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Previous genetic studies on hereditary Parkinson's disease (PD) have identified a set of pathogenic gene mutations that have strong impacts on the pathogenicity of PD. In addition, genome-wide association studies (GWAS) targeted to sporadic PD have nominated an increasing number of genetic variants that influence PD susceptibility. Although the clinical and pathological characteristics in hereditary PD are not identical to those in sporadic PD, α-synuclein, and LRRK2 are definitely associated with both types of PD, with LRRK2 mutations being the most frequent cause of autosomal-dominant PD. On the other hand, a significant portion of risk genes identified from GWAS have been associated with lysosomal functions, pointing to a critical role of lysosomes in PD pathogenesis. Experimental studies have suggested that the maintenance or upregulation of lysosomal activity may protect against neuronal dysfunction or degeneration. Here we focus on the roles of representative PD gene products that are implicated in lysosomal pathway, namely LRRK2, VPS35, ATP13A2, and glucocerebrosidase, and provide an overview of their disease-associated functions as well as their cooperative actions in the pathogenesis of PD, based on the evidence from cellular and animal models. We also discuss future perspectives of targeting lysosomal activation as a possible strategy to treat neurodegeneration.

Objective: To identify functional changes in the brains of women with climacteric symptoms. Images of regional cerebral blood flow (rCBF) were compared statistically between women with and women without symptoms to identify changes in rCBF. Results may provide a better understanding of the neural basis of the symptoms, which are divided into three symptom clusters: vasomotor, psychological, and somatic. Design: The study participants consisted of 12 women with moderate to severe climacteric symptoms (age 47.5 ± 5.9 years, mean ± SD) and 7 women with no symptoms (control group; age 49.6 ± 4.2 years, mean ± SD). The study participants were patients at a menopause clinic, and the latter were healthy volunteer nurses and hospital staff. Climacteric symptoms were evaluated by an assessment of the severity of 17 symptoms immediately before positron emission tomography examination of rCBF. The symptoms had been used previously to generate the Kupperman Kohnenki Shogai Index, a modified Kupperman Menopausal Index adapted to Japanese women. rCBF was measured by positron emission tomography with the C 15 O 2 dynamic inhalation method. Results: Reductions in relative rCBF in the patient group were observed in the bilateral rectal gyrus and in the left subcallosal gyrus on a voxel-by-voxel basis as compared with the control group. Conclusions: The present study revealed reductions in relative rCBF of the prefrontal cortex of Japanese women with moderate to severe climacteric symptoms. This area is close to that previously addressed in studies of familial bipolar depression and familial unipolar depression, although our participants did not satisfy criteria for depression. This reduction of rCBF may be related to the three climacteric symptom clusters, but further studies are needed for evaluation of its significance. Our results should stimulate investigations into the positron emission tomography rCBF change of these women as to the integration of multiple entities in climacteric symptoms.

Background: We have developed a system to monitor, simultaneously and continuously, ambulatory SaO2 measured using a pulse-oximeter and ECG data for 24 hours. Methods: The ambulatory SaO2-ECG monitoring system consisted of a portable monitoring device (SM50) with two channels for ECG data and one channel for SaO2 data input; a sensor for SaO2 recording; and a pulse-oximeter. An ambulatory monitoring analyzer was used. The SaO2 report from the present analyzer included two types of data (i.e., a profile of heart rate [HR], pulse rate [PR], and SaO2 value per min), and a trend graph of HR, arrhythmia, ST level and slope, PR, and SaO2 per minute. We also designed and produced an analytical program to automatically remove noise errors relating to the SaO2 measurement. Results: Using this system, we performed a clinical study on ten healthy volunteers (Group N) and seven patients with chronic pulmonary diseases (Group CPD) to evaluate the usefulness of the system as a diagnostic means for respiratory failure and arrhythmia. Group N showed a stable value of 90% or over in SaO2 during the 24-hour monitoring while Group CPD showed values under 90% SaO2 in all patients at rest during the night or after a 15-minute walk. Transient atrial tachycardia (TAT) was observed in 3 of 7 CPD patients, and each episode was preceded by a decrease of SaO2. The occurrence of a single or double ventricular extrasystole was high in Group CPD compared with Group N (1.21 ± 0.89 vs 0.6%± 0.3%, P < 0.05), its occurrence was not associated with a decrease in SaO2. Conclusions: In outpatients, especially patients who are taken care of at home, the present system will certainly contribute greatly to the diagnosis of respiratory failure and arrhythmia as well as to evaluate the effects on these diseases of therapy. In addition it is suggested that in CPD, patients’hypoxemia may induce TAT.

