Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease

Dopaminergic cell death in the substantia nigra (SN) is central to Parkinson's disease (PD), but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation, and neuronal death. The mechanisms involved in iron accumulation also remain unclear. Here, we describe an increase in the expression of an isoform of the divalent metal transporter 1 (DMT1/Nramp2/Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increases in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss. In addition, we report that a mutation in DMT1 that impairs iron transport protects rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine. This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD.     

帕金森病大鼠行为学模型实用性研究

目的探讨帕金森病（PD）大鼠行为学模型的实用性及黑质神经元的凋亡特征。方法注射6-羟基多巴胺（6-OHDA）制备大鼠模型,5周后用自制梯子和跑步机模型测试大鼠行为学指标。冰冻切片HE染色观察大鼠黑质神经元的形态特征,对比其凋亡情况。结果在梯子实验中,PD模型大鼠与正常对照组和假手术组大鼠相比,行走速度下降,行走时间延长（P〈0．05）,行走失误率显著增加（P〈0．01）;在跑步机实验中,PD模型大鼠较正常对照组持续爬行时间显著缩短,一定时间内的跌落次数增加（P〈0．01）。组织学观察PD模型大鼠注射药物侧黑质神经元显著减少,凋亡细胞显著增多,胞质染色加深。结论本文造模大鼠在自制梯子和跑步机实验中的行为学改变与黑质神经元凋亡程度相一致,此实验方法可以初步用于PD大鼠模型的鉴定。     

Effects of age and gender on physical performance

Our purpose was to examine the effects of age and gender on physical performance. We assessed a one-hour swimming performance and participation of 4,271 presumably healthy men and women, aged 19–91 years, from the 2001–2003 United States Masters Swimming long-distance (1 h) national competition. The decline in performance with increasing age was found to be quadratic rather than linear. The equation which best fit variation in 1 h swimming distance in meters (m) according to variations in age in years (y) in men was: distance (m) = 4058 + 2.18 age−0.29 age (), with the same equation for women except that 380 m needed to be subtracted from the calculated value at all ages (about a 10% difference). There was a large overlap in performance between men and women. The overall mean decline in performance with age was about 50% and was parallel in men and women. The mean difference in distance for a 1-year increment in age was −9.7 m at 21 y of age, −21.3 m at 40 y, and −44.5 m at 80 y. Far greater declines of about 96% in numbers participating with advanced age (80 y and over, 4% of peak numbers) were observed than in the 40–49 y age group. In conclusion, the declines in performance were parallel in men and women at all ages, and the 1-year age-related declines in performance were about twice as great at 40 y and more than four-times as great at 80 y than at 20 y of age, with even greater age-related declines in participation being noted for both men and women.     

Effects of substantia nigra lesions on the volumes of A,B, and D cells and the content of insulin and glucagon in the rat pancreas

Summary The effects of substantia nigra lesions on the volume densities of islet cells and on the content of insulin and glucagon in the pancreas were examined using five groups of age-matched, Sprague-Dawley rats. Two groups received bilateral substantia nigra lesions using intrathecal injections of either a low (6 g/hemisphere) or a high (12 g/hemisphere) dose of 6-hydroxydopamine. Rats given sham lesions served as controls for the effects of the neurotoxic drug. These three groups, plus a fourth consisting of unoperated controls, were provided with a high-fat diet to minimize lesion-induced alterations of food intake and body weight. Eleven weeks after lesion placement, tissue was collected from all animals for the assessment of islet cell volume densities and the pancreatic content of insulin and glucagon. Plasma samples also were obtained to determine the levels of glucose, insulin, and glucagon. Data from those animals were compared with that obtained from a fifth group, termed pre-lesion controls, sacrificed at the beginning of the experiment. Linear-scan morphometry documented an increase of B-cell volume density in the pancreas of non-lesioned rats over the 11-week period (p<0.05). However, the volume density of B cells in the pancreas of lesioned animals did not increase compared with that of pre-lesion controls. In terms of A or D cells, no significant differences of volume density were found between the five groups. Compared with that of the pre-lesion controls, pancreatic insulin and glucagon content increased in the lesioned and neurally-intact animals. However, the molar ratio of those hormones in the pancreas of lesioned rats remained similar to that of pre-lesion controls. The current findings suggest that the substantia nigra is an important autonomic area involved in controlling islet growth and development, and possibly islet function as well.     

