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Hypercoagulability associated with malignant tumors causes thrombosis, termed Trousseau's syndrome, but is rarely associated with benign gynecological tumors, such as myoma and adenomyosis. We herein report a 47-year-old Japanese woman with uterine adenomyosis who developed multiple cerebral infarcts during menstruation. Edoxaban was initially used for prevention but failed to prevent recurrence of thrombosis. However, hysterectomy and bilateral salpingo-oophorectomy resulted in the successful prevention of recurrence of cerebral infarct for five years without antiplatelet or anticoagulant agents. In our patient, the surgical removal of adenomyosis was highly effective for preventing thrombosis in a patient with adenomyosis.

Taq1A polymorphism is a DRD2 gene variant located in an exon of the ANKK1 gene and has an important role in the brain’s dopaminergic functions. Some studies have indicated that A1 carriers have an increased risk of developing Parkinson’s disease (PD) and show poorer clinical performance than A2 homo carriers. Previous studies have suggested that A1 carriers had fewer dopamine D2 receptors in the caudate and increased cortical activity as a compensatory mechanism. However, there is little information about morphological changes associated with this polymorphism in patients with PD. The study aim was to investigate the relationship between brain volume and Taq1A polymorphism in PD using voxel-based morphometry (VBM). Based on Taq1A polymorphism, 103 patients with PD were divided into two groups: A1 carriers (A1/A1, A1/A2) and A2 homo carriers (A2/A2). The volume of the left prefrontal cortex (PFC) was significantly decreased in A2 homo carriers compared to A1 carriers. This finding supports the association between Taq1A polymorphism and brain volume in PD and may explain the compensation of cortical function in A1 carriers with PD.

Purpose We aimed to evaluate sleep-related hypoventilation in multiple system atrophy (MSA) using polysomnography (PSG) with transcutaneous partial pressure of carbon dioxide (PtcCO2) monitoring. Methods This prospective study included 34 patients with MSA. Motor and autonomic function, neuropsychological tests, PSG with PtcCO2 monitoring, and pulmonary function tests were performed. Sleep-related hypoventilation disorder (SRHD) was defined according to the International Classification of Sleep Disorders, third edition. Results Nine (27%) of the 34 patients met the diagnostic criteria of SRHD. Twenty-nine (85%) patients had sleep-related breathing disorders based on an Apnea–Hypopnea Index of ≥ 5/h. The patients with MSA and SRHD had a higher arousal index (p = 0.017) and obstructive apnea index (p = 0.041) than those without SRHD. There was no difference in the daytime partial pressure of carbon dioxide in arterial blood or respiratory function between MSA patients with and without SRHD. Conclusion Sleep-related hypoventilation may occur in patients with MSA even with a normal daytime partial pressure of carbon dioxide. This can be noninvasively detected by PSG with PtcCO2 monitoring. SRBD and sleep-related hypoventilation are common among patients with MSA, and clinicians should take this into consideration while evaluating and treating this population. Supplementary Information The online version contains supplementary material available at 10.1007/s11325-022-02568-4.

Background: Indications for subthalamic nucleus deep brain stimulation (STN-DBS) surgery are determined basically by preoperative motor function; however, postoperative quality of life (QOL) is not necessarily associated with improvements in motor symptoms, suggesting that neuropsychiatric symptoms might be related to QOL after surgery in patients with Parkinson's disease.Objectives: We aimed to examine temporal changes in neuropsychiatric symptoms and their associations with QOL after STN-DBS.Materials and Methods: We prospectively enrolled a total of 61 patients with Parkinson's disease (mean age = 65.3 ± 0.9 years, mean disease duration = 11.9 ± 0.4 years). Motor function, cognitive function, and neuropsychiatric symptoms were evaluated before and after DBS surgery. Postoperative evaluation was performed at 3 months, 1 year, and 3 years after surgery.Results: Of the 61 participants, 54 completed postoperative clinical evaluation after 3 months, 47 after 1 year, and 23 after 3 years. Frontal lobe functions, depression, and verbal fluency significantly worsened 3 years after STN-DBS. Non-motor symptoms such as impulsivity and the Unified PD Rating Scale (UPDRS) part I score were associated with QOL after STN-DBS.Conclusions: Frontal lobe functions, depression, and verbal fluency significantly worsened 3 years after STN-DBS. The UPDRS part I score and higher impulsivity might be associated with QOL after STN-DBS.

Background The “hot cross bun” (HCB) sign, a cruciform hyperintensity in the pons on magnetic resonance imaging (MRI), has gradually been identified as a typical finding in multiple system atrophy, cerebellar-type (MSA-C). Few reports have evaluated the sensitivity of an HCB, including a cruciform hyperintensity and vertical line in the pons, which precedes a cruciform hyperintensity, in the early stages of MSA-C. Moreover, the difference in frequency and timing of appearance of an HCB between MSA-C and spinocerebellar ataxia type 3 (SCA3) has not been fully investigated. Methods This study investigated the time at which an HCB and orthostatic hypotension (OH) appeared in 41 patients with MSA-C, based on brain MRI and head-up tilt test. The MRI findings were compared with those of 26 patients with SCA3. The pontine signal findings on T2-weighted MRI were graded as 0 (no change), 1 (a vertical T2 high-intensity line), or 2 (a cruciform T2 high-intensity line), with grades 1 or 2 considered as an HCB. OH 30/15 was defined as a decrease in systolic blood pressure of > 30 mmHg or diastolic blood pressure of > 15 mmHg. Results Among the 24 patients with MSA-C within 2 years from the onset of motor symptoms, an HCB was detected in 91.7%, whereas OH 30/15 was present in 60.0%. Among the 36 patients with MSA-C within 3 years from the onset of motor symptoms, a grade 2 HCB was detected in 66.7% of those with MSA-C but in none of those with SCA-3. Conclusions HCB is a highly sensitive finding for MSA-C, even in the early stages of the disease. A grade 2 HCB in the early stage is an extremely specific finding for differentiating MSA-C from SCA-3.

