Clinical subtypes of older adults starting long-term care in Japan and their association with prognoses: a data-driven cluster analysis.

We aimed to identify the clinical subtypes in individuals starting long-term care in Japan and examined their association with prognoses. Using linked medical insurance claims data and survey data for care-need certification in a large city, we identified participants who started long-term care. Grouping them based on 22 diseases recorded in the past 6 months using fuzzy c-means clustering, we examined the longitudinal association between clusters and death or care-need level deterioration within 2 years. We analyzed 4,648 participants (median age 83 [interquartile range 78-88] years, female 60.4%) between October 2014 and March 2019 and categorized them into (i) musculoskeletal and sensory, (ii) cardiac, (iii) neurological, (iv) respiratory and cancer, (v) insulin-dependent diabetes, and (vi) unspecified subtypes. The results of clustering were replicated in another city. Compared with the musculoskeletal and sensory subtype, the adjusted hazard ratio (95% confidence interval) for death was 1.22 (1.05-1.42), 1.81 (1.54-2.13), and 1.21 (1.00-1.46) for the cardiac, respiratory and cancer, and insulin-dependent diabetes subtypes, respectively. The care-need levels more likely worsened in the cardiac, respiratory and cancer, and unspecified subtypes than in the musculoskeletal and sensory subtype. In conclusion, distinct clinical subtypes exist among individuals initiating long-term care.

A mixed-methods study on the pharmacological management of pain in Australian and Japanese nursing homes.

BACKGROUND: Understanding how analgesics are used in different countries can inform initiatives to improve the pharmacological management of pain in nursing homes. AIMS: To compare patterns of analgesic use among Australian and Japanese nursing home residents; and explore Australian and Japanese healthcare professionals' perspectives on analgesic use. METHODS: Part one involved a cross-sectional comparison among residents from 12 nursing homes in South Australia (N = 550) in 2019 and four nursing homes in Tokyo (N = 333) in 2020. Part two involved three focus groups with Australian and Japanese healthcare professionals (N = 16) in 2023. Qualitative data were deductively content analysed using the World Health Organization six-step Guide to Good Prescribing. RESULTS: Australian and Japanese residents were similar in age (median: 89 vs 87) and sex (female: 73% vs 73%). Overall, 74% of Australian and 11% of Japanese residents used regular oral acetaminophen, non-steroidal anti-inflammatory drugs or opioids. Australian and Japanese healthcare professionals described individualising pain management and the first-line use of acetaminophen. Australian participants described their therapeutic goal was to alleviate pain and reported analgesics were often prescribed on a regular basis. Japanese participants described their therapeutic goal was to minimise impacts of pain on daily activities and reported analgesics were often prescribed for short-term durations, corresponding to episodes of pain. Japanese participants described regulations that limit opioid use for non-cancer pain in nursing homes. CONCLUSION: Analgesic use is more prevalent in Australian than Japanese nursing homes. Differences in therapeutic goals, culture, analgesic regulations and treatment durations may contribute to this apparent difference.

Radioiodine uptake after monotherapy with potassium iodide in patients with Graves' disease.

The effect of potassium iodide (KI) on radioiodine uptake (RAIU) before radioisotope therapy in Graves' disease (GD) patients was investigated. A total of 82 patients who had been treated with KI monotherapy before 24-hour RAIU (24 h RAIU) were evaluated and 354 of those who had been treated with thiamazole (MMI) monotherapy were extracted from the 1,130 GD patients who were identified as having had appropriate iodine restriction based on urinary iodine excretion. Urinary iodine excretion (UIE) <200 µg/day was confirmed in all subjects. Propensity score-matching was performed to identify the difference in 24 h RAIU between the KI group and the MMI group. In addition, multiple regression analysis was performed to evaluate related to 24 h RAIU. Propensity score-matching resulted in 57 matched patients in each group. After matching, 24 h RAIU was still significantly lower in the KI group than in the MMI group (median 53% (interquartile range 47-61%) vs. 63% (56-66%); p = 0.001). In addition, KI monotherapy was weakly negatively correlated with 24 h RAIU, whereas the female sex and FT3 were very weakly positively correlated on multiple regression analysis. The results suggest that KI monotherapy likely suppressed 24 h RAIU more than MMI monotherapy in GD patients with appropriate iodine restriction, given the difference in the mechanism of hormone suppression.