A case of primary hyperparathyroidism with a thyroid adenoma following two times histories of myocardial infarction was experienced. A 69-year-old female was transferred to the hospital with the diagnosis of myocardial infarction. With 210Tl-chloride scintigram image, an accumulation in the neck was demonstrated. Serum calcium and C-PTH were as high as 7.9 mEq/l and 13.5 ng/ml (

Human cytochrome P450IIE1 (CYP2E) is involved in the metabolic activation of procarcinogens such as N-nitrosodimethylamine, benzene and ethyl carbamate. We screened DNA from 28 individuals for restriction fragment length polymorphisms (RFLPs) is the human P450IIE1 gene and detected an RFLP for the restriction endonuclease DraI. The distribution of the genotypes of this polymorphisms among lung cancer patients (n = 74) differed from that among controls (n = 73) with statistical significance of p < 0.05. In addition, the distribution among patients with cancers of the digestive system (n = 38) was also different from that among controls. Our findings indicate an association between the DraI polymorphism of the IIE1 gene and susceptibility to cancers of the lung and the digestive system.

The serum levels of estradiol, progesterone, LH and FSH were determined by radioimmunoassay in post-menopausal and castrated women and the data obtained at the same periods after menopause and castration were compared. The serum levels of estradiol and progesterone in post-menopausal women within 1 year after menopause were higher than those of castrated women. The result suggested that ovarian function was indeed depressed in the post-menopausal women but was still preserved for 1 to 2 years after menopause. In the post-menopausal women, the levels of serum LH and FSH rose gradually to reach a peak at 1 to 3 years after menopause, when the production of ovarian sex steroid hormones presumably ceased. On the contrary, the serum LH and FSH levels of castrated women began to decrease gradually 4 to 9 years after castration. It is highly suggestive from these findings that a negative feedback mechanism is elicited by ageing.

Although climacteric symptoms, particularly, vasomotor symptoms such as hot flushes, have been suggested to correlate with depletion of ovarian estrogen secretion, its precise mechanism to producing these symptoms has still remained unknown. On the other hand, catecholamines have been presumed to be related to an onset of the climacteric symptoms. This study was carried out to elucidate the correlation between the climacteric symptoms and plasma levels of catecholamines. Thirty-eight women complaining of climacteric symptoms were studied. These subjects were evaluated for their symptoms and the severity of the symptoms was expressed in numerical figure, 0 to 3, according to its degrees: none, slight, moderate, and marked, respectively. At the same time venous blood samples were drawn to determine the plasma levels of catecholamines, using an Renzini's fluorimetric assay method improved by Miura. Eventually, a correlation between severities of the symptoms and plasma catecholamines was made. Plasma epinephrine levels were found to be elevated as the severity of the hot flush progressed from none to marked. No symptoms other than hot flush showed such significant correlation with plasma epinephrine or norepinephrine levels. This result suggests that the onset of hot flush is closely related with an increased activity of the adrenomedullary sympathetic nervous system.

In order to screen the neurotics and non-neurotics of climacteric women with menopausal symptoms, conjugated estrogen was injected intravenously and the reactions were compared. Menopausal symptoms were represented by Kupperman's menopausal index. After estrogen injection the non-neurotics showed a decrease of the index, i.e., alleviation of the symptoms, while the neurotics showed no change of the index. Taking advantage of this difference, a discriminant function between neurotics and non-neurotics was calculated using, as variables, Kupperman's menopasual indices determined before and after administration of the conjugated estrogen. The calculative screening obtained from this discriminant function yielded consistency with clinical diagnosis in about 94% of the neurotics and about 87% of the non-neurotics, suggesting that this test is of value in the screening of neurotics and non-neurotics in the climacteric women with menopausal symptoms.