Background The “hot cross bun” (HCB) sign, a cruciform hyperintensity in the pons on magnetic resonance imaging (MRI), has gradually been identified as a typical finding in multiple system atrophy, cerebellar-type (MSA-C). Few reports have evaluated the sensitivity of an HCB including a cruciform hyperintensity and vertical line in the pons, which precedes a cruciform hyperintensity, in the early stages of MSA-C. Moreover, the difference in frequency and timing of appearance of an HCB between MSA-C and spinocerebellar ataxia type 3 (SCA3) has not been fully investigated. Methods This study investigated the time at which an HCB and orthostatic hypotension (OH) appeared in 41 patients with MSA-C, based on brain MRI and head-up tilt test. The MRI findings were compared with those of 26 patients with SCA3. The pontine signal findings on T2-weighted MRI were graded as 0 (no change), 1 (a vertical T2 high-intensity line), or 2 (a cruciform T2 high-intensity line), with grades 1 or 2 considered as an HCB. OH 30/15 was defined as a decrease in systolic blood pressure of > 30 mmHg or diastolic blood pressure of > 15 mmHg. Results Among the 24 patients with MSA-C within 2 years from the onset of motor symptoms, an HCB was detected in 91.7%, whereas OH 30/15 was present in 60.0%. Among the 36 patients with MSA-C within 3 years from the onset of motor symptoms, a grade 2 HCB was detected in 66.7% of those with MSA-C but in none of those with SCA-3. Conclusions HCB is a highly sensitive finding for MSA-C, even in the early stages of the disease. A grade 2 HCB in the early stage is an extremely specific finding for differentiating MSA-C from SCA-3.

Background Dopamine replacement therapy is an established treatment for motor symptoms of Parkinson's disease, but its long-term use is often limited by the eventual development of motor complications, including levodopa-induced dyskinesia. Genetic background, particularly polymorphisms of dopamine metabolism genes, may affect the occurrence of dyskinesia in Parkinson's disease patients. Methods We investigated polymorphisms of dopamine metabolism genes, including catechol-O-methyltransferase, monoamine oxidase B, dopamine beta-hydroxylasedopamine, dopamine receptors D1, D2, and D3, and dopamine transporter, in 110 patients with Parkinson's disease. Cox proportional hazards regression was used to detect associations between genotypes and levodopa-induced dyskinesia. Results Monoamine oxidase B rs1799836 was the only polymorphism correlated with risk of dyskinesia. Patients with an AG or GG genotype were more likely to have dyskinesia than those with an AA genotype (adjusted hazard ratio, 3.41; 95% confidence interval, 1.28–9.10). Also, Kaplan-Meier curves demonstrated that patients with an AG or GG genotype developed dyskinesia earlier than those with an AA genotype (log-rank test, p = .004). Conclusions In Parkinson's disease patients, the monoamine oxidase B rs1799836 G allele is associated with a greater likelihood of developing dyskinesia than the A allele, possibly due to its association with lower monoamine oxidase B activity in the brain. Thus, detection of monoamine oxidase B polymorphisms may be useful for determining the optimal dosing of antiparkinson medications., Graphical abstract Unlabelled Image, Highlights • Average dose of L-dopa induced dyskinesia in Parkinson's disease was over 400 mg/day. • MAO-B rs1799836 G allele increases risk of L-dopa induced dyskinesia in PD. • 50% of PD with MAO-B G allele developed L-dopa induced dyskinesia within 8 years.

Introduction. Patients with Parkinson’s disease (PD) showed reduced myocardial123I-MIBG uptake, which may affect autonomic regulation. We investigated correlation between MIBC accumulation and cardiovascular autonomic function in PD.Methods. We performed myocardial MIBG scintigraphy, heart rate variability (HRV) analysis, and the head-up tilt test (HUT) in 50 PD patients (66.4±7.8years; duration5.5±5.9years). Autonomic function tests were also performed in 50 healthy controls (66.5±8.9years). As HRV parameters, a high-frequency power (HF, 0.15–0.4 Hz), a low-frequency power (LF, 0.04–0.15 Hz), and LF/HF ratio were used.Results. Our PD patients had a significant reduction in LF and HF compared with the controls (P=0.005andP=0.01). In HUT, systolic and diastolic blood pressure falls in the PD group were significantly greater than those in the controls (P=0.02andP=0.02). The washout rate of MIBG was negatively correlated with blood pressure changes during HUT.Conclusion. Our PD patients showed reduced HRV, blood pressure dysregulation, and reduced MIBG accumulation, which was correlated with blood pressure dysregulation. Orthostatic hypotension in PD may be mainly caused by sympathetic postganglionic degeneration.