Factors Affecting Care-Level Deterioration among Older Adults with Mild and Moderate Disabilities in Japan: Evidence from the Nationally Standardized Survey for Care-Needs Certification.

This study aims to investigate the factors of care-level deterioration in older adults with mild and moderate disabilities using nationally standardized survey data for care-needs certification. We enrolled people aged 68 years or older, certified as support levels 1-2 (mild disability) or care levels 1-2 (moderate disability) with no cancer. The outcome was care-level deterioration after two years. The possible factors were physical and mental functions which were categorized as the following five dimensions according to the survey for care-needs certification: body function, daily life function, instrumental activities of daily living (IADL) function, cognitive function, and behavioral problems. A multivariate logistic regression analysis was conducted after stratifying the care level at baseline. A total of 2844 participants were included in our analysis. A low IADL function was significantly associated with a risk of care-level deterioration in all participants. In addition, low cognitive function was linked to care-level deterioration, except for those with support level 1 at baseline. Participants with more behavioral problems were more likely to experience care-level deterioration, except for those with care level 2 at baseline. Our study showed the potential utility of the care-needs certification survey for screening high-risk individuals with care-level deterioration.

Successful endovascular therapy involving direct puncture for spontaneous internal iliac artery aneurysm rupture.

Neurofibromatosis type 1 (NF-1) is associated with fatal vascular complications. A 40-year-old woman with NF-1 who had previously undergone left iliac artery ligation and femorofemoral bypass grafting for internal iliac artery (IIA) aneurysm rupture was transported to our hospital for the treatment of a newly developed IIA aneurysm. Although endovascular therapy was difficult owing to the previous surgery, we successfully performed embolization of the aneurysm and its feeding vessels via direct percutaneous puncture under ultrasound guidance. Aneurysm enhancement had completely disappeared at 2 months postoperatively. We have reported a novel approach of direct percutaneous puncture for IIA aneurysm embolization in a patient with NF-1.

The Relationship Between Primary Thyroid Lymphoma and Various Types of Thyroid Autoimmunity: A Retrospective Cohort Study of 498 Cases, Including 9 Cases with Graves' Disease.

Background: Primary thyroid lymphoma (PTL) is known to develop mostly in patients with Hashimoto's thyroiditis (HT), and it is rare for it to develop in patients with Graves' disease (GD). The objective of this study was to investigate the clinical features, pathological findings, and long-term outcomes of PTL patients, grouped according to the presence of GD, HT, or no autoimmune thyroid disease (AITDs). The GD group was of major interest due to limited knowledge of the relationship with PTL. Methods: In this single-center retrospective cohort study, we reviewed the medical records of all patients diagnosed with PTL between August 1979 and October 2021, and we characterized the patients according to the presence of HT, GD, or no AITDs. Pathological specimens were classified according to the World Health Organization classification. Staging was performed in accordance with the Ann Arbor classification. Results: During the 42-year period, 498 participants were diagnosed with PTL. The median age was 68 (interquartile range 61-76) years, and 221 patients were stage IE, whereas the remaining 277 patients were stage IIE. Of the PTL patients, 431 (86.6%) were diagnosed with HT, 9 (1.8%) were diagnosed with GD, and 58 (11.6%) did not have AITDs. All nine patients with GD were positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. All patients with GD were treated with anti-thyroid medication. There were no significant differences in the proportions of each subtype of PTL between the PTL patients with GD and all subjects with PTL (p = 0.51), PTL patients with HT (p = 0.51), or PTL patients without AITDs (p = 0.48). The median follow-up time was 6.2 (interquartile range 3.0-10.7) years after the diagnosis of PTL. The Kaplan-Meier curve analyses showed no significant differences in overall survival and event-free survival between PTL patients with GD and those with HT (p = 0.37), or between PTL patients with GD and those without AITDs (p = 0.43). Conclusions: The PTL was observed with HT in a majority of cases, and rarely with GD (1.8%). The proportions of each pathological subtype of PTL and the prognosis of PTL were not different between the patients with GD and those with HT or those without AITDs.

Enhanced recovery after surgery program involving preoperative dexamethasone administration for head and neck surgery with free tissue transfer reconstruction: Single-center prospective observational study.

