Autonomic function test in progressive lacunar infarction.

OBJECTIVE: Neurological progression is a major problem in managing the patients with acute lacunar infarction. The purpose of this was to investigate whether autonomic dysfunction is associated with neurological progression in patients with acute lacunar infarction. MATERIALS AND METHODS: The study comprised 60 patients with acute lacunar infarction. All enrolled subjects underwent autonomic function tests including the 30° head-up tilt test, Valsalva test, heart rate response to deep breathing, and sympathetic skin response. The primary endpoint is the neurological progression, and the secondary endpoint is the 3-month outcome. RESULTS: Increased initial National Institute of Health stroke scale (NIHSS), decreased time to admission from onset, decreased rise of heart rate in the 30° head-up tilt test, abnormal blood pressure response in the Valsalva test, and decreased rise of systolic blood pressure in stage IV of the Valsalva test are associated with neurological progression of acute lacunar infarction; an abnormal blood pressure response in the Valsalva test is significant in logistic regression analysis of neurological progression. Advanced age, increased initial NIHSS and modified Rankin scale, decreased expiration/inspiration ratio of heart rate to deep breathing, decreased rise of systolic blood pressure in stage IV of the Valsalva test, and neurological progression were associated with an unfavorable 3-month outcome; neurological progression was significant in logistic regression analysis of 3-month outcome. CONCLUSIONS: An abnormal blood pressure change in the Valsalva test is associated with neurological progression in patients with acute lacunar infarction, and neurological progression can induce an unfavorable 3-month outcome.

Progressive topological disorganization of brain network in focal epilepsy.

OBJECTIVE: Increasing evidence has suggested that epilepsy is a network disease. Graph theory is a mathematical tool that allows for the analysis and quantification of the brain network. We aimed to evaluate the influences of duration of epilepsy on the topological organization of brain network in focal epilepsy patients with normal MRI using the graph theoretical analysis based on diffusion tenor imaging. METHODS: We prospectively enrolled 66 patients with focal epilepsy (18/66 patients were newly diagnosed) and 84 healthy subjects. All of the patients with epilepsy had normal MRI on visual inspection. All of the subjects underwent diffusion tensor imaging that was analyzed using graph theory to obtain network measures. RESULTS: The measures of characteristic path length and small-worldness in the patients with focal epilepsy were significantly decreased, even after multiple corrections (P < .01). Moreover, the measures including mean clustering coefficient and global efficiency in the patients with epilepsy had strong tendency to decrease compared to those in healthy subjects (P = .0153 and P = .0138, respectively). When comparing the measures among the patients with newly diagnosed/chronic epilepsy and healthy subjects using ANOVA, the characteristic path length (P = .006), small-worldness (P = .032), and global efficiency (P = .004) were significantly different. In addition, the duration of epilepsy was negatively correlated with global efficiency (r = -.249, P = .0454). CONCLUSIONS: We newly found a progressive topological disorganization of the brain network in focal epilepsy. In addition, we demonstrated disrupted topological organization in focal epilepsy, shifting toward a more random state.

Effective connectivity in temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: We hypothesized that temporal lobe epilepsy (TLE) patients with and without hippocampal sclerosis (HS) showed differences in their limbic networks. This study aimed to evaluate the role of the thalamus in TLE patients with HS. MATERIALS AND METHODS: Twenty-nine TLE patients with HS and 30 controls were enrolled in this study. In addition, we included eight TLE patients without HS as a disease control group. Using whole-brain T1-weighted MRIs, we analyzed the volumes of the limbic structures, including the hippocampus, thalamus, and total cortex, with FreeSurfer 5.1. We also investigated the effective connectivity among these structures using SPSS Amos 21 based on these volumetric measures. Moreover, we quantified correlations between epilepsy duration and the volumes of these structures. RESULTS: There was a statistically significant effective connectivity from the hippocampus to the thalamus in TLE patients with HS. Moreover, the volumes of the left and right thalamus were negatively correlated with epilepsy duration (r=-.42, P=.0315 and r=-.52, P=.0062, respectively). However, neither TLE patients without HS nor normal controls had a significant effective connectivity from the hippocampus to the thalamus. CONCLUSIONS: The limbic networks of TLE patients with and without HS could be different, and the thalamus might play a critical role in TLE patients with HS.

Cerebral hemodynamics in orthostatic intolerance with normal head-up tilt test.