Cortical cerebellar atrophy (CCA) and multiple system atrophy with predominant cerebellar ataxia (MSA-C) are the two major forms of adult-onset sporadic ataxia. Contrary to MSA-C, there are neither diagnostic criteria nor neuroimaging features pathognomonic for CCA. Therefore, it is assumed that the category of CCA in the Japanese national registry include heterogeneous cerebellar ataxic disorders. To refine this category in more detail, we here used a clinical-based term, "idiopathic cerebellar ataxia (IDCA)", and proposed its diagnostic criteria. We collected 346 consecutive patients with the core features of the criteria (sporadic, insidious-onset and slowly progressive cerebellar ataxia in adults, and cerebellar atrophy on brain imaging). Of these, 212 (61.3%) were diagnosed with probable or possible MSA, and 30, who did not meet the diagnostic criteria for MSA at examination, were also excluded because of MRI findings suggestive of MSA. Twenty two were proven to have hereditary spinocerebellar ataxias by genetic testing, and 19 had secondary ataxias. Finally, the remaining 63 (18.2%) were diagnosed with IDCA. The mean (standard deviation) age at onset was 57.2 (10.8) years. Of these, 25 (39.7%) showed pure cerebellar ataxia, and the remaining 38 (60.3%) had some of extracerebellar features including abnormal tendon reflexes (46.0%), positive Babinski sign (9.5%), sensory disturbance (12.7%), cognitive impairment (9.5%), and involuntary movements (7.9%). Our results show that IDCA refined by the diagnostic criteria still includes clinically and genetically heterogeneous ataxic disorders. More extensive genetic analyses will be of significance for further clarification of this group.

OBJECTIVE To determine the ability of sphincter electromyography (EMG) and post-void residual urine volume (PVR) during a free-flow study and a pressure-flow study (PFS) for distinguishing multiple system atrophy (MSA) from Parkinson's disease (PD). METHODS We retrospectively reviewed 241 case records; both urodynamic study and sphincter EMG were performed in patients with MSA (n = 147) and PD (n = 94). RESULTS There was a statistically significant difference (p < 0.01) in the mean PVR during the free-flow study (113.1 ± 7.5 mL in MSA and 40.4 ± 3.8 mL in PD), mean PVR during PFS (230.1 ± 12.6 mL in MSA and 71.7 ± 6.6 mL in PD), and mean duration of MUP for sphincter EMG (9.3 ± 0.1 ms in MSA and 7.7 ± 0.1 ms in PD). The area under the curve used for differentiating MSA from PD was 0.79 and 0.73 for PVR during PFS and the free-flow study, respectively. There was a mean duration of 0.69 ms for the sphincter EMG. CONCLUSIONS The present results suggested that PVR was more appropriate than sphincter EMG for differentiating MSA from PD.

BACKGROUND: According to Braak staging of Parkinson's disease (PD), detection of autonomic dysfunction would help with early diagnosis of PD. OBJECTIVE: To determine whether the autonomic nervous system is involved in the early stage of PD, we evaluated cardiovascular and sudomotor function in early untreated PD patients. METHODS: Orthostatic blood pressure regulation, heart rate variability, skin vasomotor function, and palmar sympathetic sweat responses were examined in 50 early untreated PD patients and 20 healthy control subjects. RESULTS: The mean decrease in systolic blood pressure during head-up tilt in PD patients was mildly but significantly larger than in controls (p = 0.0001). There were no differences between the 2 groups in heart rate variability, with analysis of low frequency (LF; mediated by baroreflex feedback), and high frequency (HF; mainly reflecting parasympathetic vagal) modulation. However, LF/HF, an index of sympatho-parasympathetic balance, was lower in the PD group than in controls (p = 0.02). Amplitudes of palmar sweat responses to deep inspiration (p = 0.004), mental arithmetic (p = 0.01), and exercise (p = 0.01) in PD patients were lower than in controls, with negative correlations with motor severity. Amplitudes of palmar skin vasomotor reflexes in PD patients did not differ from controls. CONCLUSIONS: Our study indicates impairment of sympathetic cardiovascular and sudomotor function with orthostatic dysregulation of blood pressure control, reduced LF/HF and reduction in palm sweat responses even in early untreated PD patients.

Aims Deep brain stimulation (DBS) is known to dramatically improve motor complications in patients with Parkinson's disease (PD), but its effect on urinary symptoms and health‐related quality of life (HRQOL) remains unknown. We aimed to examine the relationship between urinary symptoms and HRQOL in patients with PD who underwent DBS. Methods The International Prostate Symptom Score (IPSS) and overactive bladder symptom score (OABSS) were determined to evaluate urinary symptoms in patients with PD who underwent DBS. Postoperative evaluations were performed at 3 months, 1 year, and 3 years postoperatively. We also performed a urodynamic study (UDS) in 13 patients with PD preoperatively and postoperatively. A follow‐up UDS was performed 2.0 ± 0.5 years postoperatively. Results The preoperative urinary symptoms questionnaire was completed by 28 patients, of whom 14 completed the postoperative urinary symptoms questionnaire after 3 months, 18 after 1 year, and 10 after 3 years. The mean OABSS and IPSS did not change significantly at any follow‐up periods postoperatively. When assessing the relationship between urinary symptoms and HRQOL and motor functions, the OABSS and IPSS showed significant positive correlations with HRQOL at 3 months postoperatively. The OABSS and IPSS showed significant positive correlations with activities of daily living (ADL) during the off‐phase at 3 years postoperatively. All urodynamic parameters remained unchanged postoperatively. Conclusions Deep brain stimulation did not significantly affect urinary dysfunctions in patients with PD. Urinary symptoms might partially contribute to HRQOL at 3 months postoperatively and ADL during the off‐phase at 3 years postoperatively.

