Nacc1 Mutation in Mice Models Rare Neurodevelopmental Disorder with Underlying Synaptic Dysfunction.

A missense mutation in the transcription repressor Nucleus accumbens-associated 1 (NACC1) gene at c.892C>T (p.Arg298Trp) on chromosome 19 causes severe neurodevelopmental delay ( Schoch et al., 2017). To model this disorder, we engineered the first mouse model with the homologous mutation (Nacc1+/R284W ) and examined mice from E17.5 to 8 months. Both genders had delayed weight gain, epileptiform discharges and altered power spectral distribution in cortical electroencephalogram, behavioral seizures, and marked hindlimb clasping; females displayed thigmotaxis in an open field. In the cortex, NACC1 long isoform, which harbors the mutation, increased from 3 to 6 months, whereas the short isoform, which is not present in humans and lacks aaR284 in mice, rose steadily from postnatal day (P) 7. Nuclear NACC1 immunoreactivity increased in cortical pyramidal neurons and parvalbumin containing interneurons but not in nuclei of astrocytes or oligodendroglia. Glial fibrillary acidic protein staining in astrocytic processes was diminished. RNA-seq of P14 mutant mice cortex revealed over 1,000 differentially expressed genes (DEGs). Glial transcripts were downregulated and synaptic genes upregulated. Top gene ontology terms from upregulated DEGs relate to postsynapse and ion channel function, while downregulated DEGs enriched for terms relating to metabolic function, mitochondria, and ribosomes. Levels of synaptic proteins were changed, but number and length of synaptic contacts were unaltered at 3 months. Homozygosity worsened some phenotypes including postnatal survival, weight gain delay, and increase in nuclear NACC1. This mouse model simulates a rare form of autism and will be indispensable for assessing pathophysiology and targets for therapeutic intervention.

Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model.

Expansion of a triplet repeat tract in exon 1 of the HTT gene causes Huntington's disease (HD). The mutant HTT protein (mHTT) has numerous aberrant interactions with diverse, pleiomorphic effects. Lowering mHTT is a promising approach to treat HD, but it is unclear when lowering should be initiated, how much is necessary, and what duration should occur to achieve benefits. Furthermore, the effects of mHTT lowering on brain lipids have not been assessed. Using a mHtt-inducible mouse model, we analyzed mHtt lowering initiated at different ages and sustained for different time-periods. mHTT protein in cytoplasmic and synaptic compartments of the striatum was reduced 38-52%; however, there was minimal lowering of mHTT in nuclear and perinuclear regions where aggregates formed at 12 months of age. Total striatal lipids were reduced in 9-month-old LacQ140 mice and preserved by mHtt lowering. Subclasses important for white matter structure and function including ceramide (Cer), sphingomyelin (SM), and monogalactosyldiacylglycerol (MGDG), contributed to the reduction in total lipids. Phosphatidylinositol (PI), phosphatidylserine (PS), and bismethyl phosphatidic acid (BisMePA) were also changed in LacQ140 mice. Levels of all subclasses except ceramide were preserved by mHtt lowering. mRNA expression profiling indicated that a transcriptional mechanism contributes to changes in myelin lipids, and some but not all changes can be prevented by mHtt lowering. Our findings suggest that early and sustained reduction in mHtt can prevent changes in levels of select striatal proteins and most lipids, but a misfolded, degradation-resistant form of mHTT hampers some benefits in the long term.

Focused Ultrasound-Mediated Disruption of the Blood-Brain Barrier for AAV9 Delivery in a Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the HTT gene. There are no cures for HD, but the genetic basis of this disorder makes gene therapy a viable approach. Adeno-associated virus (AAV)-miRNA-based therapies have been demonstrated to be effective in lowering HTT mRNA; however, the blood-brain barrier (BBB) poses a significant challenge for gene delivery to the brain. Delivery strategies include direct injections into the central nervous system, which are invasive and can result in poor diffusion of viral particles through the brain parenchyma. Focused ultrasound (FUS) is an alternative approach that can be used to non-invasively deliver AAVs by temporarily disrupting the BBB. Here, we investigate FUS-mediated delivery of a single-stranded AAV9 bearing a cDNA for GFP in 2-month-old wild-type mice and the zQ175 HD mouse model at 2-, 6-, and 12-months. FUS treatment improved AAV9 delivery for all mouse groups. The delivery efficacy was similar for all WT and HD groups, with the exception of the zQ175 12-month cohort, where we observed decreased GFP expression. Astrocytosis did not increase after FUS treatment, even within the zQ175 12-month group exhibiting higher baseline levels of GFAP expression. These findings demonstrate that FUS can be used to non-invasively deliver an AAV9-based gene therapy to targeted brain regions in a mouse model of Huntington's disease.

Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model.