Estrogen and SERM neuroprotection in animal models of Parkinson's disease

A higher prevalence and incidence of Parkinson disease (PD) is observed in men and beneficial motor effects of estrogens are observed in parkinsonian women. Lesion of the dopamine (DA) nigrostriatal pathway in animals with 1-methyl 4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) provides a model of PD and this is based on its use in humans as side-product of a drug abuse. Presently treatment of PD is mainly symptomatic. The MPTP mouse is used to study the neuroprotective roles of estrogenic drugs on the DA system. Estrogens, but not androgens, are active neuroprotectants as well as progesterone and dehydroepiandrosterone. An estrogen receptor agonist PPT and the selective estrogen receptor modulator raloxifene are also neuroprotective. Striatal DA neurons of estrogen receptor alpha knockout mice are more susceptible to MPTP toxicity than wild-type mice and neuroprotection by estradiol is associated with the activation of the PI3-K pathway involving Akt, GSK3beta, Bcl2 and BAD.     

Neural stem cell transplantation and melatonin treatment in a 6-hydroxydopamine model of Parkinson's disease

Melatonin has multiple roles including neuroprotection. Melatonin signaling involves diverse targets including two G-protein-coupled receptors, MT(1) and MT(2), which have both been localized to the nigrostriatal pathway. Previous studies in our laboratory demonstrated preservation of tyrosine hydroxylase immunoreactivity, following chronic treatment with a physiological dose of melatonin, in the 6-hydroxydopamine rat model of Parkinson's disease. Additionally, we reported the presence of the melatonin MT(1) receptor subtype in cultured C17.2 neural stem cells (NSCs). In the present study, we examined the effects of C17.2 NSC transplantation on dopaminergic denervation following 6-hydroxydopamine lesioning in the rat striatum. Moreover, based on our detection of the MT(1) in these cells, we examined the effects of combined C17.2 NSC transplantation and melatonin treatment, following striatal lesioning. Behavioral studies indicated a marked inhibition of apomorphine-induced rotations in lesioned animals that received C17.2 NSC transplantation, melatonin, or the combined regimen. In addition, these treatments resulted in a significant protection of tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra of lesioned animals, when compared with untreated controls. Lesioned animals treated with C17.2 NSCs, melatonin or a combination of both agents exhibited no significant differences in the number of tyrosine hydroxylase-positive cells in the substantia nigra or ventral tegmental area ipsilateral or contralateral to the lesioned striatum. These findings suggest that stem cell therapy and concomitant use of neuroprotective agents such as melatonin could be a viable approach in Parkinson's disease.     

Effects of age,gender and menstrual cycle on platelet function assessed by impedance aggregometry

Platelets are needed to prevent or arrest bleeding and aggregate at the site of injury upon vascular damage. Platelets express receptors for estrogens which might affect the function of the platelets and their hemostatic ability. The aim was to identify possible differences in platelet function related to age, gender, and phases of the menstrual cycle by use of impedance aggregometry with Multiplate. In the first part of the study, platelet function was assessed in 60 healthy individuals (30 men and 30 women) in each of three age groups (20–25, 40–45, and 60–65 years). In the second part of the study, the platelet function was analyzed on four occasions during the menstrual cycle in women without oral contraceptives (OCs) (n = 17) and compared to 19 women on OCs and 18 men of similar age (20–40 years). For the women on OCs, aggregation was analyzed once during the tablet-free week and once late during the period with OCs. The men were sampled once. Women of younger age (<45 years) had significantly higher agonist-induced aggregation response than both men and post-menopausal women (60–65 years). The agonist-induced aggregation response did not differ between phases of the menstrual cycle or OC use. The results suggest that estradiol and/or progesterone affect spontaneous aggregation since it was found to be lowest in the mid-luteal phase. Spontaneous aggregation was significantly lower in women on OCs than in both men and women without OCs. Our findings indicate that fertile age is associated with higher aggregation response capacity of the platelets, possibly to prevent excessive bleeding during menstruation, but this response capacity is not altered during the menstrual cycle or by use of OCs.     