Background Autonomic urinary dysfunction affects patients with progressive supranuclear palsy (PSP); however, the severity and prevalence of urinary dysfunctions in these patients compared with those observed in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA) are unknown. Objective We compared urinary dysfunction characteristics in patients with PSP, PD, and MSA. Patients and Methods Forty-seven patients who satisfied the probable or possible criteria of the National Institute for Neurological Diseases and Stroke and Society for PSP were assessed using the urinary symptoms questionnaire and the urodynamic study at Chiba and Toho Universities (n = 26 and 21, respectively). The results were compared with those of patients with PD and MSA (n = 218 and 193, respectively). Results The mean disease duration of PSP and the mean age were 2.97 ± 0.26 and 71.4 ± 0.88 years, respectively. The mini-mental state examination and frontal assessment battery scores were 22.6 ± 0.70 and 10.7 ± 0.49, respectively. Urinary storage and voiding symptoms were observed in 57% and 56% of patients with PSP, respectively. Detrusor overactivity in the urodynamic study was detected in 81% of patients with PSP, which was slightly more than that found in patients with PD (69%) and MSA (67%); however, this was not statistically significant. Postvoid residual volume in patients with PSP was significantly more than that in patients with PD (P < 0.01), but was equivalent to that in patients with MSA. Conclusions The present study demonstrated that patients with PSP experienced various urinary dysfunctions. Urinary storage dysfunction in patients with PSP was not different from that in patients with PD or MSA, whereas urinary voiding dysfunction in patients with PSP was milder than that in patients with MSA and more severe than that in patients with PD. These features should be taken into account for the differentiation of PSP from PD and MSA.

Background MSA is clinically classified into two phenotypes: parkinsonism predominant (MSA-P) and cerebellar ataxia predominant (MSA-C). However, little is known about the differences in urinary dysfunctions between MSA-C and MSA-P. We investigated the differences in urinary and cardiovascular dysfunctions between MSA-C and MSA-P. Methods We retrospectively reviewed the medical records of patients with MSA diagnosed as having probable or possible MSA according to Gilman's second consensus criteria from January 2007 to September 2013 in our hospital. Data regarding the initial symptoms, onset of urinary symptoms, and results of urodynamic (including anal sphincter electromyography) and head-up tilt tests were collected. Results A total of 100 patients with MSA, including 59 patients with MSA-C and 41 with MSA-P, were reviewed. Initial symptoms were autonomic (n = 12) and cerebellar (n = 47) in the MSA-C phenotype and were autonomic (n = 14) and parkinsonian (n = 27) in the MSA-P phenotypes. Urodynamic study indicated that bladder contraction was more severely impaired in patients with MSA-P than in those with MSA-C. In the head-up tilt test, the decrease in diastolic blood pressure was significantly larger in the MSA-P phenotype than that in the MSA-C phenotype. Acontractile bladder during the pressure flow study increased likelihood that the phenotype is MSA-P (odds ratio: 6.67; 95% confidence interval: 1.004–44.284; P = 0.050). Conclusions Urinary dysfunctions were more severe in MSA-P compared with MSA-C. Detailed urodynamic study was helpful for detecting subtle differences between MSA-C and MSA-P.

Aims Although subthalamic nucleus deep brain stimulation (STN-DBS) is effective in patients with advanced Parkinson’s disease (PD), its physiological mechanisms remain unclear. Because STN-DBS is effective in patients with PD whose motor symptoms are dramatically alleviated by L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, the higher preoperative catecholamine levels might be related to the better clinical outcome after surgery. We aimed to examine the correlation between the preoperative catecholamine levels and postoperative clinical outcome after subthalamic nucleus deep brain stimulation. The effectiveness of STN-DBS in the patient who responded well to dopaminergic medication suggest the causal link between the dopaminergic system and STN-DBS. We also examined how catecholamine levels were modulated after subthalamic stimulation. Methods In total 25 patients with PD were enrolled (Mean age 66.2 ± 6.7 years, mean disease duration 11.6 ± 3.7 years). Mean levodopa equivalent doses were 1032 ± 34.6 mg before surgery. Cerebrospinal fluid and plasma catecholamine levels were measured an hour after oral administration of antiparkinsonian drugs before surgery. The mean Unified Parkinson’s Disease Rating Scale scores (UPDRS) and the Parkinson’s disease Questionnaire-39 (PDQ-39) were obtained before and after surgery. Of the 25 patients, postoperative cerebrospinal fluid and plasma were collected an hour after oral administration of antiparkinsonian drugs during on stimulation at follow up in 11 patients. Results Mean levodopa equivalent doses significantly decreased after surgery with improvement in motor functions and quality of life. The preoperative catecholamine levels had basically negative correlations with postoperative motor scores and quality of life, suggesting that higher preoperative catecholamine levels were related to better outcome after STN-DBS. The preoperative plasma levels of L-DOPA had significantly negative correlations with postoperative UPDRS- III score in off phase three months after STN-DBS. The preoperative cerebrospinal fluid (CSF) 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) levels had significantly negative correlations with postoperative UPDRS- III score in off phase one year after STN-DBS and the preoperative CSF homovanilic acid (HVA) levels had significant negative correlations with postoperative UPDRS- III score in on phase three months after STN-DBS. In PDQ-39 SI (summary index), preoperative plasma dopamine (DA) level had significantly negative correlations with postoperative PDQ-39 SI one year after STN-DBS suggesting that higher preoperative plasma DA level resulted in better quality of life (QOL) one year after STN-DBS. The stepwise multiple linear regression study revealed that higher preoperative plasma HVA levels had negative influence on the postoperative motor symptoms (i.e., increase in the score of UPDRS), whereas higher preoperative CSF L-DOPA levels had positive influence on the postoperative motor symptoms and QOL (decrease in the score of UPDRS and PDQ-39 SI) The catecholamine levels were not significantly reduced postoperatively in 11 patients despite the significant reduction in levodopa equivalent doses. Unexpectedly, CSF HVA levels significantly increased from 0.00089±0.0003 ng/μl to 0.002±0.0008 ng/μl after STN-DBS. Conclusion The preoperative catecholamine levels might affect the postoperative motor symptoms and quality of life. The catecholamine levels were not significantly reduced postoperatively despite the significant reduction in levodopa equivalent doses.

