Update to the Hong Kong Epilepsy Guideline: evidence-based recommendations for clinical management of women with epilepsy throughout the reproductive cycle.

Since the publication of the Hong Kong Epilepsy Guideline in 2009, there has been significant progress in antiepileptic drug development. New AEDs have emerged, and data about their uses have been published. Women require special attention in epilepsy care. Drug teratogenicity, pregnancy, breastfeeding, contraception, reproduction technology, menopause, and catamenial epilepsy are major topics. Antiepileptic drugs should be chosen individually for patients who are pregnant or may become pregnant with consideration of their teratogenicity and seizure control properties. Folate is commonly prescribed for women of childbearing age who are taking antiepileptic drugs. Spontaneous vaginal delivery and breastfeeding are not contra-indicated in most cases but need to be considered individually based on the patient's medical condition and wishes. Serum drug level monitoring of certain antiepileptic drugs during pregnancy and puerperium can guide dosage adjustment. For catamenial epilepsy, intermittent benzodiazepines such as clobazam during the susceptible phase of the menstrual cycle could be a treatment option.

Factors associated with depression in people with epilepsy: a retrospective case-control analysis.

PURPOSE: This study investigated factors associated with depression in people with epilepsy. METHODS: All adult patients attending our epilepsy clinic in 2018 were screened for inclusion in this study. Eligible patients were divided into case and control groups, depending on the presence of co-morbid depression. Depressive disorders were diagnosed by a psychiatrist. Demographics and clinical characteristics, including epilepsy features and antiepileptic drug use, were compared between groups. The factors contributing to onset of depression after diagnosis of epilepsy were further analysed by binomial logistic regression. Statistical significance was set at P<0.05. RESULTS: Forty four patients with epilepsy who had depression and 514 patients with epilepsy who did not have depression were included in this study (occurrence rate=7.9%). Female sex (P=0.005), older age (P<0.001), temporal lobe epilepsy (P=0.01), and higher number of antiepileptic drugs used (P=0.003) were associated with depression in patients with epilepsy. No differences were observed in other epilepsy-related factors including aetiology, seizure type, and laterality of epileptic focus. Binomial logistic regression showed that female sex (P=0.01; odds ratio [OR]=3.56), drug-resistant epilepsy (P<0.001; OR=4.79), and clonazepam use (P<0.001; OR=14.41) were significantly positively associated with risk of depression after epilepsy diagnosis, whereas valproate use (P=0.03; OR=0.37) was significantly negatively associated with risk of depression. CONCLUSION: Female sex, refractoriness, and clonazepam use may be risk factors for depression after epilepsy diagnosis. Valproate may protect against depression in people with epilepsy. Better understanding of clinical features may aid in medical management or research studies regarding co-morbid depression in people with epilepsy.

Clinical outcome of generalized myasthenia gravis in Hong Kong Chinese.

BACKGROUND: Myasthenia gravis (MG) is an organ-specific autoimmune disease characterized by autoantibody-mediated impairment of skeletal muscle neuromuscular transmission. MG causes significant morbidity and even mortality. We studied the long-term clinical outcome of generalized MG (gMG) patients. METHODS: Records of Chinese gMG patients managed in Queen Mary Hospital from 1997 to 2012 were reviewed. Clinical, serological and radiological characteristics were studied for independent predictors of good long-term clinical outcome. RESULTS: A total of 123 Chinese gMG patients were studied. Their mean onset age was 44.8 years (range 7-83 years), 87 (70.7%) were female, and median follow-up duration was 114 months (interquartile range 67-188 months). Thymoma were detected in 45 patients (36.6%). Acetylcholine receptor autoantibodies were detected in 99 patients (87.6%). Ninety-three patients (75.6%) received immunosuppressant therapy (corticosteroid 75.6%, azathioprine 58.5%, mycophenolate mofetil 5.7%, cyclosporin 5.7%) and 77 (62.6%) received thymectomy. Thirty-five (28.5%) patients experienced MG crisis and two died. Ninety-six (78.0%) patients had good outcome defined by Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) of complete stable remission (CSR), pharmacological remission (PR) or minimal manifestation (MM) at latest follow-up, whereas 24 patients (19.5%) had intermediate outcome defined by MGFA PIS of Improved (I); 3 patients (2.4%) had poor prognosis defined by MGFA PIS of unchanged (U), worse (W), exacerbation (E) or died of MG (D). Azathioprine therapy was the only independent predictor of good outcome (OR 3.57, 95% CI 1.05-12.10, p=0.042). CONCLUSION: 78.0% of gMG patients had good long-term clinical outcome. Azathioprine therapy independently predicted good clinical outcome.

