Connectomic Basis for Tremor Control in Stereotactic Radiosurgical Thalamotomy.

BACKGROUND AND PURPOSE: Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, we hypothesized that a "connectome fingerprint" can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy. MATERIALS AND METHODS: We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn-Tolosa-Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, "connectivity fingerprints" representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps. RESULTS: The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement (r = 0.52; P = .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement (r = 0.50; P = .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices. CONCLUSIONS: Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy.

High prevalence of slight and mild hearing loss across mid-life: a cross-sectional national Australian study.

OBJECTIVES: Although presbycusis typically becomes symptomatic only in older age, slight and mild hearing loss may be detectable well before this. We studied current prevalence and characteristics of hearing loss in Australian mid-life adults. STUDY DESIGN: This was a population-derived national cross-sectional study nested within the Longitudinal Study of Australian Children. METHODS: A total of 1485 parents/guardians (87.3% female) aged 30-59 years underwent air-conduction audiometry. Hearing loss was defined in three ways to maximize cross-study comparability: high Fletcher index (mean of 1, 2 and 4 kHz; primary outcome relevant to speech perception), lower frequency (mean of 1 and 2 kHz) and higher frequency (mean of 4 and 8 kHz). Multivariable logistic regression examined how losses vary by age, sex and neighbourhood disadvantage. RESULTS: On high Fletcher index, 27.3% had bilateral and 23.8% unilateral thresholds >15 dB hearing level (HL) (slight or worse), and 4.9% had bilateral and 6.3% unilateral thresholds >25 dB HL (mild or worse). Bilateral higher frequency losses were more common than lower frequency losses for thresholds >15 dB HL (30.9% vs. 26.4%) and >25 dB HL (11.0% vs. 4.6%). Age increased the risk of bilateral speech and higher frequency losses (all P for trend < 0.05), but not lower frequency losses >25 dB HL. Although sex was not associated with speech and lower frequency losses, men were more likely to have bilateral higher frequency losses (e.g. >15 dB HL: odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.5-3.2, P < 0.001). CONCLUSIONS: Both slight and mild hearing loss show high and rising prevalence across mid-life. This offers opportunities to prevent progression to reduce the profound later burden of age-related hearing loss.

Surgical management of pelvic organ prolapse.

Despite pelvic organ prolapse being a universal problem experienced in nearly 50% of parous women, the surgical management of vaginal prolapse remains an enigma to many, with wide variation in the rates and types of intervention performed. As part of the 6th International Consultation on Incontinence (ICI) our committee, charged with producing an evidence-based report on the surgical management of prolapse, produced a pathway for the surgical management of prolapse. The 2017 ICI surgical management of prolapse evidence-based pathway will be presented and summarized. Weaknesses of the data and pathway will be discussed and avenues for future research proposed.

A novel use of reticulated hyaluronic acid (Healaflow) for hypotony eyes in patients with uveitis.

Persistent ocular hypotony is a complex and ongoing challenge faced in ophthalmology. It can result in early ocular phthisis and associated visual decline, pain and deformity. We present the first case series, in which repeated intracameral injections of highly reticulated hyaluronic acid (Healaflow) have successfully prevented the complications of ocular hypotony in the long term. We believe it is a viable management option that can bring about a significant improvement to the quality of life in this subgroup of patients while avoiding frequent intervention.

The UK National Cyclodiode Laser Survey.

PURPOSE: To evaluate current practice of transscleral diode laser cyclophotocoagulation (cyclodiode) laser treatment among consultant ophthalmologists in the United Kingdom. METHODS: A 31-question survey was emailed to all practising consultant ophthalmologists who were members of the Royal College of Ophthalmologists. All non-responders were sent a postal version of the questionnaire. This paper looked at cyclodiode practice patterns and consisted of questions on demographic data, transillumination, and power settings, factors influencing practice, post-operative care, and repeat treatment. RESULTS: A total of 510 participants (53.6%) responded. A total of 180 (35.3%) responders reported performing cyclodiode laser treatment, of which 84 (46.7%) were glaucoma subspecialists (GSS). Initial median power settings used were 1500 mW and 2000 ms. The average number of applications delivered per sitting was 25.5 ± 1.2 applications for GSS vs 20.6 ± 2.0 for non-GSS in a seeing eye (P = 0.0013). In all, 65% routinely transilluminated the globe of which 78% were GSS and 52.3% were non-GSS (P = 0.0009). In all, 43% of the GSS vs 17% of the non-GSS lowered power settings in uveitic glaucoma (P = 0.013). In blind eyes, 30% of the GSS vs 12% of the non-GSS increased energy levels (P = 0.0014). In all, 60% of the responders performed cyclodiode at any visual acuity, whereas 22% performed combined cyclodiode and cataract surgery. CONCLUSIONS: This survey highlights a wide variation in the use of cyclodiode laser treatment amongst GSS and non-GSS. However, the most frequently used practice may not be the optimal practice. A more individualised parameter according to the condition of the eyes may optimise the outcome.