Objective: Dementia of Lewy body (DLB) type is the second commonest degenerative cause of dementia and autonomic dysfunction has been recognised in DLB. Lower urinary tract (LUT) function in DLB has not been fully delineated. We investigated LUT function in DLB by evaluating clinical and urodynamic data. Methods: We examined 11 patients (eight men, three women; age range 65–81; disease duration 2–14 years) with probable DLB. Urodynamic studies consisted of: measurement of postvoid residual in all patients, uroflowmetry in five, and electromyography (EMG) cystometry in seven. Results: All patients had symptoms of LUT: urinary incontinence (urgency type/functional type due to dementia and immobility/both urgency and stress type in 7/2/1 patients, respectively); night-time frequency; urgency; and daytime frequency and voiding difficulty. Seven had postvoid residuals, and three had residual urine volume >100 ml. Decreased urinary flow was seen in all five and detrusor overactivity in 5/7 patients who underwent flowmetry and EMG cystometry, respectively. Low compliance detrusor (storage phase, n = 2; with bethanechol supersensitivity), an underactive detrusor (n = 4), an acontractile detrusor (n = 1), and detrusor–sphincter dyssynergia (voiding phase) (n = 1) were also seen; 2/3 patients who underwent motor unit potential analysis had neurogenic changes. Conclusion: LUT dysfunction is a common feature in DLB, not only due to dementia and immobility, but also to central and peripheral types of somato-autonomic dysfunction.

Insulin-like growth factor binding protein-3 (IGFBP-3) binds to specific membrane proteins located on human breast cancer cells, which may be responsible for mediating the IGF-independent growth inhibitory effects of IGFBP-3. In this study, we evaluated IGFBP-3 binding sites on breast cancer cell membranes by competitive binding studies with IGFBP-1 through -6 and various forms of IGFBP-3, including synthetic IGFBP-3 fragments. Scatchard analysis revealed the existence of high-affinity sites for IGFBP-3 in estrogen receptor-negative Hs578T human breast cancer cells (dissociation constant (Kd) = 8.19 +/- 0.97 x 10(-9) M and 4.92 +/- 1.51 x 10(5) binding sites/cell) and 30-fold fewer receptors in estrogen receptor-positive MCF-7 cells (Kd = 8.49 +/- 0.78 x 10(-9) M and 1.72 +/- 0.31 x 10(4) binding sites/cell), using a one-site model. These data demonstrate binding characteristics of typical receptor-ligand interactions, strongly suggesting an IGFBP-3:IGFBP-3 receptor interaction. Among IGFBPs, only IGFBP-5 showed weak competition, indicating that IGFBP-3 binding to breast cancer cell surfaces is specific and cannot be attributed to nonspecific interaction with glycosaminoglycans. This was confirmed by showing that synthetic IGFBP-3 peptides containing IGFBP-3 glycosaminoglycan-binding domains competed only weakly for IGFBP-3 binding to the cell surface. Rat IGFBP-3 was 20-fold less potent in its ability to compete with human IGFBP-3(Echerichia coli), as well as 10- to 20-fold less potent for cell growth inhibition than human IGFBP-3, suggesting the existence of species specificity in the interaction between IGFBP-3 and the IGFBP-3 receptor. When various IGFBP-3 fragments were evaluated for affinity for the IGFBP-3 receptor, only those fragments that contain the midregion of the IGFBP-3 molecule were able to inhibit 125I-IGFBP-3(Escherichia coli) binding, indicating that the midregion of the IGFBP-3 molecule is responsible for binding to its receptor. These observations demonstrate that specific, high-affinity IGFBP-3 receptors are located on breast cancer cell membranes. These receptors have properties that support the notion that they may mediate the IGF-independent inhibitory actions of IGFBP-3 in breast cancer cells.

To evaluate the role of serum free or unbound insulin-like growth factor I (IGF-I) on bone growth, we measured serum free IGF-I levels in 354 healthy children and adults (193 males and 161 females, aged 0–40 yr) and in 21 prepubertal GH-deficient (GHD) children (complete GHD, n = 5; partial GHD, n = 16) using a recently developed immunoradiometric assay. We obtained the following results. 1) In the normal children, the serum free IGF-I levels were low in infancy ( These results show that free IGF-I in the serum has an essential role in bone formation because the higher free IGF-I levels were observed when the growth rate accelerated. The measurement of serum free IGF-I may become a useful tool for both diagnosing GH deficiency and predicting growth responses to long term GH therapy.

