The Glymphatic System: A Review of the Challenges in Visualizing its Structure and Function with MR Imaging

The central nervous system (CNS) was previously thought to be the only organ system lacking lymphatic vessels to remove waste products from the interstitial space. Recently, based on the results from animal experiments, the glymphatic system was hypothesized. In this hypothesis, cerebrospinal fluid (CSF) enters the periarterial spaces, enters the interstitial space of the brain parenchyma via aquaporin-4 (AQP4) channels in the astrocyte end feet, and then exits through the perivenous space, thereby clearing waste products. From the perivenous space, the interstitial fluid drains into the subarachnoid space and meningeal lymphatics of the parasagittal dura. It has been reported that the glymphatic system is particularly active during sleep. Impairment of glymphatic system function might be a cause of various neurodegenerative diseases such as Alzheimer’s disease, normal pressure hydrocephalus, glaucoma, and others. Meningeal lymphatics regulate immunity in the CNS. Many researchers have attempted to visualize the function and structure of the glymphatic system and meningeal lymphatics in vivo using MR imaging. In this review, we aim to summarize these in vivo MR imaging studies and discuss the significance, current limitations, and future directions. We also discuss the significance of the perivenous cyst formation along the superior sagittal sinus, which is recently discovered in the downstream of the glymphatic system.     

Dietary intake of seaweed and minerals and prevalence of allergic rhinitis in Japanese pregnant females: baseline data from the Osaka Maternal and Child Health Study

PURPOSE: It may be worthwhile to assess the possible protective effect of the traditional Japanese diet on allergic disorders. This cross-sectional study investigated the relationship between dietary intake of seaweed, vegetables, fruit, antioxidants, fiber, and minerals and the prevalence of allergic rhinitis. METHODS: Study subjects were 1002 Japanese pregnant women. Allergic rhinitis (including cedar pollinosis) was defined as present if subjects had received drug treatment at some point during the previous 12 months. Information on dietary factors was collected by using a self-administered diet history questionnaire. RESULTS: Seaweed intake was associated independently with a decreased prevalence of allergic rhinitis. Significant inverse dose-response relationships were found between calcium and phosphorus intake and allergic rhinitis prevalence. There also was a tendency for an inverse association between magnesium consumption and allergic rhinitis. Additional adjustment for calcium or magnesium intake apparently did not influence the inverse association with seaweed consumption. Consumption of vegetables, fruit, vitamins C and E, fiber, and zinc showed no association with allergic rhinitis, whereas a significant positive relationship was observed between beta-carotene intake and allergic rhinitis. CONCLUSIONS: High dietary intake of seaweed, calcium, magnesium, and phosphorus may be associated with a decreased prevalence of allergic rhinitis.     

Significant accumulation of KRAS mutations in bronchiolar metaplasia-associated honeycomb lesions of interstitial pneumonia

Interstitial pneumonia (IP) is a major risk factor for lung adenocarcinoma (LADC). IP-related LADC predominantly develops in the bronchiolar metaplasia lining in honeycomb lesions. Kirsten rat sarcoma virus (KRAS) is the most common oncogene mutated in IP-related LADC. The present study examined the metaplastic epithelia in honeycomb lesions for KRAS mutations using digital droplet polymerase chain reaction (ddPCR), a sensitive method used to detect infrequent mutations. Significantly higher KRAS mutation variant allele frequencies (VAFs) were detected in the metaplastic lung epithelia from 13 patients with IP compared with those in 46 non-lesioned lung samples from patients without IP (G12V, P=0.0004, G12C, P=0.0181, and G12A, P=0.0234; Mann Whitney U test). Multivariate analyses revealed that higher KRAS G12V (logistic regression model; P=0.0133, odds ratio=7.11) and G12C (P=0.0191, odds ratio=5.81) VAFs in patients with IP were independent of confounding variables, such as smoking and age. In patients with IP, metaplastic epithelia exhibited significantly higher KRAS G12V and G12C VAFs compared with the non-lesioned counterparts (paired t-test; G12V, P=0.0158, G12C, P=0.0465). These results suggested that IP could increase KRAS mutations and supported the hypothesis that bronchiolar metaplasia could be a precursor for IP-related LADC.     