Intraocular pressures after ketamine and sevoflurane in children with glaucoma undergoing examination under anaesthesia.

AIM: For accurate intraocular pressure (IOP) measurement in very young children examination under anaesthesia (EUA) may be necessary. Most anaesthetic agents used for EUA have some effect on IOP. We compared IOPs in children after ketamine and sevoflurane anaesthesia. METHODS: Consecutive patients with definite or suspected glaucoma, uncooperative for reliable IOP measurement in clinic and requiring EUA, were included in this study. IOPs were measured after intramuscular injection (5 mg/kg) or intravenous injection (2 mg/kg) of ketamine using a Perkins applanation tonometer. Three measurements were taken from each eye. The IOPs were rechecked after sevoflurane, given for maintenance anaesthesia. Mean IOPs were used for analysis. Paired t test was used to assess the differences in IOPs for the whole group and one-way ANOVA for the three subgroups (ketamine IOP <20, 20-30, >30 mmHg). RESULTS: The records of eight patients (16 eyes) were available for review. The mean age was 55.42 (SD 25, range 26-89) months. Seventy data-points from both eyes (35 EUAs) were used for the analysis. The mean IOP after sevoflurane (17 (SD 10) mmHg) was statistically lower than after ketamine (24.4 (SD 12.7) mmHg, p<0.001). The percentage difference was 28.5 (SD 20.8; 95% CI 23.5 to 33.4)). The difference between the subgroups was not statistically significant (p = 0.192). CONCLUSION: Sevoflurane lowers the IOP significantly compared with the IOP measured after ketamine. This difference is independent of the IOP level. It may be important to use ketamine as the induction anaesthetic agent when accurate IOP measurement is necessary during EUA for children.

Urinary symptoms and impact on quality of life in women after treatment for endometrial cancer.

The primary objective of our study is to describe urinary symptoms in women treated for endometrial cancer. We performed a cross-sectional survey of women who had undergone surgical treatment for endometrial cancer. Three validated questionnaires were utilized: the Sandvik Severity Index, the Urinary Distress Inventory-6 (UDI-6), and Incontinence Impact Questionaire-7 (IIQ-7). Our study included 70 women treated for endometrial cancer; 35.7% (25/70) of women reported adjuvant radiation therapy after surgical staging. Urinary incontinence was reported in over 80% of women. Mean UDI-6 and IIQ-7 scores for women treated with adjuvant radiation therapy were higher compared to women with no adjuvant radiation therapy [47(+/-26.8) vs. 35.6(+/-21.7; p = 0.05)] and [24.4(+/-28.5) vs. 8.1(+/-16.4; p = 0.004)], respectively. Treatment with adjuvant radiation therapy was associated with more severe incontinence symptoms and impact on quality of life.

Management of stress urinary incontinence.

Stress urinary incontinence (SUI) is a common disorder that does not require treatment unless bothersome to the patient. The evaluation includes a thorough history and physical in order to evaluate for other bladder and pelvic floor disorders. Multichannel urodynamics are not necessary for the diagnosis of SUI, but may be helpful when choosing among appropriate treatment options and for patient counseling. Behavioral and physical therapies are appropriate first-line treatments and should be discussed with all patients, even those desiring surgical treatment. Conservative treatments include the use of pessaries to improve urethral support. Multiple surgical options exist. While mid-urethral slings are commonly used today, there is a still a role for traditional pubovaginal slings and the Burch retropubic urethropexy.

Longitudinal glaucoma screening for siblings of patients with primary open angle glaucoma: the Nottingham Family Glaucoma Screening Study.