生後30~33日齢の未成熟ラットに,種々の量のPMSG又はPMSGとhCGを投与して,着床に及ぼす影響を比較検討すると共に,下垂体移植による着床についても調べた。1)種々の量のGTHを投与した未成熟ラットの交配率は88.7%であった。2)PMSG•hCG 5~101U投与の妊娠率(80~90%)はPMSG 5~101U投与の場合(73.3~76.7%)に比較してやや高いが,有意な差ではなかった。20及び401U投与においても同様の傾向であり,かつ5~101U投与に比較して有意(p

高単位のGTHを投与した未成熟ラットの着床困難の要因を検討するため,種々の量のPMSG(A群),PMSG•hCG(B群)の投与及び下垂体移植を行って,これら各群の採卵及び卵子の受精と発育過程を比較検討すると共に,血清中のPとE2濃度を測定した。1)採卵出来た個体の割合は,A, B群共に,20IU投与の交配後108h,40IU投与の84~108hに低下した(P

With a view to evaluating pituitary-ovarian relationships in women approaching the menopause, serial determinations of basal body temperature (BBT) and of serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and oestradiol were performed in 5 pre-menopausal and 9 young women throughout a complete menstrual cycle. The hormone levels in the early follicular phase and on LH peak-days in the two groups were then compared. In the pre-menopausal group the age range was 43–45 yr and the length of the menstrual cycles investigated varied from 30–56 days, the BBT curves being biphasic. Two pre-menopausal women demonstrated concentrations of FSH and LH that were higher than those in the young women, even though their serum oestradiol levels in the early follicular phase remained within the upper and lower mean values observed in the young women. This finding confirmed that, in addition to reduced ovarian oestrogen secretion, another, as yet unknown, factor must exist, which can produce a rise in serum gonadotrophin levels in women approaching the menopause.

Etude par mesure des isothermes pression-composition, spectre Mossbauer, diffraction RX des relations entre proprietes thermodynamiques, structure cristalline et etats electroniques des composes Fe 1−y Ni y TiH x (avec 0

Aryl(chloromethyl)thallium chlorides, Ar(ClCH2)TlCl (Ar=C6H5, p-CH3C6H4) have been prepared by treatment of arylthallium dichlorides with diazomethane. The derived carboxylates, Ar(ClCH2)TlX, react with HgX2 to give the dicarboxylates, (ClCH2)TlX2 (X = OCOCH3, OCOC3H7-i) and with tetramethyltin to give CH3(ClCH2)TlX compounds. R(ClCH2)TIX compounds (R = CH3, C6H5, p-CH3C6H4) undergo disproportionation in methanol to R2TlX and (ClCH2)2TlX compounds.

The preparation of the compound CH 3 (C 5 H 5 )TIX [where X = OCOCH 3 , OCOC 2 H 5 , OCO-i-C 3 H 7 , tropolonate and 4-isopropyltropolonate] is described and their chemical behaviours as well as their PMR and IR spectra are discussed.

Several methyl(allyl)thallium derivatives have been prepared for the first time. The IR and PMR spectra of these compounds indicate the presence of σ-allylthallium bonds. In the cleavage reactions of these compounds with tetramethyltin in methanol or with metal salts such as Hg(OCOCH3)2, PdX2 (X  OCOC2H5 and Cl) and RhCl3·3H2O, preferential cleavage of the allylthallium bond occurs to give propylene in the case of tetramethyltin and allylic derivatives of the metals in the other cases.

1) The estradiol-17β dehydrogenase was extracted from human abdominal rectus muscle as a non-target organ, various kinds of human uterus and term placenta as the target organ of sex hormones and its activities were assayed by the Langer and Engel's method. 2) The activity of the estradiol-17β dehydrogenase was neglegible in abdominal rectus muscle, markedly low in senile atrophic uterus, moderately low in normal uterus, moderately high in fibroid or pregnant uterus and markedly high in the term placenta in both estradiol-17β dehydrogenation and estrone hydrogenation reaction. These results suggest that this enzyme is closely related with the uterus-sensitivity to sex hormones.