Influence of Altered Knee Angle on Electromyographic Activity of Hamstring Muscles Between Nordic Hamstring Exercise and Nordic Hamstring Exercise with Incline Slope Lower Leg Board

BackgroundPrevious studies have shown that performing the Nordic hamstring exercise (NHE) with different board slope angles can affect hamstring activation. However, changes in muscle length with different board slopes can alter joint angles leading to the moment arm (MA) at the knee changing during the NHE.PurposeThis study aimed to investigate the influence of changing muscle length on hamstring electromyographic activity during an isometric NHE, while maintaining an equal moment arm.Study DesignA crossover study designMethodsSixteen male volunteers performed two types of conventional NHE, one with knees on the floor (NHE) and one with the legs placed upon an incline slope of a lower leg board (NHEB). To compare between the conventional and inclined NHE, the moment arm at the knee was calculated to be equal by an examiner holding the lower legs at points marked at 77% and 94% of the length of the lower leg. The four sub-groups comprised of: 1) NHE-77%, 2) NHE-94%, 3) NHEB-77%, and 4) NHEB-94%. The hamstring EMG activity was measured at the biceps femoris long head (BFlh) and at the semitendinosus (ST) and related compensatory muscles. The RMS data were normalized as a percentage of the maximum isometric values (normalized EMG [nEMG]). Significant main effects findings were followed up with Tukey’s post-hoc test using SPSS software and statistical significance was set at the p < 0.05 level.ResultsThe BFlh EMG activity values for NHE-77% were significantly higher than those for NHE-94% (p= 0.036) and NHEB-77% (p < 0.001), respectively, while ST during NHE-77% was significantly higher only in NHEB-77% (p < 0.001). In addition, NHEB-94% was significantly greater than NHEB-77% for both BFlh (p < 0.001) and ST (p < 0.001).ConclusionThese results indicate that hamstring electromyographic activity is decreased when the hamstring muscle is lengthened during the Nordic hamstring exercise.Level of Evidence3     

Factors Associated with Pneumocystis jirovecii Pneumonia in Patients with Rheumatoid Arthritis Receiving Methotrexate: A Single-center Retrospective Study

Objective To investigate the risk factors for the development of Pneumocystis jirovecii pneumonia (PCP) in patients with rheumatoid arthritis (RA) undergoing methotrexate (MTX) therapy. Methods This single-center retrospective cohort study included consecutive patients with RA who received MTX for at least one year. The study population was divided into PCP and non-PCP groups, depending on the development of PCP, and their characteristics were compared. We excluded patients who received biologic disease-modifying anti-rheumatic drugs (DMARDs), Janus kinase inhibitors, and anti-PCP drugs for prophylaxis. Results Thirteen patients developed PCP, and 333 did not develop PCP. At the initiation of MTX therapy, the PCP group had lower serum albumin levels, a higher frequency of pulmonary disease and administration of DMARDs, and received a higher dosage of prednisolone (PSL) than the non-PCP group. A multivariate Cox regression analysis revealed that the concomitant use of PSL [hazard ratio (HR) 5.50, p=0.003], other DMARDs (HR 5.98, p=0.002), and serum albumin <3.5 mg/dL (HR 4.30, p=0.01) were risk factors for the development of PCP during MTX therapy. Patients with these risk factors had a significantly higher cumulative probability of developing PCP than patients who lacked these risk factors. Conclusion Clinicians should pay close attention to patients with RA who possess risk factors for the development of PCP during MTX therapy.     

Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand.

Recent studies have revealed the essential role of the receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) in osteoclast differentiation and activation. Adenovirus vector could efficiently transduce genes into RAW264.7 cells, which differentiate into osteoclast-like multinucleated cells in the presence of RANKL. The role of NF-kappaB and c-jun N-terminal kinase (JNK) activation in RANKL-induced osteoclast differentiation was investigated using an adenovirus vector carrying the dominant negative 1kappaB kinase 2 gene (AxIKK2DN) or dominant negative MKK7 gene (AxMKK7DN). IKK2DN and MKK7DN overexpression in RAW cells specifically suppressed the NF-kappaB activation and JNK activation in response to RANKL, respectively, without affecting other signaling pathways. Either inhibition of NF-kappaB or JNK pathways dose-dependently inhibited osteoclast formation induced by RANKL. These results suggest that both NF-kappaB and JNK activation are independently required for osteoclast differentiation.     

Insulin is a potent survival factor in mesangial cells: role of the PI3-kinase/Akt pathway