AIMS: To assess the prevalence and cumulative incidence of open angle glaucoma (OAG) in a cohort group of siblings of OAG probands. METHODS: Between 1994 and 2003, a group of siblings of OAG probands underwent both initial and follow up standardised ophthalmic examinations. Siblings were classified as "definite glaucoma" (primary OAG (POAG) and normal tension glaucoma (NTG)), "glaucoma suspects" (NTG suspects or ocular hypertension (OHT)), and normal. The prevalence and cumulative incidence of OAG over the follow up interval were calculated. RESULTS: At the initial study, 271 siblings (mean age 63.6 years; female to male ratio 1.2) from 156 probands were examined. 32 (11.8%) were classified as definite glaucoma and 15 (5.5%) as suspects. In the follow up study, 157 of the 224 "normal" siblings from the initial study were examined (mean interval from initial study 7.0 (SD 1.0) years). 11 (7%) were classified as definite glaucoma and 30 (19.1%) as suspects. There were significant trends of increasing prevalence and incidence of OAG with age and a lifetime risk estimated at approximately 20% by age 70. CONCLUSION: Siblings of glaucoma patients have an increased risk of developing glaucoma and the risk increases with age. An effective and repeated screening programme should be considered for this high risk group.

Impact of menopause on collagen subtypes in the arcus tendineous fasciae pelvis.

OBJECTIVE: The arcus tendineous fasciae pelvis (ATFP) provides support to the anterior vagina. The objective of this study was to determine the impact of menopause on the structural components of the ATFP. STUDY DESIGN: Biopsy specimens of the ATFP were obtained from 10 premenopausal, 5 postmenopausal, and 12 postmenopausal women on hormone therapy. Scanning confocal microscopy of fluorescent micrographs was used to define the amount of collagen subtypes, smooth muscle, and elastin. Collagen fiber orientation was determined by scanning electron microscopy. RESULTS: The ATFP is comprised primarily of parallel bundles of type III collagen fibers (84%), an intermediate amount of elastin (13%), and very little smooth muscle. The ratio of collagen I/(III+V) was decreased in postmenopausal not on hormones relative to premenopausal women (P=.04) due to a 75% decrease in collagen I (P=.046). The decrease in collagen I and change in collagen ratios was not present in women on hormone therapy. Comparison of the amounts of elastin and smooth muscle showed no difference in the ATFP of premenopausal and postmenopausal women. CONCLUSION: Menopause in the absence of hormone therapy is associated with a decrease in quantity of collagen I in the ATFP resulting in a decrease in the ratio of collagen I/(III+V). This may compromise the tensile strength and an increase susceptibility to anterior vaginal wall prolapse.

Association of macular involvement with proliferative retinopathy in Type 2 diabetes.

AIMS: To determine whether documented evidence of pre-existing maculopathy is present in Type 2 diabetic patients who require photocoagulation or vitrectomy for proliferative disease. This is a retrospective case notes review. METHODS: The study was performed at Queen's Medical Centre, UK. All patients listed in the laser register and operating theatre register over 5 years (March 1994 to March 1999) who had undergone pan retinal photocoagulation (PRP) for diabetic retinopathy, in one consultant firm, were studied. The medical records of patients who had undergone vitrectomy as their first treatment for proliferative diabetic retinopathy in a vitreo-retinal firm over the 5 years were examined. The proportion of patients with documented maculopathy before development of proliferative retinopathy was determined. RESULTS: All except 1/134 or 0.7% (95% confidence interval 0.1-4.5%) patients had documentation of macular signs in at least one eye prior to the patient's first session of PRP. Of the remaining 133, 104 (78%) had had focal or grid photocoagulation of the macula. The median time between the documentation of maculopathy before the first PRP treatment session was 16 months (interquartile range 7-36). Fourteen patients had vitrectomy and endolaser performed as the initial treatment for proliferative disease. All patients had documented maculopathy before the onset of proliferative disease. CONCLUSIONS: The results of this study suggest that in Type 2 diabetes, proliferative disease occurs relatively late compared with maculopathy. In such patients, maculopathy is almost invariably present when proliferative disease is detected.

Non-enhanced trabeculectomy by non-glaucoma specialists: are results related to risk factors for failure?