OBJECTIVES: Orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS) are well-known causes of orthostatic intolerance (OI). In addition, there are OI patients who are characterized by the symptoms of OI and lack of abnormal findings in head-up tilt (HUT) test. The aim of this study was to determine the cerebral hemodynamic changes in HUT test of OI patients with normal HUT (OINH). MATERIALS AND METHODS: Two hundred and sixty-one OI patients and 50 healthy controls were enrolled in this study. All subjects underwent transcranial Doppler test while performing the HUT test. Forty-five patients had OH, 33 patients had POTS, and 183 patients had OINH. Blood pressures, heart rate, cerebral blood flow velocities (CBFVs), end-tidal carbon dioxide (ET-PCO2 ), cerebral critical closing pressure (CCP), cerebral perfusion pressure (CPP), and cerebral vascular resistance (CVR) were measured during HUT test. We compared the hemodynamic parameters of OINH with those of OH, POTS, and healthy controls. RESULTS: Reduced CBFVs, CPP, and ET-PCO2 and elevated CCP were observed in the HUT test of all four groups. CVR was reduced in three OI patients. The drops in systolic CBFV, CPP, and CVR of OINH patients were greater than those of healthy controls. The changes in parameters in the HUT test of OINH group were not different from those of OH and POTS groups except prominent decrements of CPP and CVR in OH group. CONCLUSION: Our findings suggest that OINH is true OI sharing the common pathomechanism of OH and POTS.

Brain morphology in juvenile myoclonic epilepsy and absence seizures.

OBJECTIVE: We evaluated the differences in brain morphology among patients with juvenile myoclonic epilepsy according to the occurrence of absence seizures. MATERIALS AND METHODS: Twenty-one juvenile myoclonic epilepsy patients with (n = 6) and without (n = 15) absence seizures were enrolled. We analyzed whole-brain T1-weighted magnetic resonance imaging using FreeSurfer 5.1. Measures of cortical morphology, such as thickness, surface area, volume, and curvature, and the volumes of subcortical structures, the cerebellum, and cerebrum, were compared between the groups. Moreover, we quantified correlations between clinical variables and each measures of abnormal brain morphology. RESULTS: Compared to normal controls, patients without absence seizures demonstrated thinning of the cortical thickness in the right hemisphere, including the post-central, lingual, orbitofrontal, and lateral occipital cortex. Compared to normal controls, patients with absence seizures had more widespread thinning of the cortical thickness, including the right post-central, lingual, orbitofrontal, and lateral occipital cortexes as well as the right inferior temporal cortex. Additionally, the volume of cerebellar white matter in patients without absence seizures was significantly smaller than that in normal controls. Patients with absence seizures had a much smaller cerebellar white matter volume than normal controls or patients without absence seizures. Moreover, there was significantly positive correlation between the age of seizure onset and the volume of cerebellar white matter in patients with juvenile myoclonic epilepsy. CONCLUSIONS: We demonstrated that there were significant brain morphology differences in patients with juvenile myoclonic epilepsy according to the presence of absence seizures. These findings support the hypothesis that juvenile myoclonic epilepsy may be a heterogeneous syndrome.

Morphological and morphometric study of the androgenetic alopecic scalp using two- and three-dimensional analysis comparing regional differences.

BACKGROUND: Androgenetic (male-type) alopecia (AGA) is caused by genetic and androgenetic effects. The progression of baldness results in smaller hair papillae, thinner hair and a shortened hair cycle. Alopecia occurs mainly in the frontal region and, to a lesser extent, in the occipital region. OBJECTIVES: The morphological differences in the hair follicular units between the alopecic frontal scalp and the vertex and occipital regions were compared using cross-sectional histology and three-dimensional reconstruction. METHODS: Skin specimens were obtained from the frontal, vertex and occipital regions of 24 male human cadavers with fully progressed AGA, and from the frontal region of 32 normal cadaveric scalps. These specimens were fixed, processed using routine histological methods, serially sectioned at a thickness of 10 µm and then stained with Masson's trichrome. The serial sections were reconstructed three-dimensionally using 'Reconstruct' software. RESULTS: The ratios between the numbers of terminal and vellus hairs in the frontal and occipital regions in the AGA scalps were 0·2 : 1 and 3·5 : 1, respectively. Almost all of the hair follicles in the frontal region were vellus hair follicles. The sebaceous gland and arrector pili muscle were larger in the frontal region than in the occipital region. CONCLUSIONS: The morphology of the AGA scalp has been characterized. The terminal-to-vellus hair ratio in the occipital (normal) region was different from that in the frontal (alopecic) region. Moreover, sebaceous glands were larger in the frontal alopecic region than in the occipital region. These larger glands may be associated with other dermatological pathologies, such as seborrhoeic dermatitis.