The insulin-like growth factors (IGFs) are transported by a family of high-affinity binding proteins (IGFBPs) that protect IGFs from degradation, limit their binding to IGF receptors, and modulate IGF actions. The six classical IGFBPs have been believed to have no affinity for insulin. We now demonstrate that IGFBP-7/mac25, a newly identified member of the IGFBP superfamily that binds IGFs specifically with low affinity is a high-affinity insulin binding protein. IGFBP-7 blocks insulin binding to the insulin receptor and thereby inhibiting the earliest steps in insulin action, such as autophosphorylation of the insulin receptor beta subunit and phosphorylation of IRS-1, indicating that IGFBP-7 is a functional insulin-binding protein. The affinity of other IGFBPs for insulin can be enhanced by modifications that disrupt disulfide bonds or remove the conserved COOH terminus. Like IGFBP-7, an NH2-terminal fragment of IGFBP-3 (IGFBP-3((1-87))), also binds insulin with high affinity and blocks insulin action. IGFBPs with enhanced affinity for insulin might contribute to the insulin resistance of pregnancy, type II diabetes mellitus, and other pathological conditions.

We used flow cytometry to measure platelet-derived microparticle levels in plasma obtained from 16 patients during peripheral blood stem cell harvest (PBSC) and in platelet concentrates prepared by apheresis from 10 normal controls. We also studied the binding of an anti-P-selectin antibody and annexin-V to platelets. When all 60 harvests were assessed, we noted a significant difference in microparticle levels between patients with a platelet count >10 x 104/μl and those with a platelet count 4/μl (12.3 ± 4.4 vs. 75 ± 3.9%). In both the first and total harvests, the percentage of platelets and microparticles positive for anti-P-selectin and annexin-V were significantly higher than the normal control levels. These results suggest that patients undergoing mobilization by granulocyte colony-stimulating factor (G-CSF) who have a platelet count >10 X 104/μl are at risk of increased procoagulant activity after retransfusion following PBSC harvest. Key Words: Platelet-derived microparticle— Peripheral blood stem cell harvest—Granulocyte colony-stimulating factor.

A 47-year-old woman was referred to our hospital because of severe anemia and polyclonal gammopathy. She developed sicca syndrome after admission. Laboratory data revealed pancytopenia (white blood cells, 2,800/microliter; hemoglobin, 6.4 g/dl; platelets, 6.1 x 10(4)/microliter) and hyper gamma globulinemia (5.2 g/dl), and bone marrow was hypoplastic. Histology of the salivary gland showed infiltration of lymphocytes. We report a good response to immunosuppressive therapy in a rare case of aplastic anemia complicating Sjögren's syndrome.

A 51-year-old male patient with Behcet syndrome was found by venography to be complicated with superior vena cava syndrome. Flow cytometrical analysis revealed that the patient's platelet surface glycoprotein (GP) Ib and GPIX were decreased by 40 and 10%, respectively, after administration of 80, 000 U/body weight kg of urokinase. The decrease in the total platelet GPIb was confirmed by quantitative immunoblotting. The patient's plasma concentration of glycocalicin increased after administration of urokinase. In contrast, the patient's platelet surface GPIIb/IIIa were not changed after urokinase therapy. These results suggest that administration of urokinase caused proteolysis of the circulating platelet surface GPIb/IX molecules.

It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson’s disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson’s disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of 13CO2 excretion ( T max) in the 13C-acetate breath test and was assessed in patients with and without administration of 100–150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of 13CO2 excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of 13CO2 excretion ( T max) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively ( P = not significant), thus demonstrating levodopa resistance. The peak time of 13CO2 excretion ( T max) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min ( P

Clonidine stimulates GH release via release of GH releasing hormone from the hypothalamus. There has been controversy as to its usefulness in the therapy of children with constitutional growth delay.To evaluate the effect of clonidine treatment we administered clonidine (0.1mg/m2) daily for more than 6 months to 31 prepubertal children (20 male and 11 female) and 24 pubertal children (16 male and 8 female) with non-endocrine short stature. Then we analyzed the height velocity (HV), height velocity SD score (HVSD), and height SD score (HSD) as indicators of their growth response to this therapy. Furthermore, we determined the serum levels of IGF- I and IGFBP-3.In prepubertal children the mean HV and HVSD were increased at 6 months, and remained high thereafter. Four children showed a 2cm increase of HV at 6 months. In pubertal children both HV and HVSD were increased at 6 months, but not increased further. Both IGF- I and IGFBP-3 were significantly increased at 6 months and remained high until 12 months. There was no evidence of accelerated bone maturation or noticeable side-effects.In conclusion, administration of clonidine could be a useful mode of treatment in some children with non-endocrine short stature because of the low cost and the convenience of oral intake. The administration period should be kept within 6 months at a time.