Expansion of a triplet repeat tract in exon1 of the HTT gene causes Huntington's disease (HD). The mutant HTT protein (mHTT) has numerous aberrant interactions with diverse, pleiomorphic effects. No disease modifying treatments exist but lowering mutant huntingtin (mHTT) by gene therapy is a promising approach to treat Huntington's disease (HD). It is not clear when lowering should be initiated, how much lowering is necessary and for what duration lowering should occur to achieve benefits. Furthermore, the effects of mHTT lowering on brain lipids have not been assessed. Using a mHtt-inducible mouse model we analyzed whole body mHtt lowering initiated at different ages and sustained for different time-periods. Subcellular fractionation (density gradient ultracentrifugation), protein chemistry (gel filtration, western blot, and capillary electrophoresis immunoassay), liquid chromatography and mass spectrometry of lipids, and bioinformatic approaches were used to test effects of mHTT transcriptional lowering. mHTT protein in cytoplasmic and synaptic compartments of the caudate putamen, which is most affected in HD, was reduced 38-52%. Little or no lowering of mHTT occurred in nuclear and perinuclear regions where aggregates formed at 12 months of age. mHtt transcript repression partially or fully preserved select striatal proteins (SCN4B, PDE10A). Total lipids in striatum were reduced in LacQ140 mice at 9 months and preserved by early partial mHtt lowering. The reduction in total lipids was due in part to reductions in subclasses of ceramide (Cer), sphingomyelin (SM), and monogalactosyldiacylglycerol (MGDG), which are known to be important for white matter structure and function. Lipid subclasses phosphatidylinositol (PI), phosphatidylserine (PS), and bismethyl phosphatidic acid (BisMePA) were also changed in LacQ140 mice. Levels of all subclasses other than ceramide were preserved by early mHtt lowering. Pathway enrichment analysis of RNAseq data imply a transcriptional mechanism is responsible in part for changes in myelin lipids, and some but not all changes can be rescued by mHTT lowering. Our findings suggest that early and sustained reduction in mHtt can prevent changes in levels of select striatal proteins and most lipids but a misfolded, degradation-resistant form of mHTT hampers some benefits in the long term.

On the solution arising in two-cylinders electrostatics.

The electrostatics of two cylinders charged to the symmetrical or anti-symmetrical potential is investigated by using the null-field boundary integral equation (BIE) in conjunction with the degenerate kernel of the bipolar coordinates. The undetermined coefficient is obtained according to the Fredholm alternative theorem. The uniqueness of solution, infinite solution, and no solution are examined therein. A single cylinder (circle or ellipse) is also provided for comparison. The link to the general solution space is also done. The condition at infinity is also correspondingly examined. The flux equilibrium along circular boundaries and the infinite boundary is also checked as well as the contribution of the boundary integral (single and double layer potential) at infinity in the BIE is addressed. Ordinary and degenerate scales in the BIE are both discussed. Furthermore, the solution space represented by the BIE is explained after comparing it with the general solution. The present finding is compared to those of Darevski[2] and Lekner[4] for identity.

Chinese validation of Urogenital Distress Inventory and Incontinence Impact Questionnaire short form.

INTRODUCTION AND HYPOTHESIS: UDI-6 and IIQ-7 are useful disease-specific questionnaires evaluating the impact of urinary incontinence on the QOL of women. We aim at validating them in Chinese language. METHODS: Both instruments were translated; 207 urinary incontinent women completed UDI-6 and IIQ-7, SF-36, bladder diary and urodynamic evaluation. The reliability and validity were assessed. RESULTS: There were high internal consistency (Cronbach's alpha for UDI-6 and IIQ-7 was 0.80 and 0.93) and test-retest reliability (Intraclass correlation coefficient was 0.72 and 0.75, P < 0.001). Scoring of UDI-6 and IIQ-7 was negatively correlated with SF-36 (P < 0.001); positively correlated with daytime urinary frequency and incontinent episodes (P < 0.001), and women's VAS (P < 0.001). Subscales of UDI-6 and IIQ-7 could discriminate women with different urodynamic diagnoses. CONCLUSIONS: The Chinese UDI-6 and IIQ-7 is reliable and valid. Study on the responsiveness to treatment is in progress. They are useful in assessing impact of the urinary incontinence in Chinese women.

Psychological morbidity and female urinary incontinence.

Female urinary incontinence is a common yet distressing condition. It affects women of all ages, but is especially common in the elderly. Its prevalence ranges from 15 to 55%, depending on age and population studied. Despite the ubiquity of female urinary incontinence, many incontinent women do not voice their suffering, and urinary incontinence has therefore been dubbed 'the silent epidemic'. The physical impact and social isolation associated with urinary incontinence lead to impairment of quality of life and psychological well-being. It is the aim of this review to discuss the epidemiology and psychological impact of urinary incontinence. The recognition and management of incontinence-related psychological morbidity are also explored.

