Pterygoid venous plexus anastomosis in trigeminal percutaneous glycerol rhizotomy: illustrative case.

BACKGROUND: Percutaneous glycerol rhizotomy (PGR) is a common, effective, and relatively safe treatment for trigeminal neuralgia that is refractory to medical management. Anastomotic skull base venous anatomy should be considered when delivering percutaneous agents. OBSERVATIONS: The authors report an anastomotic connection, not previously described in the literature, between the bilateral pterygoid venous plexuses upon air injection during PGR with computed tomography (CT) guidance for trigeminal neuralgia. Pertinent microsurgical and skull base venous anatomy is reviewed. LESSONS: Anastomoses between the pterygoid venous plexuses present a potential passage for materials used during PGR to reach unintended contralateral neurovascular structures. The use of CT guidance may identify this anastomotic connection and decrease the likelihood of an aberrant flow of materials used during the PGR.

P73 C-terminus is dispensable for multiciliogenesis.

The p53 family transcriptional factor p73 plays a pivotal role in development. Ablation of p73 results in severe neurodevelopmental defects, chronic infections, inflammation and infertility. In addition to this, Trp73-\- mice display severe alteration in the ciliated epithelial lining and the full-length N-terminal isoform TAp73 has been implicated in the control of multiciliogenesis transcriptional program. With our recently generated Trp73Δ13/Δ13 mouse model, we interrogate the physiological role of p73 C-terminal isoforms in vivo. Trp73Δ13/Δ13 mice lack exon 13 in Trp73 gene, producing an ectopic switch from the C-terminal isoforms p73α to p73ß. Trp73Δ13/Δ13 mice show a pattern of expression of TAp73 comparable to the wild-type littermates, indicating that the α to ß switch does not significantly alter the expression of the gene in this cell type. Moreover, Trp73Δ13/Δ13 do not display any significant alteration in the airway ciliated epithelium, suggesting that in this context p73ß can fully substitute the function of the longer isoform p73α. Similarly, Trp73Δ13/Δ13 ciliated epithelium of the brain ependyma also does appear defective. In this district however expression of TAp73 is not detectable, indicating that expression of the gene might be compensated by alternative mechanisms. Overall our work indicates that C-terminus p73 is dispensable for the multiciliogenesis program and suggests a possible tissue-specific effect of p73 alternative splicing.

Education-based Solutions to the Global Burden of Neurosurgical Disease.

OBJECTIVE: Low- and middle-income countries continue to suffer from a lack of access to basic neurosurgical care. The 2015 Lancet Commission on Global Surgery estimated essential surgical care was lacking to 5 billion people and that 143 million essential surgeries were not performed annually. A significant part of this need is neurosurgical care. Countries lacking basic neurosurgical services cannot have a true trauma system, or complete care for tumor, stroke, pain, and congenital defects in children. Episodic service missions from developed countries cannot fill these large gaps. To maximize the impact of global neurosurgery, the framework through which humanitarian neurosurgeons respond to international need should incorporate sustainable practices that empower the recipient population. METHODS: A historical and anecdotal review of global neurosurgery. RESULTS: The success of sustainable, locally championed neurosurgery educational programs will be dependent on the simultaneous, parallel development of anesthesia, critical care, nursing, and biomedical services. Each of these disciplines will reciprocally benefit from these neurosurgical programs. These programs cannot exist in a vacuum. They will require the thoughtful collaboration of all major neurosurgical societies with a humanitarian emphasis while championing the local surgeons in the area of need who must assume leadership to achieve a self-sustaining program. CONCLUSIONS: To meet the global need for neurosurgical care, self-sustaining neurosurgical programs must be locally developed in the countries of need. International support must be built on "Service through Education" rather the service alone.

Pallister-Hall Syndrome Presenting in Adolescence.

Pallister-Hall syndrome (PHS) is an extremely rare syndrome of unknown prevalence with autosomal dominant inheritance due to GLI3 gene mutations classically characterized by the presence of a hypothalamic hamartoma and polydactyly. Additional diagnostic criteria include bifid epiglottis, imperforate anus, small nails, hypopituitarism, growth hormone deficiency, and genital hypoplasia. It is typically diagnosed in infancy and early childhood, presenting with seizures and/or precocious puberty due to the hypothalamic hamartoma, and with limb anomalies due to central polydactyly. Our patient had presented with polysyndactyly at birth. However, as this is not uncommon in infants and is usually as part of the sporadic, isolated form of polydactyly, no further work up was done. He then presented at age 16 years with a headache and subjective visual changes, with brain imaging revealing a hypothalamic hamartoma. He did not have a history of seizures or central precocious puberty. Genotyping revealed a pathogenic variant affecting the GLI3 gene. We encourage all clinicians to consider PHS or an associated syndrome with a clinical finding of polydactyly. Further, as the natural history continues to reveal itself, this patient's presentation provides important new data to the broad phenotypic spectrum of PHS.