Introduction: Achondroplasia (Ach), the most common form of short-limb short stature, and related disorders are caused by constitutively active point mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Recent studies have provided a large body of evidence for the role of the proliferation and differentiation of chondrocytes in these disorders. Furthermore, a G380R mutation in FGFR3 (FGFR3 Ach ), which results in achondroplasia, induces apoptosis in the chondrogenic cell line ATDC5. This is associated with a decrease in the expression of PTHrP, which shares the same receptor with PTH, and it is significant that PTHrP rescues these cells from apoptosis. Methods: Fetuses derived from transgenic mice expressing FGFR3 Ach under the control of the type II collagen promoter (AchTG) or from wildtype mice were obtained on the 15th day of pregnancy. The femurs were collected from these specimens and cultured for 4 days with PTH. The effects of PTH treatment were then determined by morphometric and histological analyses, in situ hybridization of type X collagen mRNA, and the TUNEL assay. Results: AchTG femurs showed suppressed growth compared with wild type (0.29±0.10 mm vs. 0.46±0.06 mm, respectively; p

Leucocytoclastic vasculitis (LCV) is a clinicopathological entity that preferentially involves capillaries or small vessels rather than the medium sized or large arteries typical of polyarteritis nodosa. Its histopathological features are characterised by the presence of perivascular polymorphonuclear leucocytes with fragmented nuclear debris (leucocytoclasis).1 It may be limited to skin lesions such as erythematous macules, purpuric papules, and haemorrhagic vesiculobullous lesions. Although LCV often involves organ systems other than the skin, it is rarely associated with neurological complications, unlike polyarteritis nodosa or Churg-Strauss syndrome. We report a patient who presented with leucocytoclastic vasculitic neuropathy without skin lesions, and discuss the value of doing a combined biopsy of the skin, nerves, and muscle in this patient for the detection of vasculitis. A 44 year old man was admitted to our hospital because of progressive asymmetrical paraesthesiae in all four limbs. Eight months before admission, a tingling sensation had begun in the second finger of his left hand, but it disappeared spontaneously within one month. Over the next seven months, he experienced dysaesthesia which spread gradually on the lateral sides of his feet, and later to his left hand, and he developed drop foot on the right. Two weeks before admission, he had dysaesthesia in his right hand and …

Laryngeal abductor paralysis (LAP) and stridor are well known features that occur in over one third of patients with multiple system atrophy (MSA).1 The pathogenesis of LAP is thought to be crico-arytenoid abductor muscle denervation,2 although there is a lack of consistent evidence of motor cell loss in the nucleus ambiguus.2,3 More recently, dystonia of the laryngeal adductor muscle has also been proposed.4 LAP/stridor usually occurs in the advanced stages of the disease,6 and is considered to be a poor prognostic feature.1,2 In contrast, some MSA cases have shown LAP initially, with most of these reported by otolaryngology departments.5–7 However, there are no systematic surveys as to the extent to which MSA patients initially …

An activated mutation in the FGFR3 gene causes ACH. To examine the effects of IGF-1, which is an important mediator of GH, on apoptosis, we analyzed a chondrogenic cell line expressing the FGFR3 mutants. Our findings that IGF-1 prevented the apoptosis through P13K and MAPK pathways may explain how GH treatment improves the disturbed bone growth in ACH. Introduction: Achondroplasia (ACH), which is caused by a point mutation of the fibroblast growth factor receptor 3 (FGFR3) gene in the transmembrane domain (G380R), is one of the most common genetic forms of dwarfism. Recently, using a chondrogenic cell line, ATDC5, we have showed that the constitutively active FGFR3 mutants induced an apoptosis of chondrocytes. We have also reported that growth hormone (GH) treatment increased the growth rate in achondroplasia in parallel with the increment of serum levels of insulin-like growth factor (IGF)-1, suggesting an important role of IGF-1 in skeletal development. In this study, to clarify the mechanism by which GH treatment improved the phenotype of ACH patients, we examined the possible effects of IGF-1 on an apoptosis induced by FGFR3 mutant in ATDC5. Materials and Methods: Using adenovirus vector, wildtype or mutant FGFR3 (G380R) was introduced into ATDC5. Analysis of apoptosis was estimated by TUNEL assay. Expression levels of apoptosis-related genes and activation of signaling molecules were analyzed by immunoblot. Results: MTT assay showed that the cell number was reduced in ATDC5 cells expressing the mutant FGFR3 (G380R; ATDC5-mtR3 cells), suggesting that ATDC5-mtR3 cells might fall into apoptosis. IGF-1, which is an important mediator of GH, restored cell proliferation and reduced apoptosis in ATDC5-mtR3 cells. IGF-1 also decreased the ratio of Bax/Bcl-2 in the cells. To investigate which signaling cascade is responsible for antiapoptotic effects of IGF-1, we examined the role of phosphatidylinositol 3-kinase (PI3K) and MAPK in ATDC5-mtR3 cells. Specific inhibitors of PI3K or MAPK blocked the antiapoptotic effects of IGF-1 in ATDC5-mtR3 cells. Conclusions: Our findings, showing IGF-1 prevents the apoptosis induced by FGFR3 mutation through the PI3K pathway and MAPK pathway, explain the mechanisms by which GH treatment improves the disturbed bone growth in ACH.