Mycobacterium ulcerans disease: role of age and gender in incidence and morbidity

During the 5-year period, 1997-2001, 1700 patients with a clinical diagnosis of Mycobacterium ulcerans disease [Buruli ulcer (BU)] were treated at the Centre Sanitaire et Nutritionnel Gbemoten, Zagnanado, Benin. The patients lived in the four regions of southern Benin: Atlantique, Mono, Oueme and Zou, with the largest number coming from the Zou Region where the centre is located. The median age of BU patients was 15 years (q1=7, q3=30). Lower limbs are involved 3.2 times more frequently than upper limbs in older patients and younger patients have the highest prevalence of multiple lesions. The latter are frequently associated with bone lesions. Specific detection rates for age and gender showed a distribution with maximum peaks in the 10-14 years group and among adults between 75 and 79 years. Over 59 years, males are more at risk of developing M. ulcerans disease than females. Children under 15 years represent the largest part of the BU disease burden and of the general population. The highest detection rates (per 100,000 population) were in the 75-79-year-old patients. The most likely explanation of this was reactivation of disease from a latent infection of M. ulcerans. Educational programmes should target especially these two groups of population at risk.     

Alzheimer病与帕金森综合征：附六例临床病理报告

目的 Ａｌｚｈｅｉｍｅｒ病（ＡＤ）临床多合并帕金森综合征。报道６例经尸检证实的ＡＤ临床及病理资料，旨在为ＡＤ合并锥体外系受损的病因探讨提供参考资料。 方法 回顾性分析６例ＡＤ及４例原发性帕金森病的临床及病理资料 结果 ６例ＡＤ中有３例临床合并帕金森综合征，其黑质、蓝斑均有不同性质及程度的损伤，２例系非特征性色素细胞脱失伴胶质细胞增生，１例为球形体色素变性。 结论 ＡＤ合并帕金森综合征者多有黑质、蓝     

Gastric acid secretion of normal Japanese subjects in relation to Helicobacter pylori infection,aging, and gender

Background: In Japan, where the incidence of gastric cancer is high, Helicobacter pylori infection could affect gastric acid secretion differently from that in Western countries. The aim of this study was to investigate the relationship between H. pylori infection, acid secretion, aging, and gender in normal Japanese subjects. Methods: The study comprised 193 Japanese subjects who had undergone routine endoscopy. Gastrin‐stimulated acid output was performed during the routine endoscopic examination using the endoscopic method of gastric acid secretory testing (EGT: endoscopic gastrin test), which has been reported previously. H. pylori status was determined by histology, rapid urease test, and serology. Results: Mean EGT values were 3.9?±?1.5?mEq/10?min in H. pylori‐negative men, 1.6?±?2.5 in H. pylori‐positive men, 2.2?±?0.9 in H. pylori‐negative women, and 1.5?±?1.2 in H. pylori‐positive women. Although acid secretion was lower in H. pylori‐positive subjects compared with H. pylori‐negative subjects in both men and women, the decrease was more marked in men with H. pylori infection. Multiple linear regression analysis showed that aging is positively associated with gastric acid secretion in the H. pylori‐negative subjects, whereas a negative association was found between them in the H. pylori‐positive subjects. Conclusions: In Japanese subjects, aging affects gastric acid secretion differently depending on the status of H. pylori infection. H. pylori infection showed a stronger inhibitory effect on the acid secretion in men than in women. This gender‐related difference in the susceptibility of acid secretion to H. pylori infection may explain the higher rates of gastric cancer in men in Japan.     

Cytogenetic features of multiple myeloma: impact of gender,age, disease phase,culture time,and cytokine stimulation

Relatively little is known about the cytogenetic features of multiple myeloma (MM) when compared to other hematologic malignancies. The reasons for this are most likely manifold, and include a low mitotic index of the malignant cells and the presence of cytogenetically cryptic abnormalities as well as of complex karyotypes with poor chromosome morphology. In the present study, we have investigated whether various culture conditions may influence the yield of abnormal metaphases in MM and, in the related plasma cell dyscrasias, monoclonal gammopathy of undetermined significance (MGUS) and plasmacytomas (PC). In addition, the possible impact of age, gender, and disease phase on the cytogenetic features has been analyzed. A total of 95 samples from 74 cases (68 MM, three PC, and three MGUS patients) were obtained for cytogenetic analysis. The samples were cultured either in conventional medium or in medium containing IL-6 and GM-CSF, and the culture times varied from 24 to 120 h. In total, 186 cultures were analyzed. Metaphase fluorescence in situ hybridization analysis using probes specific for 14q32, i.e. IGH rearrangements, could be performed in 57 of the 74 cases, and revealed 14q32 aberrations in 10 cases not seen by conventional G-banding. Abnormal karyotypes were detected in 77 (41%) of the 186 cultures, 46 (48%) of the 95 samples, and in 41 (55%) of the 74 patients, revealing a total of 20 chromosomal aberrations previously not reported in plasma cell dyscrasias. We found no evidence that gender, age, disease phase, culture time, or cytokine stimulation significantly influences the karyotypic features of MM.     