Does lumbar puncture at night prevent post-dural puncture headache?

OBJECTIVES: The aim of this study was to identify the patient-related risk factors for post-dural puncture headache with same standardized procedures. MATERIALS AND METHODS: The inclusion criteria were patients (i) who underwent lumbar puncture for diagnostic purposes, (ii) with ≥10 years of age, and (iii) with no structural lesions that could cause headache from brain-computed tomography or magnetic resonance images. The primary endpoint for this study was post-dural-puncture headache as a dependent variable. The differences were analyzed with demographic and cerebrospinal fluid profiles as independent variables. RESULTS: Four hundred and thirteen patients met the inclusion criteria for this study, and 36 patients developed post-dural puncture headache. Patients with post-dural puncture headache were younger, had lower body mass index, and had less diabetes and hypertension. In cerebrospinal fluid profile, the counts of white blood cell and protein, and cerebrospinal fluid pressure were lower in patients with post-dural puncture headache than those without post-dural puncture headache, but glucose ratio was higher. Interestingly, patients who underwent puncture at daytime developed more post-dural puncture headache than those who were performed puncture at nighttime. After adjusting the clinical variables, multiple logistic regression analysis showed that younger age, lower cerebrospinal fluid pressure, and puncture at daytime were independently significant variables for predicting post-dural puncture headache. CONCLUSIONS: We confirmed the risk factor for post-dural puncture headache such as young age, and newly found that patients who underwent puncture at daytime developed more post-dural puncture headache than those who were performed puncture at nighttime.

Antinociceptive curcuminoid, KMS4034, effects on inflammatory and neuropathic pain likely via modulating TRPV1 in mice.

BACKGROUND: Curcumin, the active ingredient of turmeric (Curcuma longa), has a wide range of beneficial effects including anti-inflammation and analgesia. However, poor bioavailability of curcumin hinders its clinical application. To overcome this limitation, we modified the structure of curcumin and synthesized new derivatives with favourable pharmacokinetic profiles. Recently, curcumin has been shown to have an antagonizing effect on transient receptor potential vanilloid type 1 (TRPV1) ion channels. We investigated the antinociceptive activity of KMS4034 which had the most favourable pharmacokinetics among the tested curcumin derivatives. METHODS: To evaluate the mechanism of the antinociceptive effects of KMS4034, capsaicin (I(CAP))- and heat (I(heat))-induced currents in TRPV1 expressing HEK293 cells were observed after the application of KMS4034. Nociceptive behavioural measurement using the hot-plate test, formalin test, and chronic constriction injury (CCI) model were evaluated in mice. Also, calcitonin gene-related peptide (CGRP) was stained immunohistochemically in the L4/5 dorsal horns in mice with neuropathic pain. RESULTS: I(CAP) (P<0.01) and I(heat) (P<0.05) of TRPV1 were significantly blocked by 10 µM KMS4034. Behaviourally, noticeable antinociceptive effects after 10 mg kg(-1) of KMS4034 treatment were observed in the first (P<0.05) and second phases (P<0.05) of the formalin and hot-plate tests. The mechanical threshold of CCI mice treated with 10 mg kg(-1) KMS4034 was significantly increased compared with control. Immunohistochemical CGRP expression was decreased in the lamina I-II of the lumbar dorsal horns in KMS4034-treated CCI mice compared with the control (P<0.05). CONCLUSIONS: KMS4034 may be an effective analgesic for various pain conditions.

Synthesis and antibacterial activities of new 1beta-methylcarbapenems having aminopyrimidinylthioether moiety.

The synthesis of new 1beta-methylcarbapenems 1a-d bearing aminopyrimidinylthioether moiety at C-5 position of pyrrolidine ring and their antibacterial activities are described. All the compounds exhibited potent antibacterial activity. Of these carbapenems, 1d showed the best combination of antibacterial activity and stability to dehydropeptidase-I (DHP-I).

Anatomy of the deep branch of the ulnar nerve.