Loss of Innate Host Defense Following Unprotected Vaginal Sex.

BACKGROUND: Multiple host defense mechanisms protect the female genital tract from pathogens, but the impact of sexual intercourse on defense is unknown. METHODS: As part of a hypothesis-generating study, 17 women provided cervicovaginal lavage (CVL) specimens at baseline (all had abstained from sexual intercourse, masturbation, and vaginal product use for 72 hours prior to screening), 2-6 hours and 10-14 hours after vaginal intercourse with a male condom, and 2-6 hours and 10-14 hours after vaginal intercourse without a male condom (5 visits total, including the baseline visit). Vaginal pH, concentrations of immune molecules, and antimicrobial activity at postcoital visits were compared to baseline values. RESULTS: Vaginal pH and the transforming growth factor ß1 level increased, but human beta-defensin 2 (HBD-2), HBD-3, and interleukin 8 levels decreased after unprotected sex. Median Escherichia coli inhibitory activity in CVL specimens decreased significantly from baseline at the visit 2-6 hours after unprotected sex (63% [range, -34% to 99%] vs 5% [range, -51% to 100%]; P = .02) and remained low at the visit 10-14 hours after unprotected sex (6% [range, -19% to 92%]; P = .02). Pooled human seminal plasma enhanced E. coli growth in vitro in a dose-dependent manner and, when added to CVL samples with high anti-E. coli activity, reversed the inhibition. CONCLUSIONS: Unprotected vaginal sex results in a reduction in endogenous anti-E. coli activity, which may reflect, in part, enhancement of bacterial growth by seminal plasma. This finding may contribute to the risk of E. coli vaginal colonization following sexual intercourse.

Association of High-Risk Human Papillomavirus with Genital Tract Mucosal Immune Factors in HIV-Infected Women.

PROBLEM: High-risk human papillomavirus (HR-HPV) is prevalent in HIV-infected women and may be associated with mucosal changes that promote HIV replication. METHOD OF STUDY: Innate immune molecules, antimicrobial activity, HIV RNA, and HPV DNA genotypes were measured in a cross-sectional study of 128 HIV-infected women categorized into HPV-16 (n = 8), other HR-HPV (n = 41), and non-HR-HPV controls (n = 79). RESULTS: Compared to controls, HR-HPV groups had higher plasma viral loads (P = 0.004), lower CD4 cells (P = 0.02), more genital tract HIV RNA (P = 0.03), greater number of different HPV types (P < 0.001), higher cervicovaginal lavage (CVL) IL-1α (P = 0.03) and human beta-defensin 2 (HBD2) (P = 0.049), and less anti-HIVB al activity (P = 0.03). HPV-16 remained significantly associated with higher HBD2 (P = 0.03), higher IL-1α (P = 0.009), and lower anti-HIVB aL activity (P = 0.03) compared to controls after adjusting for plasma viral load and CD4 T cell count. CONCLUSION: HR-HPV is associated with mucosal changes in HIV-infected women that could adversely impact genital tract health.

Activity of Genital Tract Secretions and Synthetic Antimicrobial Peptides against Group B Streptococcus.

PROBLEM: Genital tract secretions inhibit Escherichia coli (E. coli) through antimicrobial peptides (AMP) secreted by the host and vaginal microbiota. However, there are limited data against group B Streptococcus (GBS). METHOD OF STUDY: Group B Streptococcus were incubated with cervico-vaginal lavage (CVL) samples from healthy non-pregnant women (n = 12) or synthetic AMP and monitored for bacterial growth using a turbidimetric approach. E. coli inhibitory activity was determined by a colony-forming unit assay. RESULTS: None of the CVL samples inhibited GBS. The human neutrophil peptide-1 and human defensin 5 inhibited GBS growth by ≥80% at concentrations ≥20 µg/mL and ≥50 µg/mL, respectively, while human beta-defensin 2 and LL-37 did not inhibit at highest concentration tested (100 µg/mL). In contrast, all AMP inhibited E. coli. CONCLUSIONS: Antimicrobial peptides may protect against E. coli colonization but have more limited activity against GBS. Future studies will focus on augmenting host defense with specific AMP to prevent genitourinary infection with these pathogenic organisms.