When a protein preparation containing estrogen-dependent pyridine nucleotide transhydrogenase extracted from human or bovine uterus was injected into ovariectomized rats in combination with estradiol, it exhibited a synergistic effect in promoting uterine growth. Other protein preparations from the uterus or other proteins such as human serum albumin or partially purified placental estradiol dehydrogenase did not show the synergistic activity. Heating of this preparation at 70 C for 5 min inactivated this material, indicating that some specific protein in the preparation is responsible for this biological activity. The protein preparation was separated by starch grain electrophoresis into 2 fractions, one of which had estrogen-dependent pyridine nucleotide transhydrogenase activity, and the other of which was effective in the stimulation of uterine growth. (Endocrinology 76: 844, 1965)

The uterus and such target organs to sex-hormones sometimes fall into dysfunction. The sensitivity of the target organ was analysed by determinations of the weight of the uterus of mice, of ATP in the human endometrium, of acetylcholine in the human endometrium, of 321) uptake of the human endometrium and of the tissue respiration of the human endometrium. In such cases, we must not limit ourselves to hormone administration but also not neglect treatment of the organs with impaired sensitivity to sex hormones. The sensitivity of the target organ was enhanced by treating the endometrium with the co-enzyme DPN.

Climacteric symptoms and complaints were defined at the First International Congress on the Menopause [l] as deriving from three main causes, viz decreased ovarian activity with subsequent hormonal deficiency, sociocultural factors and psychological factors. However, even though the aetiology of climacteric symptoms and complaints is thus known to be multifactorial, the studies conducted to date have been fragmentary in their approach. Consequently, correlations have been investigated between only two or at most three of the variables linked with clinical and pathophysiological factors, such as menstrual status; the various symptoms, responses to oestrogen therapy, plasma and serum hormone concentrations, the psychosocial environment, etc. As a result, there is still controversy as regards the correlation between climacteric symptoms, including vasomotor and other complaints and hormone profiles [2--51. While it is broadly true that the aetiology of climacteric symptoms and complaints involves a variety of causes, the main factors are acknowledged to be endocrinological and psychological [3]. Thus, in studying these symptoms and complaints, consideration should be given simultaneously to these two groups of factors in order to gain an overall understanding. To date, however, most studies [3-111 aimed at clarifying the aetiology of climacteric symptoms have focused separately on either endocrinological or psychological factors and their isolated correlations with the symptoms. This may account for the discrepancies between the reports of Chakravarti et al. (41 and Erlik et al. [5] on the one hand, and those of Aksel et al. [6] and Hutton et al. on the other [7]. The first two studies [4,5] reported that women complaining of vasomotor symptoms were found to have significantly lower levels of serum oestradiol than women without such symptoms when plasma or serum oestradiol levels were compared in either pre-menopausal or post-menopausal women. However, the latter two studies [6,7] revealed no significant differences between

Correlation between the climacteric symptoms and serum levels of estradiol. progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) was studied in 191 premenopausal and postmenopausal women. Significant correlation was obtained between the climacteric symptoms represented by the menopausal index of Kupperman and associates and serum levels of estradiol as well as LH in a subgroup of the premenopausal women, ages 35 to 39 years. The symptoms were shown to be significantly related in serum levels of LH and inversely related to estradiol. These results confirmed that climacteric symptoms, at least in premenopausal women 35 to 39 years of age, could result from a low output of ovarian estrogen and a high production of pituitary gonadotropin.

In order to quantify the changes of feed-back effect of estrogen on the. release of pituitary gonadotropin which is regulated by the hypothalamic-pituitary-ovarian system, the responses of LH and FSH to the intravenous infusion of 20 mg of conjugated estrogen were studied in 49 post-menopausal and 20 castrated women. In the group of women within 1 year after menopause, serum LH levels were elevated following the infusion of the conjugated estrogen. The responses of serum LH and FSH levels were different between post-menopausal and castrated women. The data indicated that the difference between the two groups was probably due to the difference of secretion patterns of the gonadotropins in post-menopausal and castrated women.