UNLABELLED: The aim of this study was to provide a clear description of the course, precise branching pattern and distribution of the deep branch of the ulnar nerve. A total of 36 hands from 18 preserved cadavers were dissected. The vertical distance from the pisoscaphoid line to the crossing points between the deep branch of the ulnar nerve and each metacarpal was about 4 cm. The deep branch of the ulnar nerve gave off two types of muscular branches: (1) trunks that innervate more than two intrinsic hand muscles; and (2) multiple separate branches innervating only a single muscle. The median numbers of trunks and separate branches were 5 and 6, respectively. LEVELS OF EVIDENCE: N/A.

Prevalence and risk factors of silent cerebral infarction in apparently normal adults.

Cerebrovascular disease is a major cause of death and disability in adults. Silent cerebral infarction (SCI) portends more severe cerebral infarctions or may lead to insidious progressive brain damage resulting in vascular dementia. This study was designed to evaluate the prevalence and risk factors of SCI in an apparently normal adult population. Nine hundred ninety-four consecutive symptom-free adults (mean age 49.0+/-7.7; men:women 830:164) who underwent brain magnetic resonance imaging at the Center for Health Promotion at Samsung Medical Center were assessed. All were neurologically normal in history and physical examination. A total of 121 SCI lesions was observed in 58 subjects. The lesion prevalence adjusted for patient age was 5.1%. There was no gender difference in prevalence. Ninety-nine lesions were <1 cm in diameter, 15 were between 1 and 2 cm, 3 were between 2 and 3 cm, and 4 were >3 cm in diameter. The most frequent site of the SCI lesion was basal ganglia, after which the periventricular white matter, cerebral cortex, and thalamus were the most frequent sites. Old age, hypertension, a history of coronary artery disease, evidence of cardiomegaly in chest radiographs, and high fasting glucose/hemoglobin A1c levels were associated with SCI on univariate analysis. Multivariate analysis demonstrated old age and hypertension to be independent risk factors for SCI, and mild alcohol consumption was revealed as an independent protective factor against SCI.

Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists.

Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A(1) and A(3) receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A(1), A(2A), and A(3) receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A(3) receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N(6)-substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A(1) or A(3) receptors, respectively, were synthesized. The N(6)-cyclopentyl derivatives were A(1) receptor-selective and maintained high efficacy at recombinant human but not rat brain A(1) receptors, as indicated by stimulation of binding of [(35)S]GTP-gamma-S. The (N)-methanocarba-N(6)-(3-iodobenzyl)adenosine and its 2-chloro derivative had K(i) values of 4.1 and 2.2 nM at A(3) receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A(3) receptors (EC(50) < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y(1) receptors, at least three adenosine receptors favor the ribose (N)-conformation.

Comparative analysis of transcriptional profiles between two apoptotic pathways of light-induced retinal degeneration.

Light exposure can exacerbate the condition of a variety of human retinal diseases by increasing the rate of photoreceptor cell death. How light negatively affects photoreceptor cell survival is not yet fully understood. Previous studies involving light damage models have revealed two independent apoptotic pathways: low levels of light induce retinal degeneration in the arrestin -/- mouse via constitutive activation of the phototransduction cascade, whereas strong light exposure to the retina, such as in an albino eye, elicits photoreceptor cell death via activator protein (AP-1) induction. In order to better understand the initial gene expression changes underlying light damage, dark-reared arrestin -/- and albino BALB/c mice were exposed to constant white light (2000 lux), and their retinal morphology was assessed as a function of time. The expression profiles of retinal transcripts were then compared between dark-adapted and light-exposed arrestin -/-, pigmented wild-type and BALB/c mice at a time point when morphological changes were minimal. As expected, the dark-adapted samples showed little difference in expression pattern between the three genotypes. Among the genes differentially regulated by light in BALB/c, but not arrestin -/- retinas, were c-fos and other stress-induced early response genes. In both mouse models, a marked increase in expression of the bZIP family of transcription factors was observed. Our results show a select group of unique and overlapping sets of genes induced by light in the two mouse models. These expression changes may constitute the underlying initiating events leading to the two distinct mechanisms of light damage.

Changes of tetanus specific IgG, IgM and IgG subclasses after DPT vaccination.