BACKGROUND: There are few reports on Enhanced Recovery After Surgery (ERAS)-based perioperative management following head and neck surgery with free tissue transfer reconstruction (HNS-FTTR). Here, we prospectively evaluated our ERAS program involving preoperative glucocorticoid administration in HNS-FTTR. METHODS: This prospective study included 60 patients who underwent HNS-FTTR at the Miyagi Cancer Center from June 2017 to December 2018. Their treatment plan included receiving perioperative management in accordance with our head and neck ERAS program. Major outcomes of hospitalization periods, early mobilization, early enteral nutrition, and patient satisfaction were assessed, and blood date and vital signs were compared with control patients who underwent HNS-FTTR from January 2014 to September 2016 at our institution before ERAS was implemented. RESULTS: The duration of hospital stay and the duration until completion of the discharge criteria was a median of 25 days and 17 days, respectively. Early mobilization was achieved in 86.0% of the patients at postoperative-day (POD)1 and 96.5% at POD2. Enteral nutrition was started in 80.1% at POD1 and 100% at POD2. Postoperative pain was controlled at mean VAS scores of 1.51-3.13. Clavien-Dindo grade II or higher postoperative complications were evident in 27.6% of the patients. The mean QOR40 score was 179.6 preoperatively, 146.1 at POD3, and 167.8 at POD7. Compared with the control group, there were significantly lower C-reactive protein levels, higher albumin levels, a lower body temperature, a lower neutrophil-to-lymphocyte ratio, less body weight fluctuation, and fewer incidences of decreased blood pressure in the ERAS group. CONCLUSION: Patients who underwent HNS-FTTR with ERAS-based perioperative management achieved early mobilization, early enteral nutrition, favorable pain control, remarkable recovery of patient satisfaction at POD7, and there was evidence of better hemodynamic stability and less inflammatory response compared with control patients.

Histone deacetylase inhibitors sensitize 5-fluorouracil-resistant MDA-MB-468 breast cancer cells to 5-fluorouracil.

Resistance to 5-fluorouracil (5-FU) is a serious problem in cancer therapy and overcoming it is required in order to improve the efficacy of cancer chemotherapy. Histone deacetylase (HDAC) inhibitors are used in cancer treatments and, recently, it has been reported that HDAC inhibitors can overcome resistance to various anti-cancer drugs in vitro. In the present study, a 5-FU-resistant breast cancer cell line was established, and the effects of HDAC inhibitors in these cells were examined. The 5-FU-resistant cell line MDA-MB-468 (MDA468/FU) was established by continuous exposure of the parental cells to 5-FU. This subline was characterized by high resistance to 5-FU, higher mRNA expression levels of thymidylate synthetase and dihydropyrimidine dehydrogenase (DPD), and lower mRNA expression levels of uridine monophosphate synthetase (UMPS) than the parental cells. Gimeracil, a DPD inhibitor, did not affect the sensitivity of MDA468/FU cells to 5-FU. Oteracil, a UMPS inhibitor, decreased the cytotoxicity of 5-FU in MDA468 cells, but not in MDA468/FU cells. The HDAC inhibitors, valproic acid and suberanilohydroxamic acid sensitized the two cell lines to 5-FU in a concentration-dependent manner. In conclusion, the results of the present study revealed that HDAC inhibitors increase the sensitivity to 5-FU in 5-FU-sensitive and -resistant cells.

Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia.

OBJECTIVES: Tumour hypoxia is a major obstacle in cancer therapy that leads to poor prognosis. Therefore, the development of cancer treatments that are effective in hypoxia is necessary. Nitrogen-containing bisphosphonates (N-BPs), which are used to treat bone disease, are cytotoxic to several cancer cells in normoxia. Therefore, we investigated the cytotoxicity of N-BPs in cancer cells in hypoxia. METHODS: We studied the cytotoxicities of N-BPs, statins and anticancer drugs in human cancer cells under hypoxic conditions (1% O2 ). The expression levels of enzymes in the mevalonate pathway in hypoxia were measured by real-time reverse transcription polymerase chain reaction and Western blotting. KEY FINDINGS: In hypoxia, cell growth inhibition by 5-fluorouracil and cisplatin was not changed as compared to that in normoxia; however, cell growth inhibition by N-BPs and via zoledronate-induced apoptosis was higher in hypoxia than that in normoxia. Furthermore, geranylgeraniol completely inhibited the growth inhibitory effects of zoledronate. Additionally, the mRNA and protein levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase significantly decreased in hypoxia. Moreover, simvastatin potentiated the growth inhibitory effect of zoledronate. CONCLUSIONS: The cytotoxicity of N-BPs, but not 5-fluorouracil and cisplatin, is potentiated in hypoxia, through the loss of HMG-CoA reductase function. N-BPs may be effective against cancer in normoxia and hypoxia.