A new simple test for the screening of pre-, mid- and post-menopausal women with unidentified complaints overlaid by psychiatric disorders has been devised. This test is performed by intravenous injection of conjugated estrogen and by comparing Kupperman's menopausal indices before and after the injection. That is, the discriminant function between groups with and without psychiatric abnormalities was obtained from Kupperman's menopausal indices before and after intravenous injection of conjugated estrogen, and from this function was made a calculative differential diagnosis between the two groups. The calculative diagnosis agreed fairly well with the clinical diagnosis by the psychiatrist.

ABE, T., SUZUKI, M., MORITSUKA, T. and BOTAN, Y. Statistical Factor Analysis and Cluster Analysis in the Etiology of Climacteric Symptoms. Tohoku J. exp. Med., 1984, 143 (4), 481-489 - Factor analysis and cluster analysis were applied to a set of 17 climacteric symptoms data obtained from 194 premenopausal and postmenopausal women. Six distinct factors were extracted and the women were divided into 7 groups by hierarchical cluster analysis in terms of their factor scores. Only one representative factor was identified in 3 groups out of the 7. These 3 groups including 87 women were tentatively designated as vasomotor symptom, neurotic, and sensory disturbance groups. These results confirmed statistically that at least 3 simple etiological factors exist among climacteric symptoms.

Serum estradiol, progesterone, LH and FSH were concomitantly measured by radioimmunoassay in pre- and post-menopausal women in an attempt to study hormonal changes occurring in menopause. The level of serum estradiol in post-menopausal women was maintained at the same level as in pre-menopausal stage within one year after menopause and thereafter began to decrease to the senile minimal level. On the other hand, the mean serum levels of FSH and LH were elevated gradually after menopause. At the conclusion of this study, it was suggested that the key point of the mechanism of menopause may exist not only in the depletion of ovarian function but in the change of the regulatory mechanism of LH and FSH secretion by aging.

Clinical and endocrinological features of women with climacteric symptoms, who were clustered by means of factor analysis and cluster analysis, were evaluated as to serum concentrations of estradiol, progesterone, follicle-stimulating hormone and luteinizing hormone, and also as to mean ages as well as a rate of premenopausal women or that of postmenopausal women against all women in each one of the clusters. Comparison of these parameters among these clusters indicated, with statistical significance, that vasomotor symptoms, neurotic symptoms, and depressive state of the climacteric women are endocrinologically characterized by a depressed level of serum estrogen, relatively high level of serum estrogen, and an elevation of serum gonadotropin, particularly of luteinizing hormone, respectively.

Postal questionnaires about psychosocial factors of climacteric symptoms and complaints were sent to 353 women (subjects) with such symptoms and complaints and to 1024 volunteers without such symptoms and complaints. Controls were selected from the latter. Both subjects and volunteers were inhabitants of Miyagi Prefecture, North-East Japan. Two hundred and eighty-two subjects (79.9%) and 829 volunteers (81.0%) returned completed questionnaires. Two hundred and sixteen of these 282 subjects, 40-59 yr of age, were selected. Each was matched at random with one of 639 volunteers, also 40-59 yr of age and within 1 yr of the subject's age. Thus, 216 matched pairs, each consisting of a case and control, were created. Significantly high relative risks of the following variables as estimated by McNemar's test were shown by this case-control study, and were of two types. Social variables were few intimate friends, low educational level, husband employed in unskilled labor, and subject employed in unskilled labor. Psychic variables were a feeling of poor health, low self-esteem, perceived lack of respect from people surrounding the subject, dissatisfaction with present life, anxiety about the future, and a feeling of being a burden to family and/or community. Moreover, correlations between all possible pairs of variables of the above two groups were examined by means of the chi-square test. Statistically significant correlations were found for the following two pairs of variables: few intimate friends and either low self-esteem or anxiety about the future, and low educational level and either dissatisfaction with present life or a feeling of poor health. These results suggest that climacteric symptoms and complaints are closely associated with a lack of potential social support characterized by few intimate friends, etc., especially in mild symptom-type cases, and also with low socioeconomic status related to low educational level, etc., particularly in severe symptom-type cases.