We evaluated tetanus specific IgG, IgM, IgG subclasses after DPT vaccination in infants and children. Tetanus toxoid specific IgG, IgM IgG subclasses were measured to characterize the isotope profile of antibody against tetanus toxoid. The values of the tetanus specific IgG in the positive group were significantly increased compared to those of the control group, and were significantly increased after two inoculation. Tetanus specific IgG was very low in adults and neonates. In our tetanus specific IgG subclasses study, forty-five of 56 cases (80%) showed predominantly IgG1 antibody responses to tetanus toxoid, while twenty-five of 56 cases (45%) showed IgG4 responses. Both IgG1 and IgG4 responses were demonstrated in 17 cases (30%). So we suggest that IgG was mainly involved in humoral immune response after DPT vaccination, and IgG1 may play an important role among IgG subclasses. IgG4, alone or together with IgG1, can also play a role in immune response to tetanus toxoid.

Synthesis and anti-inflammatory and analgesic activities of phenoxyalkanoic acid derivatives.

The synthesis of phenoxyalkanoic acid derivatives and their anti-inflammatory and analgesic activities are described. Analysis of structure-activity relationships shows that in trichlorophenoxy derivatives anti-edematous potency is associated with the presence of 1-thiopropyl moiety and 2 or 4-aminopyridyl moiety at R' position contributes to the analgesic activity.

Synthesis and anti-inflammatory and analgesic activities of pyridyloxy- and phenoxyalkanoic acid derivatives.

Synthesis of pyridyloxy-, pyridyloxyphenoxy- and phenoxylphenoxyalkanate derivatives and their anti-inflammatory and analgesic activities were investigated. Analysis of structure-activity relationships showed that in pyridyloxyalkanoic acid derivatives anti-edematous potency was associated with the presence of chlorophenoxypropionic acid moiety and 2-nitrated methyl propionates contributed to the analgesic activity.

Characterization of dextran-producing Leuconostoc strains.

Leuconostoc strains were characterized according to their antibiotic susceptibilities, carbohydrate fermentation profiles, sucrase activity patterns and plasmid content. All the strains tested were resistant to the antibiotics sulphathiazole, trimethoprim and vancomycin, and could be separated into two groups based on whether or not they could ferment melibiose and raffinose. Six Leuconostoc strains possessed plasmids and many produced unique sucrase activity patterns in polyacrylamide gels. These data will aid in distinguishing among physiologically similar dextran-producing leuconostocs, frequently used in research and industry.

Construction of the bicyclo[3.1.0]hexane template of a conformationally locked carbocyclic adenosine via an olefin keto-carbene cycloaddition.

An intramolecular olefin keto-carbene cycloaddition reaction created the bicyclo[3.1.0]hexane template 10 that was necessary for the synthesis of carbocyclic amine 15. This amine is a direct precursor to a family of rigid nucleosides that are conformationally locked in the Southern hemisphere of the pseudorotational cycle. The synthesis of the conformationally locked adenosine analogue is reported herein as an illustrative example of the methodology. The racemic (South)-methanocarba adenosine analogue (+/-)-4 is the first example of a conformationally locked ribonucleoside version in the Southern hemisphere.

Significance of high-risk human papillomavirus detection by polymerase chain reaction in primary cervical cancer screening.

The purposes of this study were to evaluate the incidence of high-risk human papillomavirus (HPV) infection by polymerase chain reaction (PCR) and to assess its diagnostic usefulness in primary cervical screening. PCR testing for HPV type 16, 18, 31 and 33 was performed on 1305 specimens obtained during routine cervical cancer screening. We analysed the concurrent cervical smears and biopsy, and correlated them with the HPV infection status. We also evaluated histologically-proven cases with ASCUS smears according to HPV infection. HPV DNA was identified in eight (0.7%) of 1144 cytologically normal patients; nine (10.5%) of 86 ASCUS; seven (25.0%) of 28 LSIL; 26 (78.8%) of 33 HSIL; and in all of three squamous cell carcinomas (SCC). HPV positivity was significantly associated with cytohistological diagnosis for HSIL of more. In addition, HPV-positive ASCUS cases were found to be associated with histological abnormality rather than HPV-negative. The results indicate that high-risk HPV testing by PCR could be a useful adjunct tool for Pap smear in primary cervical screening. The combination of Pap smear and high-risk HPV testing by PCR might reduce unnecessary colposcopy-guided biopsy of women with cytological diagnosis of ASCUS.