Expression genomics of cervical cancer: molecular classification and prediction of radiotherapy response by DNA microarray.

PURPOSE: The incidence and mortality rates of cervical cancer are declining in the United States; however, worldwide, cervical cancer is still one of the leading causes of death in women, second only to breast cancer. This disparity is at least partially explained by the absence of or comparatively ineffective screening programs in the developing world. Recent advances in expression genomics have enabled the use of DNA microarray to profile gene expression of various cancers. These expression profiles may be suitable for molecular classification and prediction of disease outcome and treatment response. We envision that expression genomics applied in cervical cancer may provide a more rational approach to the classification and treatment of the disease. EXPERIMENTAL DESIGN: In this report, we examined the expression profiles of cervical cancer compared with normal cervical tissues in DNA microarrays that contained approximately 11,000 features that correspond to either human transcripts with known function or anonymous expressed sequence tags. RESULTS: Our results showed that normal cervical tissues were completely segregated from the cancer samples using about 40 genes whose expressions were significantly different between these specimens. In addition, clinical stage IB and stage IIB tumors could also be classified based on their signature expression patterns. Most importantly, some of the tumor samples were further stratified into two major groups based on their response to radiotherapy, and we were able to predict the response of these patients to radiotherapy from their expression profiles. CONCLUSIONS: Gene expression profiling by DNA microarray may be used for further molecular classification of disease stages and prediction of treatment response in cervical cancer.

Adjuvant low-dose aspirin therapy in poor responders undergoing in vitro fertilization: a prospective, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the effect of adjuvant low-dose aspirin on utero-ovarian blood flow and ovarian responsiveness in poor responders undergoing IVF. DESIGN: Prospective randomized, double-blind, placebo-controlled study. SETTING: University-affiliated teaching hospital. PATIENT(S): Sixty patients classified as poor responders undergoing IVF. INTERVENTION(S): Supplementation with low-dose aspirin (80 mg daily) or placebo to a long down-regulation protocol. MAIN OUTCOME MEASURE(S): Doppler measurement of intraovarian and uterine pulsatility index was performed before (baseline) and after ovarian stimulation (day of hCG administration). Duration of use and dose of gonadotropins, cycle cancellation rate, number of mature follicles recruited, and oocytes retrieved were also measured. RESULT(S): High cancellation rates were found in both groups (33.3% vs. 26.7%, placebo vs. treatment). There were no significant differences in total dose of hMG used (66 vs. 57 hMG, 75 IU ampules), median number of mature follicles recruited (3.5 vs. 3.0), or median number of oocytes retrieved (4 vs. 3). No significant differences were found in either intraovarian or uterine artery pulsatility index measured at baseline or on the day of hCG administration. CONCLUSION(S): Supplementation with low-dose aspirin failed to improve either ovarian and uterine blood flow or ovarian responsiveness in poor responders undergoing IVF.

Treatment of intractable hyperemesis gravidarum by ondansetron.

Hyperemesis gravidarum is a disabling condition. It is not uncommon that patients request termination of pregnancy because of intolerable symptoms and psychological stress. We report a case in which termination of pregnancy was avoided by the use of ondansetron to treat the hyperemesis gravidarum.

Maternal views and acceptance of antenatal HIV screening in a university teaching hospital in Hong Kong.

OBJECTIVE: To assess maternal acceptance, knowledge, attitude, perceived risks and barriers toward antenatal HIV screening. STUDY DESIGN: Prospective anonymous survey of 1,519 pregnant women recruited in a university teaching hospital RESULTS: Women demonstrated fairly good knowledge of and a positive attitude toward HIV screening. Condom usage was 61.4%, and 25.3% of women had at least 1 risk factor for HIV infection. Support for mandatory and universal screening was 31.4% and 48.8%, respectively. A total of 82.6% women agreed to HIV testing. The major reason for declining the test was that women considered themselves to be at low risk (84.3%). Women with risk factors tended to prefer more aggressive methods of antenatal testing (P < .001) and more readily accepted HIV screening (89.8% vs. 73.1%, P < .001). CONCLUSION: Given the high acceptance rate in our local population, universal offering but voluntary testing is the optimal mode of antenatal HIV screening in Hong Kong.

Large choledochal cyst present through 2 pregnancies. A case report.