New methods for clinical diagnosis of the functional endocrine disorders of the gonadal system inculding the diencephalon, the hypophysis, the gonads and the uterus were devised and clinical cases of endocrine disturbances were evaluated by these methods. 1) Various kinds of methods of laboratory testing of uterus sensitivity to ovarian hormones, i.e. the 32P-uptake test, the oxygen consumption test, the histological examination test, the cervical-mucus-crystallization test, the withdrawalbleeding test, were devised and clinical cases of lowered sensitivity of the uterus to ovarian hormones, detected by these methods, were reported. 2) A new method of evaluating function of the ovary, i.e. the gonadotrophin administration test, was devised by an intravenous administration of gonadotrophin and an estimation of the change of estrogen contents in urine and blood. 3) New methods of evaluating function of diencephalon, i.e. the basal body temperature test and the copper-salt administration test, were devised and applied clinically.

In order to clarify the in vitro action of clomiphene, F 6066 and Lychium chinense Miller (LCM) on the pituitary, the anterior pituitary of the rat was incubated with these materials and the gonadotropin in the medium was assayed. 1) Clomiphene showed no increase of LH secretion upon its addition to the incubation medium containing the pituitary alone or in the presense of the hypothalamus. The addition of a large amount of clomiphene induced a slight increase in secretion of FSH but it was not statistically significant, while prolactin secretion was significantly stimulated by a small amount of clomiphene. Secretion of prolactin was stimulated even in the presence of the hypothalamus. 2) F 6066 acted directly on the pituitary, markedly stimulating LH secretion. No significant changes of FSH and prolactin values were observed. 3) Extracts from LCM acted directly on the pituitary to stimulate LH secretion. 4) The results described above suggest that both clomiphene and F 6066 act on the diencephalon-pituitary system. Clomiphene gives a more marked effect on prolactin, while F 6066 acts on LH secretion more strongly. The action of LCM to induce ovulation is presumably consisted of a direct action on the pituitary to induce LH secretion. Further studies are necessary to elucidate the mechanism of action of these substances.

The effect of sex hormones on the target organ, the uterus, was studied electron-microscopically, histochemically and enzyme-chemically. It was found to be accomplished by a varieties of changes in the general metabolism, accompanied by changes in the activity of enzymes and co-enzymes. These effects are considered to result in the known physiological action of sex hormones and to cause morphological changes in tissues. So, when a hormone reaches the target organ, it takes, at first, part in some specific biochemical reaction, which results in inducing a series of many concomitant biochemical processes. The answer to the question of what constitutes this initiative reaction perhaps holds the key to elucidate the mechanism of sex hormone. Whether the kind of initiative reaction upon which the hormones can act is single or multiple is also a question awaiting future study. We must also study the question of the place of sex hormones in the enzymatic system, that is, whether they are substrates, enzymes, coenzymes, stimulator, or inhibitor.

Large doses of progesterone, testosterone, androsterone, Δ4-androstenedione and dehydroepiandrosterone were administered in pregnant rats to elucidate the action of these sex steroids disturbing pregnancy. Absorption or death of the fetus was observed by the administration of a relatively larger doses of these steroids, while various degrees of masculinization of the genetic female offspring was produced by the administration of smaller doses of these steroids except dehydroepiandrosterone. The degree of masculinization was found to be related with the dose of these sex hormones and also with the period of pregnancy during which they were administered. The highly modified fetus and offspring have oviduct, upper vagina combined with epididymis, vasa deferentia, seminal vesicle, prostate and penis.

In order to elucidate the problem of uterus-sensitivity to ovarian hormones, the following experiments were carried out. 1) The author proposed a new desease “Hyposensitive uterus”, provisionally denominated, and three cases of it were reported. This desease is characterized by irresponsiveness of the uterus to ovarian hormones, regardless of the normal function of ovary, confirmed by typical biphasic B. B. T. curve, normal value of estrogen and pregnanediol excretion in the urine and confirmation of corpus luteum by laparotomy. 2) Various kinds of methods of laboratory testing of uterus-sensitivity were devised to make diagnosis of anomalous sensitivity of uterus. A summation of data examined by these tests leads to the conclusion that uterus-sensitivity test by the measurement of oxygen consumption of endometrium and myometrium was most convenient and valuable in clinical use.