不同年龄、性别的冠心病患者住院费用分析

目的分析不同年龄、性别及其他临床情况对于冠状动脉造影患者住院费用的影响。方法研究对象为2001年1月1日至2006年12月3113北京协和医院心内科住院患者，年龄在40-79岁之间，有完整的各项住院费用记录。住院费用包括药费、检查费、治疗费、床位费、材料费、其他费用以及总费用。所有患者均进行了冠状动脉造影（CAG），部分患者进行了冠脉介入处理。结果40-59岁男性患者1130例，60－79岁男性患者1167例，40-59岁女性患者420例，60-79岁女性患者903例，各组患高血压病、心肌梗死、脑中风、糖尿病等疾病的比例差异有统计学意义（P〈0．01）。不同年龄性别组住院总费用在23237．11～47282．72元，从多到少排序分别为60－79岁男性患者、60～79岁女性患者、40～59岁男性患者和40～59岁女性患者。冠脉无明显狭窄患者以及CAG明显狭窄但未进行介入处理的患者，各组间总费用虽然有一定的差异，但无统计学意义。CAG明显狭窄并进行介入处理的患者，总费用在各组问差异有统计学意义，年龄大组的各项费用大于年轻组的费用。同一年龄性别组的不同冠脉处理情况的住院费用比较，有冠脉狭窄未介入处理亚组住院总费用为14771．99-21967．94元，冠状动脉无明显狭窄亚组住院总费用为8787．55—10757．86元，前者是后者的1．68－2．28倍，材料费是2．16-3．99倍，治疗费是1．12～2．51倍，检查费是1．31-1．56倍，药费是1．89~2．14倍，差异均有统计学意义（P〈0．01）；冠状动脉介入处理亚组住院总费用（57356．76-67420．77元）是冠状动脉无明显狭窄亚组的6．13-7．01倍，材料费是13．99-17．251倍，治疗费是3．53－4．50倍，检查费是1．40～1．87倍，药费是2．52～2．90倍，差异均有统计学意义（P〈0．01）。住院总费用与是否介入、性别、年龄、高血压、心肌梗死、中风病史、外周血管病史、糖尿病和肾功不全等均有一定相关性，住院总费用与以上各项参数进行多元逐步回归分析，住院费用与是否冠脉介入、心肌梗死史、年龄、高血压、糖尿病、是否有外周血管病和肾功能不全7项参数有独立相关性。结论年龄越大，住院费用越高，性别不是住院总费用的独立影响因素；影响住院总费用的其他独立因素包括是否进行冠脉介入，是否有心肌梗死史、高血压、糖尿病、外周血管病和肾功能不全。     

Effects of compound U74500A in animal models of gastric and duodenal ulceration

Pretreatment with U74500A (up to 0.65 mg/100 g) failed to affect gastric lesions induced by 100% EtOH gavage in Sprague-Dawley rats. Topical application of U74500A did not reduce lesions induced by 40% EtOH inex vivo gastric chamber preparations. However, pretreatment of rats with U74500A (0.65 g/100 gper os) reduced the incidence and severity of experimental duodenal ulcer induced by cysteamine HCl, and duodenal ulcer induced by cysteamine-HCl plus GABA. These results show U74500A to have powerful and specific antiduodenal ulcer actions. Pharmacologic analysis of organ-bath preparations of the small intestine show this compound to reduce intestinal contractility to applied cholinergic and serotonergic agonists. However, relaxations induced by electrical or nicotinic ganglionic stimulation were unaffected. U74500A itself caused concentrationdependent contractions.     