BACKGROUND: Choledochal cyst is rarely diagnosed during pregnancy, and it is very difficult to make a diagnosis of it clinically or radiologically. CASE: A woman was diagnosed as having an ovarian cyst and gallbladder mucocele on ultrasonography in both her first and second pregnancies. She was asymptomatic, and conservative management was adopted. Three days after delivery of her second child, the patient had a sudden onset of right upper quadrant pain associated with deranged liver function. Emergency laparotomy revealed a type I choledochal cyst with evidence of infection. Excision of the cyst, cholecystectomy and bilateral hepatojejunostomy in the Roux-en-Y fashion were performed. CONCLUSION: A choledochal cyst in pregnancy is difficult to diagnose and poses a threat to mother and fetus.

A 1-year longitudinal study of psychological morbidity after miscarriage.

OBJECTIVE: To examine the 1-year longitudinal course of psychological outcomes after miscarriage. DESIGN: Longitudinal observational study. SETTING: University-affiliated teaching hospital. PATIENT(S): 280 miscarrying women and 150 nonpregnant women. INTERVENTION(S): Psychological outcomes were assessed using the 12-item General Health Questionnaire (GHQ-12) and Beck Depression Inventory (BDI) immediately, 3 months, 6 months, and 12 months after miscarriage. MAIN OUTCOME MEASURE(S): Scores on GHQ-12 and BDI. RESULT(S): Half (55%) of the miscarrying women scored high (>or=4) on the GHQ-12 immediately, 25% at 3 months; 17.8% at 6 months, and 10.8% at 1 year after miscarriage; 26.8% of the patients scored high on the BDI (>or=12) immediately, 18.4% at 3 months, 16.4% at 6 months, and 9.3% at 1 year after miscarriage. Patients who were initially more distressed continued to score higher on both the GHQ-12 and the BDI along the 1-year course when compared with those who were initially less distressed. When compared with the nonpregnant controls, the miscarrying women scored statistically significantly higher on the GHQ-12 and BDI; the differences became not statistically significant only 1 year after miscarriage. CONCLUSION(S): A statistically significant proportion of patients reported psychological morbidity shortly after miscarriage, but their level of distress reduced over time until they were comparable with the controls 1 year later. Patients who were initially more distressed continued to be throughout the 1-year course.

Prevalence and associated risk factors of retention of urine after caesarean section.

Caesarean section poses higher risk of postpartum urinary retention (PUR) than vaginal delivery. The aim of this study was to identify the prevalence and the associated risk factors of PUR after caesarean section. Two hundred seven parturients (mean age = 31.26 years old, median parity = 0) who delivered by caesarean section were recruited from the postnatal unit of a tertiary hospital in Hong Kong. Voiding was encouraged 6 h after removal of Foley catheters. Transvaginal ultrasound scan was performed immediately after voiding to estimate the postvoid residual bladder volume (PVR). PUR after caesarean section was defined as PVR of more than 150 ml. The results indicated a prevalence of 3.38%. Logistic regression analysis indicating 'lack of progress of labor' was the only significant associated factor (p < 0.001). The findings of this study provide information for further exploration on how to reduce the morbidity caused by PUR in the postoperative period of caesarean section.

Measurement of tension-free vaginal tape trocar insertion and exit forces.

BACKGROUND/AIMS: This study aims to establish a model to measure the forces required for tension-free vaginal tape (TVT) trocar application using a pressure transducer. METHODS: A 3.5 x 3.5 cm pressure transducer was constructed from piezo-resistive material. The transducer digitally recorded the surface contact pressure (pressure = force/area) profile continuously during TVT trocar application. Recordings were successfully obtained from 24 subjects. RESULTS: The mean (standard error) peak contact pressures during application at the right and left side vaginal walls, and right and left side abdominal walls were 1.05 (0.12) pounds per square inch (psi), 1.08 (0.21) psi, 2.49 (0.3) psi and 2.49 (0.3) psi, respectively. On both the right and left side, pair-wise comparisons between trocar insertion and exit forces were significantly different (p < 0.001). CONCLUSION: A model has been developed by which TVT trocar application forces can be objectively measured. The TVT trocar exit force is substantially greater than the insertion force, regardless of side.

Changing prevalence and knowledge of urinary incontinence among Hong Kong Chinese women.

A territory-wide telephone survey was conducted in Hong Kong to assess the prevalence, knowledge, and treatment-seeking behaviour of Chinese women with urinary incontinence, using validated Chinese version of Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7). Women, 540, aged between 17 to 77 years were interviewed. Of the respondents, 40.8% reported stress urinary incontinence, 20.4% had urge incontinence and 15.9% had mixed incontinence. Among these, 16.0% reported quality of life impairment; 9.3% felt frustrated with low morale, and 15.2% had nervous and anxiety problems. However, as many as 78.3% of the respondents did not know that stress urinary incontinence is a disease entity, and 60.6% thought that leakage of urine was a normal aging process. For those respondents having stress urinary incontinence, the first treatment of choice was physiotherapy. The second choice was medication, and surgical treatment was the last option. Respondents with stress urinary incontinence showed higher education level.