PURPOSE: To determine the 1 year success rate of non-enhanced trabeculectomy under the care of non-glaucoma specialists and the effects of risk factors on the surgical outcome as measured by intraocular pressure (IOP) control. METHODS: A retrospective study of 167 patients undergoing trabeculectomy was performed. One hundred and four cases were performed in a teaching hospital and 63 in a district general hospital (DGH). Non-glaucoma specialists performed all the operations, enhanced trabeculectomy with antimetabolites being excluded. Information was recorded from a retrospective review of case notes, and post-operative IOPs at 12 months follow-up were analysed. Risk factors for failure were defined as: (1) age less than 40 years old, (2) black race, (3) diabetes mellitus, (4) miotic therapy > or = 18 months, (5) sympathomimetic therapy > or = 6 months, (6) pseudophakia or aphakia, (7) previous failed filtration procedure, (8) argon laser trabeculoplasty, (9) previous ocular surgery and (10) high-risk glaucoma (angle recession glaucoma, uveitic glaucoma and neovascular glaucoma). A success was defined to be a post-operative IOP at 1 year of less than 21 mmHg and at least 20% less than the presenting IOP on no medication. RESULTS: The overall success rate was 139 of 167 (83.2%). Eighty-seven of 104 eyes (83.7%) were classified as a success in the teaching hospital group and 52 of 63 (82.5%) were classified as a success in the DGH group. There was no significant difference in the number of risk factors between the success and failure groups. Eyes with two or more risk factors had significantly higher IOPs at 1 year when compared with eyes with 0 or 1 risk factor (mean +/- SD: 17.4 +/- 6.34 mmHg vs 14.2 +/- 5.0 mmHg, p = 0.022). When only 'successful eyes' were analysed, those with two or more risk factors still had significantly higher IOPs at 1 year (mean +/- SD: 15.0 +/- 3.0 mmHg vs 12.8 +/- 3.9 mmHg, p = 0.046). There were significantly fewer eyes in the two or more risk factor group with IOPs < 16 mmHg at 1 year (26.1% vs 60.4%, p = 0.021). CONCLUSIONS: Eyes at relatively low risk for failure operated upon by non-glaucoma specialists appeared to have success rates similar to previously published series. Eyes with two or more risk factors for failure have higher IOPs at 1 year in non-enchanced trabeculectomy. Adjunctive anti-scarring agents may be considered for these patients when filtration surgery is scheduled.

Sensitivity and specificity of a new scoring system for diabetic macular oedema detection using a confocal laser imaging system.

AIM: To assess the use of the Heidelberg retina tomograph (HRT) in screening for sight threatening diabetic macular oedema in a hospital diabetic clinic, using a new subjective analysis system (SCORE). METHODS: 200 eyes of 100 consecutive diabetic patients attending a diabetologist's clinic were studied, all eyes had an acuity of 6/9 or better. All patients underwent clinical examination by an ophthalmologist. Using the HRT, one good scan was obtained for each eye centred on the fovea. A System for Classification and Ordering of Retinal Edema (SCORE) was developed using subjective assessment of the colour map and the reflectivity image. The interobserver agreement of using this method to detect macular oedema was assessed by two observers (ophthalmic trainees) who were familiarized with SCORE by studying standard pictures of eyes not in the study. All scans were graded from 0-6 and test positive cases were defined as having a SCORE value of 0-2. The sensitivity of SCORE was assessed by pooling the data with an additional 88 scans of 88 eyes in order to reduce the confidence interval of the index. RESULTS: 12 eyes in eight out of the 100 patients had macular oedema clinically. Three scans in three patients could not be analysed because of poor scan quality. In the additional group of scans 76 out of 88 eyes had macular oedema clinically. The scoring system had a specificity of 99% (95% CI 96-100) and sensitivity of 67% (95% CI 57-76). The predictive value of a negative test was 87% (95% CI 82-99), and that of a positive test was 95% (95% CI 86-99). The mean difference of the SCORE value between two observers was -0.2 (95% CI -0.5 to +0.07). CONCLUSIONS: These data suggest that SCORE is potentially useful for detecting diabetic macular oedema in hospital diabetic patients.

A new cyclobutane lignan from Cinnamomum balansae.

A new cyclobutane lignan, named cinbalansan (6), was isolated from the leaves of Cinnamomum balansae, along with five known compounds, 1,2-dimethoxy-4-(1-E-propenyl)benzene (1), 1,2-dimethoxy-4-(1-Z-propenyl)benzene (2), 1,2-dimethoxy-4-(2-propenyl)benzene (3), 3,4-dimethoxybenzaldehyde (4), and E-(3,4-dimethoxyphenyl)-2-propenal (5). The structure of cinbalansan was shown to be 1beta,2beta,3alpha,4alpha-1,2-dimethyl-3,4-bis(3,4-dimethoxyphenyl)cyclobutane by a combination of 1H-, 13C-NMR, and NOE- experiments and by direct analysis of the 1H-NMR spectrum by the method of X-application.

1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration.