TTV DNA plasma load and its association with age,gender, and HCMV IgG serostatus in healthy adults

Understanding immunosenescence and changes in antimicrobial immune response with age is of high importance. The association of immunosenescence with gender and persistent infection with human cytomegalovirus (HCMV) is a matter of intensive research. We determined whether replication of another persistent and highly prevalent virus, Torque teno virus (TTV), is related to age, gender, and HCMV IgG serostatus of the host. TTV DNA load in plasma was assessed by real-time PCR in 313 healthy persons: 20–30 years old (young, n = 104), 50–60 years old (middle-aged, n = 101), or >80 years old (elderly, n = 108). TTV DNA loads were further associated with age-groups, gender, and HCMV IgG serostatus. TTV load was significantly higher in the elderly compared to the young group (p < 0.001; Tukey’s honest significant difference (HSD)), and the higher TTV DNA levels over age were found to be gender-specific (p = 0.002; ANOVA), with young women showing the lowest TTV load compared to young men (p = 0.009, t test) and compared to the other female age-groups (middle-aged p = 0.005; elderly p < 0.001; Tukey’s HSD). TTV load of HCMV IgG-seropositive persons was significantly higher than that of the HCMV IgG seronegative in the young (p = 0.005; t test) and middle-aged (p = 0.016; t test) groups. These results indicate that the host’s immune control of TTV replication decreases with age and is gender-specific. Persistent HCMV infection is significantly related to higher TTV DNA loads, especially at a younger age. Therefore, the influence of gender and HCMV on immunosenescence earlier in life should be further explored.     

Antioxidant enzyme activities in healthy old subjects: influence of age, gender and zinc status

Enzymatic activities of plasma superoxide dismutase (pSOD), catalase (CAT) and glutathione peroxidase (GPx) and erythrocyte superoxide dismutase (eSOD) were assayed in 981 healthy community dwelling old subjects participating in the Zincage Project. The relationship between antioxidant enzyme activities and, respectively, gender, age and zinc status were assessed. eSOD activity was higher in nonagenarians than in 80 year old subjects. Plasma Zn was lower in nonagenarians compared with younger subjects. The prevalence of Zn deficiency increased with age, with normal Zn levels observed in about 80% of adult subjects and only in 37% of the nonagenarians. Women showed higher eSOD and CAT activities compared to men, whereas plasma Zn was higher in men than in women. There was a positive correlation between eSOD activity and age and a negative correlation between eSOD activity and plasma Zn concentrations. An inverse correlation was also found between plasma Zn concentration and age. Further studies on different aspects of Zn metabolism—intake, plasma concentration, peripheral cell concentration, activity and amount of Zn-dependent enzymes—are warranted.Presented at the ZincAge Conference, Madrid, February 10–13, 2006     

Influence of age and gender in Japanese patients with non-alcoholic steatohepatitis

Aim: Nonalcoholic steatohepatitis (NASH) is considered to be a manifestation of metabolic syndrome. Because prevalence and severity of metabolic syndrome are different according to ages, gender and ethnic group, it is speculated that the clinicopathological features of NASH may also vary in relation to these factors. The present study was performed to clarify the influence of age and gender on the development of Japanese NASH. Subjects: One hundred 93 biopsy-proven NASH patients (86 women and 107 men) were included in this cross-sectional study. The patients were separately analyzed by generation; a younger group (<55 years old) and an older group (>/=55 years old). These groups were compared for their clinical and histological features. Independent risk factors for advanced fibrosis were also analyzed. Results: Comparison of our younger and older groups showed that older patients had much more advanced fibrosis than the younger ones (advanced fibrosis: 23.8%; youngergroup vs. 54.3%; older group, P < 0.001). Women were predominant in the older group (23.8%; younger group vs. 67.4%; older group, P < 0.001). According to the multivariate analysis for risk factors for advanced fibrosis, age (P = 0.007) and BMI (P = 0.028) were independent predictors of advanced fibrosis in the younger group. In contrast, the absence of hyperlipidemia (P = 0.042) was the only significant independent predictor of advanced fibrosis in the older group. Gender was not a risk factor for the severity of NASH. Conclusions: Clinicians need to be aware of age- and gender-specific differences when assessing the characteristics of NASH, and the findings may be useful for prevention and treatment of this disease.