CD4+ IL-17+ cells, CD45+ CD34+ collagen I+ CXCR4+ fibrocytes, and HSP47+ activated fibroblasts that were accompanied by upregulation of collagen type Iα1, collagen type IIIα1 and NF-kB in lacrimal glands. Collectively, these pre-clinical data help prove the concept that subcutaneous and subconjunctival injection of HC-HA/PTX3 is a novel approach to prevent dry eye disease caused by cGVHD and allow us to test its safety and efficacy in future human clinical trials.

Clinical Evaluation of a Royal Jelly Supplementation for the Restoration of Dry Eye: A Prospective Randomized Double Blind Placebo Controlled Study and an Experimental Mouse Model.

BACKGROUND: Dry eye is a multifactorial disease characterized by ocular discomfort and visual impairment. Lacrimal gland function has been shown to decrease with aging, a known potent risk factor for dry eye. We have previously found that orally administrated royal jelly (RJ) restored tear secretion in a rat model of dry eye. METHODS AND FINDINGS: We examined the effects of RJ oral administration on dry eye in this prospective, randomized, double-blind, placebo-controlled study. Forty-three Japanese patients aged 20-60 years with subjective dry eye symptoms were randomized to an RJ group (1200 mg/tablet, six tablets daily) or a placebo group for 8 weeks. Keratoconjunctival epithelial damage, tear film break-up time, tear secretion volume, meibum grade, biochemical data, and subjective dry eye symptoms based on a questionnaire were investigated at baseline, and at 4 and 8 weeks after intervention. Adverse events were reported via medical interviews. In the RJ group, tear volume significantly increased after intervention (p = 0.0009). In particular, patients with a baseline Schirmer value of ≤10 mm showed a significant increase compared with baseline volume (p = 0.0005) and volume in the placebo group (p = 0.0051). No adverse events were reported. We also investigated the effect of RJ (300 mg/kg per day) administration using a mouse model of dry eye. Orally repeated administration of RJ preserved tear secretion, potentially through direct activation of the secretory function of the lacrimal glands. CONCLUSION: Our results suggest that RJ improves tear volume in patients with dry eye. TRIAL REGISTRATION: Registered NO. the University Hospital Medical Information Network in Japan (UMIN000014446).

Oral administration of royal jelly restores tear secretion capacity in rat blink-suppressed dry eye model by modulating lacrimal gland function.

Tears are secreted from the lacrimal gland (LG), a dysfunction in which induces dry eye, resulting in ocular discomfort and visual impairment. Honey bee products are used as a nutritional source in daily life and medicine; however, little is known about their effects on dry eye. The aim of the present study was to investigate the effects of honey bee products on tear secretion capacity in dry eye. We selected raw honey, propolis, royal jelly (RJ), pollen, or larva from commercially available honey bee products. Tear secretion capacity was evaluated following the oral administration of each honey bee product in a rat blink-suppressed dry eye model. Changes in tear secretion, LG ATP content, and LG mitochondrial levels were measured. RJ restored the tear secretion capacity and decrease in LG ATP content and mitochondrial levels to the largest extent. Royal jelly can be used as a preventative intervention for dry eye by managing tear secretion capacity in the LG.