An activation mutation in the FGFR3 gene causes ACH. The effects of the FGFR3 mutants on apoptosis were analyzed in a chondrogenic cell line. ACH chondrocytes exhibited marked apoptotic with downregulation of PTHrP expression. Rescue of these cells by PTHrP replacement implies a potential therapy for this disorder. Introduction: Achondroplasia (ACH), the most common form of short-limb dwarfism, and its related disorders are caused by constitutively activated point-mutated FGFR3. Recent studies have provided a large body of evidence on chondrocyte proliferation and differentiation in these disorders. However, little is known about the possible effects of the FGFR3 mutants on apoptosis of chondrocytes. Methods: The mutant FGFR3 genes causing ACH and thanatophoric dysplasia (TD), which is a more severe neonatal lethal form, were introduced into a chondrogenic cell line, ATDC5. Analysis of apoptosis was estimated by TUNEL assay, DNA laddering, and fluorescent measurement of mitochondrial membrane potential. Expression levels of parathyroid hormone-related peptide (PTHrP) and apoptosis-related genes were analyzed by Northern blot or immunoblot. Results: The introduction of these mutated FGFR3s into ATDC5 cells downregulated PTHrP expression and induced apoptosis with reduction of Bcl-2 expression. Importantly, replacement of PTHrP prevented the apoptotic changes and reduction of Bcl-2 expression in ATDC5 cells expressing the ACH mutant. In parallel with the severity of disease and the activity of FGFR3, ATDC5 cells expressing TD-mutant FGFR3 showed less expression of PTHrP and Bcl-2 and induced more remarkable apoptotic changes compared with ACH-mutant expressing cells. Furthermore, overexpression of Bcl-2 inhibited apoptotic changes, suggesting that the mutant FGFR3 caused apoptosis, at least in part, through reduction of Bcl-2 expression, which seems to be downstream of PTHrP. Conclusions: Our data suggest that excessive activation of signaling cascades mediated by the FGFR3 mutants inhibits the expression of PTHrP and Bcl-2, resulting in apoptosis of chondrocytes, possibly leading to short-limb dwarfism. Rescue of these cells by PTHrP replacement implies a potential therapy for this disorder.

Recombinant human IGFBP-3 was proteolysed with different concentrations of plasmin for various periods of time. The major IGFBP-3 fragment resulting from this digestion migrated at ca. 15 kDa in nonreducing SDS-PAGE. Following the identification of this fragment as an N-terminal IGFBP-3 fragment, by use of N-terminus-specific monoclonal antibody and amino acid sequence analysis, we constructed and expressed a similar fragment in a baculovirus expression system. The fragments resulting from plasmin digestion, as well as the baculovirus-expressed recombinant human IGFBP-3(1-97), retain weak IGF binding and show specific insulin binding on cross-linking and western ligand blot. RhIGFBP-3(1-97) can inhibit insulin receptor autophosphorylation in insulin receptor-overexpressing NIH 3T3 cells. Insulin and IGF binding to IGFBP-3 fragments could be further demonstrated in normal urine. These data indicate the physiological significance of IGFBP-3 fragments derived from proteolysis in vivo.

NNKY5-5, an IgG monoclonal antibody directed against the von Willebrand factor-binding domain of glycoprotein (GP) Ibα, induced weak but irreversible aggregation (or association) of platelets in citrate-anticoagulated platelet-rich plasma. This phenomenon was defined as small aggregate formation (SAF ). Platelets in hirudin-anticoagulated plasma or washed platelets showed little response to NNKY5-5 alone, but the antibody potentiated aggregation induced by low concentrations of adenosine diphosphate or platelet-activating factor. NNKY5-5 did not induce granule release or intracellular Ca2+ mobilization. However, NNKY5-5 caused tyrosine phosphorylation of a 64-kD protein and activation of a tyrosine kinase, p72syk. An anti-FcγII receptor antibody had no effect on SAF, suggesting that NNKY5-5 activated platelets by interacting with glycoprotein Ib. Fab′ fragments of NNKY5-5 did not induce SAF, but potentiated aggregation induced by other agonists. The Fab′ fragment of NNKY5-5 induced the activation of p72syk, suggesting that such activation was independent of the FcγII receptor. Cross-linking of the receptor-bound Fab′ fragment of NNKY5-5 with a secondary antibody induced SAF. GRGDS peptide, chelation of extracellular Ca2+, and an anti-GPIIb/IIIa antibody inhibited NNKY5-5-induced SAF, but had no effect on 64-kD protein tyrosine phosphorylation or p72syk activations. Various inhibitors, including aspirin and protein kinase C, had no effect on SAF, protein tyrosine phosphorylation, or p72syk activation. In contrast, tyrphostin 47, a potent tyrosine kinase inhibitor, inhibited NNKY5-5–induced SAF as well as tyrosine phosphorylation and p72syk activation. Our findings suggest that binding of NNKY5-5 to GPIb potentiates platelet aggregation by facilitating the interaction between fibrinogen and GPIIb/IIIa through a mechanism associated with p72syk activation and tyrosine phosphorylation of a 64-kD protein.

Chronic intestinal pseudo-obstruction (CIP) is a rare and highly morbid syndrome characterised by impaired gastrointestinal propulsion together with symptoms and signs of bowel obstruction in the absence of any lesions occluding the gut lumen (tumours, adhesive peritonitis, and so on).1 CIP is thought to have two forms: myogenic and neurogenic.1 Comorbid urinary retention may also occur.2 Postural hypotension is not a feature in CIP. However, we recently had such a CIP patient with profound postural hypotension, which was detected only by a head up tilt test, and he was finally diagnosed as pure autonomic failure (PAF). A 59 year old man gradually (over two months) developed intractable nausea and vomiting immediately after taking meals, although he did not have dysphagia. He also had abdominal distension, discomfort, and mild difficulty in defaecation. At that time, he had no features to suggest autonomic failure affecting other systems than the gut, such as postural dizziness or genitourinary dysfunction. Six months later, he was admitted to a gastrointestinal surgery hospital because of these symptoms, at which time he was emaciated. However, gastric and colonic endoscopy showed no organic lesions. As abdominal x ray findings continued to support the suspicion …