Total Synthesis of (+)-Goniodenin.

Goniodenin is a lipophilic polyketide originating from plant sources and which possesses a potent cytotoxic activity against cancer cell lines. The first total synthesis of (+)-goniodenin has been achieved in 23 steps from (R)-glycidol. The synthetic sequence featured a cross metathesis for the formation of the C8-C9 bond and installation of the terminal γ-butenolactone ring unit by the alkylation of α-phenylthio-γ-butyrolactone with the corresponding C3-O-triflate. The stereogenic center at C18 carbon was created by Hiyama-Fujita reduction of the corresponding ketone with high diastereoselectivity.

Human cell growth regulator Ly-1 antibody reactive homologue accelerates processing of preribosomal RNA.

Ribosome biogenesis is an essential process for cell growth and proliferation and is enhanced in cancer and embryonic stem cells. Mouse Ly-1 antibody reactive clone product (Lyar) is expressed at very high levels in many tumor, leukemia or embryonic stem cells; is a novel nucleolar protein with zinc-finger DNA-binding motifs and is involved in cell growth regulation. However, cellular function of Lyar remains unexplored. Here, we show that human homologue of Lyar (LYAR) accelerates ribosome biogenesis at the level of processing of preribosomal RNA (pre-rRNA). We show that LYAR is excluded from the nucleolus after actinomycin D treatment and is present in preribosomal fraction of the nuclear extract as well as in the fractions with 40S, 60S and 90S sedimentation coefficients. LYAR is required for processing of 47S/45S, 32S, 30S and 21S pre-rRNAs. In addition, we show that over-expression of LYAR increases cell proliferation without affecting the expression of c-Myc or p53. Combined, these results suggest that some rapidly growing cells enhance ribosome biogenesis by increasing the expression of LYAR.

Population pharmacokinetics of oxycodone in patients with cancer-related pain.

Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

The effect of R249S carcinogenic and H168R-R249S suppressor mutations on p53-DNA interaction, a multi scale computational study.

In this study we have undertaken the theoretical analysis of the effect of R249S carcinogenic and H168R-R249S suppressor mutation at core domain of the tumor suppressor protein p53, on its natural interaction with DNA using a newly developed method. The results show that the carcinogenic mutation R249S affects the flexibility of L3 loop region in p53, inducing the loss of important hydrogen bonds observed at interaction in the wild-type with DNA, on the other hand the suppressor mutation H168R on the R249S assists in maintaining the wild-type like flexibility of the L3 region in p53 and thus recover the interaction terms lost in the carcinogenic mutation alone. The present study sets a new direction in the development of new drugs that may restore the interactions that lost as a consequence of the carcinogenic mutations in p53.

Tribochemical reaction dynamics of molybdenum dithiocarbamate on nascent iron surface: a hybrid quantum chemical/classical molecular dynamics study.

Using a hybrid quantum chemical/classical molecular dynamics method, we have studied the tribochemical reaction dynamics of molybdenum dithiocarbamate (MoDTC), a commonly used friction modifier in automobile engine oils. MoDTC molecule adsorbed on rubbing nascent iron surface was situated. We firstly investigated the dynamic behavior of MoDTC molecule on the rubbing Fe(001) surface. During the friction simulation, the elongation of Mo-O bonds was observed, forming the Mo2S4 and thiocarbamic acid molecules. To unveil the detailed mechanism of this bond elongation, the electronic states of the MoDTC molecule and Fe(001) surface were computed, and the catalytic effects of Fe(001) surface to the molecule was found. We also found that extreme friction would influence the complete Mo-O bond dissociation. By using the hybrid quantum chemical/classical molecular dynamics method, we successfully simulated the tribochemical reaction dynamics of MoDTC as a friction modifier and obtained the influences of nascent iron surface and friction on its chemical reaction.