Developmental and evolutionary novelty in the serrated teeth of theropod dinosaurs.

Tooth morphology and development can provide valuable insights into the feeding behaviour and evolution of extinct organisms. The teeth of Theropoda, the only clade of predominantly predatory dinosaurs, are characterized by ziphodonty, the presence of serrations (denticles) on their cutting edges. Known today only in varanid lizards, ziphodonty is much more pervasive in the fossil record. Here we present the first model for the development of ziphodont teeth in theropods through histological, SEM, and SR-FTIR analyses, revealing that structures previously hypothesized to prevent tooth breakage instead first evolved to shape and maintain the characteristic denticles through the life of the tooth. We show that this novel complex of dental morphology and tissues characterizes Theropoda, with the exception of species with modified feeding behaviours, suggesting that these characters are important for facilitating the hypercarnivorous diet of most theropods. This adaptation may have played an important role in the initial radiation and subsequent success of theropods as terrestrial apex predators.

Visit-to-visit systolic blood pressure variability predicts all-cause and cardiovascular mortality after lacunar infarct.

BACKGROUND AND PURPOSE: Both blood pressure (BP) and its variability (BPV) are established risk factors for development of atherosclerotic disease and are associated with an increased risk for cardiovascular and all-cause mortality. The prognostic implications of outpatient clinic visit-to-visit BPV amongst patients with lacunar infarction are nevertheless unknown. METHODS: The clinical outcome of 281 patients with lacunar infarction was prospectively followed up. The average BP and BPV, as determined by the standard deviation of the systolic and diastolic BP, were recorded during a mean 13 ± 6 outpatient clinic visits. RESULTS: The mean age of the population was 70 ± 10 years. After a mean 78 ± 18 months follow-up, 65 patients died (23%), 31% (20/65) due to cardiovascular causes; 14% and 7% developed recurrent stroke and acute coronary syndrome. After adjusting for age, sex, mean systolic and diastolic BP, cardiovascular risk factors and comorbidities, patients with a systolic BPV of the third tertile had significantly higher risk of all-cause mortality [hazard ratio (HR) 1.97, 95% confidence interval (CI) 1.02-3.80, P = 0.04) and cardiovascular mortality (HR 7.64, 95% CI 1.65-35.41, P < 0.01) than those with systolic BPV of the first tertile. Nevertheless, systolic BPV did not predict recurrent stroke or acute coronary syndrome. Diastolic BPV did not predict various adverse clinical outcomes. CONCLUSIONS: Visit-to-visit systolic BPV predicts long-term all-cause and cardiovascular mortality after lacunar infarct, independent of conventional risk factors including average BP control.

Surgical consideration of in situ prosthetic replacement for primary infected abdominal aortic aneurysms.

OBJECTIVES: To review our surgical experience of primary infected abdominal aortic aneurysms, with the aim of assessing the safety and durability of in situ prosthetic replacement. DESIGN: Retrospective study in a university hospital. MATERIALS AND METHODS: Thirty-four patients who underwent surgery for primary infected abdominal aortic aneurysms over the past 18 years were reviewed. Operative details and outcomes were recorded for analysis. RESULTS: There were six suprarenal and 28 infrarenal infections. Salmonellae (18 patients) were the most common pathogens. Thirty patients underwent in situ prosthetic replacement, two underwent extra-anatomic bypass and two underwent endovascular repair. The surgical mortality for overall patients was 18%, and for patients reconstructed in situ, 17%. Among the 30 patients reconstructed in situ, four patients who underwent concomitant gastrointestinal procedures (e.g., repair of the duodenal defect) died. By contrast, 25 of 26 patients without gastrointestinal involvement survived surgery. After a median follow-up period of 58 months, two discharged patients who underwent in situ reconstruction died of late graft infection. CONCLUSIONS: Our experience suggests that in situ prosthetic replacement can be performed safely with durable outcomes in the majority of patients with infected abdominal aortic aneurysms. Nevertheless, we advise caution when considering this technique with concomitant gastrointestinal procedures.