1,25-Dihydroxyvitamin-D3 [1,25(OH)2D3], the active hormonal metabolite of vitamin D, acts through a specific nuclear receptor to inhibit proliferation and promote differentiation of several tumor cell types including the LNCaP, DU145 and PC-3 prostate cancer cell lines as well as primary prostate tumor lines. 1,25(OH)2D3 can also decrease invasion of breast and prostate cancer cell lines in vitro. We confirm this latter finding in the DU145 and PC-3 prostate cancer cell lines, and further show that 1,25(OH)2D3 inhibits overall invasion, cell adhesion and migration to the basement membrane matrix protein laminin. These changes appear to be due in part to a 1,25(OH)2D3-induced decrease in expression of alpha6 and beta4 integrins, both of which are receptors for laminin and associated with increased migration and invasion of prostate cancer cells in vitro. Blocking function of these particular integrins with antibodies inhibits both adhesion and migration of the cells. Collectively, these data demonstrate that 1,25(OH)2D3, in addition to decreasing proliferation of tumor cells, can also inhibit prostate cancer cell invasion through modulation of select cell surface adhesion molecules.

LCC15-MB: a vimentin-positive human breast cancer cell line from a femoral bone metastasis.

The LCC15-MB cell line was established from a femoral bone metastasis that arose in a 29-year-old woman initially diagnosed with an infiltrating ductal mammary adenocarcinoma. The tumor had a relatively high (8%) S-phase fraction and 1/23 positive lymph nodes (LN). Both the primary tumor and LN metastasis were positive for estrogen receptor (ER) and progesterone receptor (PgR), but lacked erbB2 expression. Approximately one year later, the patient presented with a 0.8 cm comedo-type intraductal mammary adenocarcinoma in the left breast that was negative for ER and PgR, but positive for erbB2. Thirty-five months after the initial diagnosis she was treated for acute skeletal metastasis, and stabilized with a hip replacement. At this time, tumor cells were removed from surplus involved bone, inoculated into cell culture, and developed into the LCC 15-MB cell line. The bone metastasis was a poorly differentiated adenocarcinoma lacking ER, PgR, and erbB2, characteristics shared by the LCC15-MB cells, although ER can be re-expressed by treatment of the LCC15-MB cells for 5 days with 75 microM 5-aza-2'-deoxycytidine. The LCC15-MB cell line is tumorigenic when implanted subcutaneously in NCr nu/nu mice and produces long-bone metastases after intracardiac injection. Although the bone metastasis from which the LCC15-MB cell line was derived lacked vimentin (VIM) expression, the original primary tumor and lymph node metastasis were strongly VIM positive, as are LCC15-MB cells in vitro and in nude mice. The karyotype and isozyme profiles of LCC15-MB cells are consistent with its origin from a human female, with most chromosome counts in the hypertriploid range. Thirty-two marker chromosomes are present. These cells provide an in vitro/in vivo model in which to study the inter-relationships between ER, VIM, and bone metastasis in human breast cancer.

Tumor cells are the source of osteopontin and bone sialoprotein expression in human breast cancer.

Bone sialoprotein (BSP) and osteopontin (OPN) are secreted glycoproteins with a conserved Arg-Gly-Asp (RGD) integrin-binding motif and are expressed predominantly in bone. The RGD tripeptide is commonly present in extracellular attachment proteins and has been shown to mediate the attachment of osteosarcoma cells and osteoclasts. To determine the origin and incidence of BSP and OPN mRNA expression in primary tumor, a cohort of archival, primary invasive breast carcinoma specimens was analyzed. BSP transcripts were detected in 65% and OPN transcripts in 77% of breast cancers examined. In general, BSP and OPN transcripts were detected in both invasive and in situ carcinoma components. The transcripts were not detected in surrounding stromal cells or in peritumoral macrophages. Despite its abundance in carcinomas, BSP expression was not detected in a panel of 11 human breast cancer cell lines (MCF-7, T47D, SK-Br-3, MDA-MB-453, MDA-MB-231, MDA-MB-436, BT549, MCF-7ADR, Hs578T, MDA-MB-435, and LCC15-MB) and OPN expression was detected only in two of these (MDA-MB-435 and LCC15-MB). To examine the possibility that expression of these genes was down-regulated in cell culture, several cell lines were grown as nude mouse xenografts in vivo; however, these tumors also failed to express BSP. OPN expression was identified in all cell lines grown as nude mouse xenografts. Our data suggest that in human primary breast tumors, the origin of BSP and OPN mRNA is predominantly the breast cancer cells and that expression of these transcripts is influenced by the tumor environment.