Biochemical alterations in the palatal processes in fetuses of biotin-deficient mice.

To clarify the role of biotin in palatal formation, we investigated the effects of biotin deficiency on the development of palatal processes in mouse fetuses at midgestation. We also investigated protein expressions in the palatal processes. Pregnant mice were given either a biotin-deficient diet or a biotin-supplemented (control) diet from day 0 of gestation (dg 0). Some dams in the biotin-deficient group were changed to a biotin-supplemented diet on dg 12, 13 or 14. On dg 15, the palatal processes were dissected from these fetuses and their peptides were characterized using two-dimensional electrophoresis and liquid chromatography/tandem mass spectrometry (LC-MS/MS) system. Regarding Trasler's stage for the growth of the palatal processes in mouse fetuses on dg 15, the average stage of palatal development was 5.83 +/- 0.39 in the biotin-supplemented group, 5.39 +/- 0.66 in the dg 13-supplemented group, and 4.64 +/- 0.90 in the biotin-deficient group. The development of the palatal processes significantly increased in relation to the earlier day of biotin supplementation. In a protein analysis of palatal processes by isoelectro focusing (IEF) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), a 19-kDa spot was confirmed around position at pI 6-7 in the biotin-supplemented group, but this protein was not present in either the biotin-deficient group or the dg 13-supplemented group. From the MS/MS database of peptides, adenosine diphosphate (ADP)-ribosylation factor 2 (arf2) and alpha-crystallin were detected in the mesenchyme of the palatal processes. It is suggested that the expression of these proteins may be downregulated by biotin deficiency, inducing the inhibited development of palatal processes.

Immunohistochemical expression of IGF-I and GSK in the spinal cord of Kii and Guamanian ALS patients.

Insulin-like growth factor-I (IGF-I) is a potent survival factor for motor neurons in animals, and glycogen synthase kinase-3beta (GSK-3beta) is suspected to play roles in apoptosis and tau phosphorylation. Here we report the immunological expression of IGF-I, GSK-3beta, phosphorylated-GSK-3alpha/beta (p-GSK-3alpha/beta) and phosphorylated-tau in the spinal cord and hippocampus of Kii and Guam amyotrophic lateral sclerosis (ALS) patients. Sixteen ALS patients (10 Japanese sporadic, 3 Kii and 3 Guam ALS) and 14 neurological controls (10 Japanese and 4 Guamanian) were examined. The immunoreactivity for each antibody was rated by the percentages of positive neurons to total anterior horn neurons in each patient and was analyzed statistically. Many normal-looking neurons from Japanese sporadic ALS, Kii ALS and Guam ALS patients, as well as from Japanese and Guam controls, were positive for anti-IGF-I antibody. A positive correlation between IR scores for anti-IGF-I antibody and clinical durations of Japanese sporadic ALS patients was found in this study (P < 0.0001). This suggested that IGF-I might have a protective effect against ALS degeneration. In Japanese sporadic ALS patients, abnormal as well as normal-looking neurons showed significant high IR scores for anti-GSK-3beta antibody than those of controls. Anterior horn neurons from Guam and Kii ALS patients characteristically showed weak staining for anti-GSK-3beta antibody but were markedly positive for anti-pGSK-3alpha/beta antibody compared to those from both Japanese controls and Japanese sporadic ALS patients, and showed the co-localization of IGF-I and p-GSK-3alpha/beta. This suggested that the IGF-I signaling pathway in Guam and Kii ALS patients might function to phosphorylate GSK-3beta to protect neurons from ALS degeneration. Neurofibrillary tangles (NFTs) in the hippocampus and spinal cord from Kii and Guam ALS patients showed the co-localization of PHF-tau and p-GSK-3alpha/beta by a confocal laser scanning technique. The predominant expression of p-GSK-3alpha/beta compared to GSK-3beta in spinal motor neurons and the co-localization of p-GSK-3alpha/beta and PHF-tau in NFT-laden neurons in the hippocampus and spinal cord were characteristic findings of Kii and Guam ALS patients.

Collaborative work on evaluation of ovarian toxicity. 9) Effects of 2- or 4-week repeated dose studies and fertility study of di(2-ethylhexyl)adipate (DEHA) in female rats.