BACKGROUND: Elucidating the mechanisms of apoptosis is important for understanding the molecular mechanisms underlying glomerular disease. The phosphatidylinositol 3 kinase (PI3-kinase)/Akt pathway is essential for survival signaling in non-renal cells. However, little is known about the anti-apoptotic effect of insulin and the role of the PI3-kinase/Akt pathway in mesangial cells (MC) apoptosis. METHODS: Apoptosis was induced in wild type, p27Kip1 (p27) -/- and p21Cip1/Waf1 (p21) -/- mouse MC by survival factor withdrawal, actinomycin D, ultraviolet (UV)-B irradiation and cycloheximide in the presence or absence of insulin (1 micromol/L) or insulin-like growth factor-I (IGF-I; 100 ng/mL). The activation and levels of Akt, extracellular signal regulated kinase (ERK) and specific cell cycle proteins were determined by Western blot analysis. RESULTS: Insulin and IGF-I inhibited wild-type MC apoptosis induced by survival factor withdrawal, actinomycin D, ultraviolet-B irradiation and cycloheximide and in p27 -/- MC when apoptosis was induced by survival factor withdrawal. Akt was activated by insulin and IGF-I during apoptosis. Blocking PI3-kinase with LY294002 reduced Akt activation and abrogated the anti-apoptotic effect of insulin. ERK was activated during apoptosis and blocking ERK activation with U0126 or PD98059 partially rescued MC from apoptosis. Moreover, insulin also suppressed ERK activation during apoptosis. Our results also showed that the CDK-inhibitor p21 was increased by insulin and that p21 up-regulation was PI3-kinase/Akt pathway dependent. Furthermore, p21 -/- MC apoptosis induced by survival factor withdrawal was not rescued by insulin in contrast to the wild-type and p27 -/- MC. These data suggest that p21 may have a critical role in the anti-apoptotic effect of insulin. CONCLUSIONS: Insulin is a potent survival factor for MC in response to a number of different apoptotic triggers, and this effect is mediated through the PI3-kinase/Akt pathway. Moreover, ERK and p21 may be involved in anti-apoptotic effect of insulin in MC.     

Recovery of postural stability following conscious sedation with midazolam in the elderly

Purpose. To investigate the differences in recovery of postural stability, after obtaining similar intravenous sedation levels with midazolam, in elderly and younger patients undergoing dental surgery. Methods. We studied 15 elderly patients (>65 years) and 15 younger patients (<55 years) after intravenous sedation. Midazolam was carefully titrated over 4–5 min until slow response to verbal commands, ptosis of the eyelid, or slight slurring of speech was obtained. Parameters were postural balance tests and an addition test, as a psychomotor function test. Results. The dose of midazolam in the elderly group (0.045 ± 0.012 mg·kg⁻¹) was 62% of that in the younger group (0.074 ± 0.026 mg·kg⁻¹). In evaluation of the percentile rank of a balance test with a visual feedback system, which contained a dynamic balance element, recovery at 60 min in the elderly group was significantly slower than that in the younger group. However, the recovery times for the balance test and the addition test, at which the significantly changed values were restored to the baseline values, were 120 min and 90 min, respectively, in both groups. Conclusion. In the recovery from sedation, elderly patients had more difficulty in acquiring postural adjustment during movement than in maintaining a standing posture. If the dose is carefully administered, however, even elderly patients might be able to return home 2 h after midazolam administration, as could the younger patients. Received: November 6, 2001 / Accepted: April 22, 2002     

Comparison of heart rate changes after neostigmine-atropine administration during recovery from propofol-N2O and isoflurane-2O anesthesia

Purpose. Propofol augments the reduction of heart rate (HR) in combination with cholinergic agents and attenuates the HR response to atropine. We examined whether propofol anesthesia was associated with an increased incidence and extent of bradycardia after neostigmine-atropine administration compared with the effects of isoflurane anesthesia. Methods. Thirty-six adult patients were randomly assigned to two groups (n = 18 each): the propofol group patients were anesthetized with propofol (5–10 mg·kg⁻¹·h⁻¹)-₂O-fentanyl, and the isoflurane group patients were anesthetized with isoflurane (0.5%–1.0%)-₂O-fentanyl. When surgery was completed, anesthetics were discontinued, and then a mixture of neostigmine 0.05 mg·kg⁻¹ and atropine 0.02 mg·kg⁻¹ was injected intravenously over 20 s. Blood pressure (BP) and HR were measured noninvasively at 1-min intervals for 10 min. Results. At the completion of the surgery, the average infusion rate of propofol was 6.2 ± 1.7 mg·kg⁻¹·h⁻¹, and the average inspired concentration of isoflurane was 0.73 ± 0.15%. Immediately before the neostigmine-atropine injections, HR and mean BP were similar in the two groups. The maximum increase in HR after the neostigmine-atropine injections was significantly less in the propofol group than in the isoflurane group (16 ± 9 and 34 ± 6 beats·min⁻¹, respectively, P < 0.01). The subsequent maximum decrease in HR was greater in the propofol group than in the isoflurane group (−9 ± 4 and −5 ± 4 beats·min⁻¹, respectively; P < 0.01). The incidence of bradycardia (HR < 50 beats·min⁻¹) after neostigmine-atropine injection was greater in the propofol group than in the isoflurane group (61% and 28%, respectively; P < 0.01). Conclusion. We conclude that propofol anesthesia attenuates the initial increases in HR, enhances the subsequent decreases in HR, and increases the incidence of bradycardia after neostigmine-atropine injections compared with the effects of isoflurane anesthesia. Received: May 21, 2001 / Accepted: August 29, 2001