Clinical outcome of relapsing remitting multiple sclerosis among Hong Kong Chinese.

BACKGROUND: Clinical outcome of Chinese relapsing remitting multiple sclerosis (RRMS) patients is uncertain. AIM: To study the long-term clinical outcome of Chinese RRMS patients. METHOD: RRMS patients with duration of 10 years or longer followed up in our hospital is retrospectively studied. RESULTS: 61 RRMS patients (75% female) were studied. Their mean symptom onset age was 25.9 years and mean duration was 20.6 years (range 10-33); 36% patients had received ß-interferon and 30% azathioprine. Their mean EDSS scores were 3.3 (range 1-7) and 4.7 (range 1-8) at 10 years and latest follow-up (mean duration 20.6 years) respectively. At 10 years, 30% patients had EDSS score ≤2, 34% EDSS 2.5-3.5, 20% EDSS 4.0-5.5 and 16% ≥6; 18% developed SPMS. At latest follow-up, 15% patients had EDSS ≤2, 20% EDSS 2.5-3.5, 19% EDSS 4.0-5.5 and 46% ≥6.0; 53% developed SPMS. The median time from symptom onset to EDSS 6 was 22 years. No differences were detected in demographic characteristics, presenting neurological features, number of attacks in first 2 years, neuroradiological findings and disease modifying therapies between patients with EDSS <6 and ≥6 at ten years. EDSS scores at 10 years and latest follow-up were similar for patients who had received ß-interferon and those who had not. CONCLUSION: Hong Kong Chinese RRMS patients may have worse long-term clinical outcome than Caucasian patients.

Generation of inhomogeneously polarized laser beams by use of a Sagnac interferometer.

A principal scheme for an external cavity technique for changing the polarization of a laser beam based on a modified Sagnac interferometer is proposed. The modified Sagnac interferometer includes standard optical components: a displacement polarizing beam splitter, an angle reflector, and a Dove prism. The radially polarized beams, obtained with the help of the developed scheme, allow the generation of a longitudinally polarized electric field by sharp focusing. The phase correction of radially polarized modes of higher orders leads to increasing the longitudinal field in the focus of the beam.

Method for producing coded micro-carrier and test method by using a novel type biochip.

This paper provides a method for producing a novel type coded micro-carrier. A simple and cost effective solution for bio-molecule applications was developed. Application relevant items such as manufacture process, biospecific interaction, and analysis method are discussed. For low cost fabrication, the use of LIGA-like process is suggested. LIGA-like process is used as a dry patterning process in which an intense beam of light from an excimer laser is used to pattern a material directly. This process has found extensive application in the microelectronics industry for patterning of polymer materials. The use of LIGA-like techniques offers two attractive features: first, we can cut the polymer into many tiny micro-carriers with micrometer precision. Second, LIGA-like process allows to encode with high precision spatial information onto the micro-carrier that can be used in the identification of the bio-molecule. This paper gives a description of the basic idea, describes the fabrication of the novel micro-carrier that we called "coded micro-carrier," and of the image processing algorithms used for the analysis of bio-molecules. This study also provides a test method for identifying a bio-molecule, which includes mixing several coded micro-carriers with the hybridized unknown bio-molecules; and identifying the codes on the micro-carrier via image recognition system. The numbers and types of the known micro-carrier can be flexibly adjusted according to the number of tested bio-molecules.