The present study was designed to confirm whether or not the ovarian toxicity of di(2-ethylhexyl)adipate (DEHA), which is known to have effects on female fertility, could be evaluated by the new method of histopathological examination of the ovaries in repeated dose toxicity. DEHA was orally administered to Crl:CD(SD) female rats at the doses of 0, 200, 1,000 and 2,000 mg/kg for 2 or 4 weeks in repeated dose toxicity study and for 2 weeks before mating, throughout mating and until Gestation Days 7 in female fertility. In the repeated dose toxicity studies, increase in atresia of large follicle, decrease in currently formed corpus luteum and follicular cyst were observed in the 1,000 mg/kg and above groups, suggesting that DEHA disturbed ovulation and large follicle growth. In the fertility study, a significant increase in mean estrus cycle length and post-implantation loss rate were observed in the 1,000 mg/kg and above groups, and a significant decrease in implantation rate and number of live embryos and a significant increase in pre-implantation loss rate were observed in the 2,000 mg/kg group. The histopathological changes of ovary observed in the repeated dose toxicity studies were correlated with the result that DEHA affected the estrus cycle in the female fertility study. In conclusion, a 2-week administration period is sufficient for detection of the ovarian toxicities following treatment with DEHA by new histopathological examination of the ovaries.

Effects of zonisamide on c-Fos expression under conditions of tacrine-induced tremulous jaw movements in rats: a potential mechanism underlying its anti-parkinsonian tremor effect.

OBJECTIVES: To examine the mechanisms underlying the anti-tremor effect of zonisamide in rats under conditions of tacrine-induced tremulous jaw movements (TJMs). METHODS: Male adult rats received systemic administration of either zonisamide (5 or 50mg/kg) or vehicle at 20min prior to the administration of tacrine hydrochloride (5mg/kg). Animals were sacrificed 2h later, and the brains collected and immunostained for quantitative assessment of c-Fos expression. RESULTS: There was no effect of zonisamide on tacrine-induced c-Fos expression in the ventrolateral striatum, a primary site of the pharmacological action of tacrine. Zonisamide suppressed the tacrine-induced c-Fos expression in the cortex, the dorsal striatum, and the nucleus accumbens, which are involved in the architecture of the cortico-basal ganglia-thalamocortical circuits. CONCLUSION: The anti-TJM effect of zonisamide may not relate to suppression of neural activity specifically in primary tremor-generating sites, but may be due to a more broad inhibitory effect on tremor-related structures such as the cortex or the striatum. This effect of zonisamide may be a contributing mechanism underlying its therapeutic efficacy on parkinsonian tremor.

Expression of insulin-like growth factor-II and leukemia inhibitory factor antibody immunostaining on the ionized calcium-binding adaptor molecule 1-positive microglias in the spinal cord of amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease involving the upper and lower motor neuron systems. Activated microglia are reported to enhance motor neuron death by secreting neurotoxic cytokines in SOD1-transgenic mice. Recent studies have provided evidence that chronic stimulation leads microglia to acquire an anti-inflammatory phenotype, characterized by activated morphology and induction of neuroprotective and immunoregulatory molecules. However, little information is available on the protective functions of microglia in the ALS spinal cord. To investigate the roles of microglia in ALS, we examined the appearance of ionized calcium-binding adaptor molecule 1-positive (Iba1-positive) microglia as correlated to the disease duration and immunohistochemical expression of neurogrowth factors in the ALS spinal cord. In this study, the number of Ibal-positive rod-like microglia significantly increased in the ALS spinal cord compared to controls. The number of ramified microglia was positively correlated with the number of normal-looking neurons and clinical duration of ALS patients; however, the number of rod-like microglia was not correlated with that of abnormal neurons, nor with the clinical duration of the disease. Some rod-like microglia were positive for anti-insulin-like growth factor-II (IGF II) and anti-leukemia inhibitory factor (LIF) immunostaining. Motor neurons in the ALS spinal cords also showed immunore-activity for IGF-II, LIF and the receptors of IGF-II and LIE Taken together, these findings suggest that at least some microglia might have a protective effect on motor neurons in the ALS spinal cord. Neuroprotective and/or neurotoxic effects of microglia on motor neurons should be further studied.