Cyclic imides as potent and selective alpha-1A adrenergic receptor antagonists.

We disclose a new compound class of potent and selective alpha-1A adrenergic receptor antagonists exemplified by the geminally, disubstituted cyclic imide 7. The optimization of lead compounds resulting in the cyclic imide motif is highlighted. The results of in vitro and in vivo studies of selected compounds are presented.

Molecular cloning and pharmacological characterization of the canine B1 and B2 bradykinin receptors.

The dog is a valuable animal model in the study of the physiological role of both the B1 and B2 bradykinin receptors. To more thoroughly characterize the pharmacological properties of the canine kinin receptors we isolated the cDNA sequence encoding the B1 and B2 bradykinin receptor subtypes and overexpressed them in Chinese hamster ovary (CHO) cells. The cDNA sequence of the canine B1 bradykinin receptor encodes a protein comprised of 350 amino acids that is 76% identical to the human B1 bradykinin receptor. The cDNA sequence of the canine B2 bradykinin receptor encodes a protein of 392 amino acids that is 81% identical to the human B2 bradykinin receptor. The amino acid sequence of the canine B1 and B2 receptors are 35% identical. Pharmacological studies of the cloned receptors revealed that the agonist affinity of the dog B1 receptor is similar to the rodent B1 receptors, and differs from the human form in that there is no preference for the presence of the N-terminal Lys residue of [des-Arg10]Lys-bradykinin. Significantly, the B1 receptor antagonist [des-Arg9,Leu8]BK behaves as partial agonist on the cloned dog B1 receptor. The dog B2 receptor exhibits the 'classical' pharmacological properties of this receptor subtype.

In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist.

L-771,688 (SNAP 6383, methyl(4S)-4-(3, 4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[(¿3-[4-(2-pyridin yl)-1-piperidinyl]propyl¿amino)carbonyl]-1,2,3, 4-tetrahydro-5-pyrimidine carboxylate) had high affinity (Ki less than or = 1 nM) for [3H]prazosin binding to cloned human, rat and dog alpha1A-adrenoceptors and high selectivity (>500-fold) over alpha1B and alpha1D-adrenoceptors. [3H]Prazosin / (+/-)-beta-[125I]-4-hydroxy-phenyl)-ethyl-aminomethylteralone ([125I]HEAT) binding studies in human and animal tissues known to contain alpha1A and non-alpha1A-adrenoceptors further demonstrated the potency and alpha1A-subtype selectivity of L-771,688. [3H]L-771,688 binding studies at the cloned human alpha1A-adrenoceptors and in rat tissues indicated that specific [3H]L-771,688 binding was saturable and of high affinity (Kd=43-90 pM) and represented binding to the pharmacologically relevant alpha1A-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha1A-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7, 8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent Kb values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha1A-adrenoceptor antagonist.

Preparation and evaluation of 1,3-diaminocyclopentane-linked dihydropyrimidinone derivatives as selective alpha1a-receptor antagonists.

Several 1,3-diaminocyclopentane linked alpha1a-receptor antagonists were prepared using a divergent chemical strategy that allows for rapid analysis of all stereochemical permutations for their effect on alpha1-receptor binding.

Phenylacetamides as selective alpha-1A adrenergic receptor antagonists.

A novel class of potent and selective alpha-1a receptor antagonists has been identified. The structures of these antagonists were derived from truncating the 4-aryl dihydropyridine subunit present in known alpha-1a antagonists. The design principles which led to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in vivo studies are described.

Selective alpha1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones.

A series of alpha1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives.

In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

Synthesis and evaluation of furo[3,4-d]pyrimidinones as selective alpha1a-adrenergic receptor antagonists.

Furo[3,4-d]pyrimidinones were found to be metabolites of dihydropyrimidinones such as 1a-b that are subtype-selective antagonists of the alpha1a-adrenergic receptor. A versatile synthesis that provides access to furo[3,4-d]pyrimidinones in high yield and in enantiomerically pure forms is described along with structure-activity relationships in the series.

Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones.

Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.