Lactobacillus crispatus dominant vaginal microbiome is associated with inhibitory activity of female genital tract secretions against Escherichia coli.

OBJECTIVE: Female genital tract secretions inhibit E. coli ex vivo and the activity may prevent colonization and provide a biomarker of a healthy microbiome. We hypothesized that high E. coli inhibitory activity would be associated with a Lactobacillus crispatus and/or jensenii dominant microbiome and differ from that of women with low inhibitory activity. STUDY DESIGN: Vaginal swab cell pellets from 20 samples previously obtained in a cross-sectional study of near-term pregnant and non-pregnant healthy women were selected based on having high (>90% inhibition) or low (<20% inhibition) anti-E. coli activity. The V6 region of the 16S ribosomal RNA gene was amplified and sequenced using the Illumina HiSeq 2000 platform. Filtered culture supernatants from Lactobacillus crispatus, Lactobacillus iners, and Gardnerella vaginalis were also assayed for E. coli inhibitory activity. RESULTS: Sixteen samples (10 with high and 6 with low activity) yielded evaluable microbiome data. There was no difference in the predominant microbiome species in pregnant compared to non-pregnant women (n = 8 each). However, there were significant differences between women with high compared to low E. coli inhibitory activity. High activity was associated with a predominance of L. crispatus (p<0.007) and culture supernatants from L. crispatus exhibited greater E. coli inhibitory activity compared to supernatants obtained from L. iners or G. vaginalis. Notably, the E. coli inhibitory activity varied among different strains of L. crispatus. CONCLUSION: Microbiome communities with abundant L. crispatus likely contribute to the E. coli inhibitory activity of vaginal secretions and efforts to promote this environment may prevent E. coli colonization and related sequelae including preterm birth.

Use of the dye stain assay and ultraviolet light test for assessing vaginal insertion of placebo-filled applicators before and after sex.

BACKGROUND: Applicator dye staining and ultraviolet (UV) light have been used in trials to measure adherence, but not in the setting of before and after sex gel dosing (BAT-24). This study was designed to determine if semen or presex gel dosing impacts the sensitivity and specificity of a dye stain assay (DSA) for measuring vaginal insertion of placebo-filled applicators with BAT-24 dosing. METHODS: Healthy monogamous couples received Microlax-type applicators (Tectubes, Åstorp, Sweden) filled with hydroxyethylcelluose placebo gel. Women were instructed to vaginally insert 1 dose of gel before and a second dose after sex and to return applicators within 48 hours after sex. Applicators were stained to detect semen, followed by UV then DSA, and scored by 2 readers. Positive and negative controls were randomly included in applicator batches. RESULTS: Fifteen couples completed the study. Each woman returned at least 6 applicators over a 30-day period. The sensitivity for insertion of postsex applicators was higher for UV (97%) compared with DSA (90%), and the specificity was similar (≥96%). For presex applicators, the sensitivity and specificity were higher for DSA (100%) compared with UV testing (87% sensitivity, 96% specificity). Among returned postsex applicators, 95% tested positive by UV compared with 87% by DSA. Agreement between readers was significantly better on the presex applicators for DSA than for UV, and for postsex readings, agreement was less than half that for UV, although the results were not statistically significant. CONCLUSIONS: Applicator tests are feasible for measuring adherence in trials with gel dosing before and after sex.

Evaluation of 3 approaches for assessing adherence to vaginal gel application in clinical trials.

BACKGROUND: Accurate measurement of adherence to product use is an ongoing challenge in microbicide trials. METHODS: We compared adherence estimates using 2 applicator tests (a dye stain assay [DSA] and an ultraviolet light assay [UVA]), the Wisebag (an applicator container that electronically tracks container openings), and self-reported adherence (ability, frequency, and percent missed doses). Healthy, HIV-negative, nonpregnant US women aged 23 to 45 years received a Wisebag and 32 applicators filled with placebo gel were instructed to insert 1 applicator daily for 30 days, returned the Wisebag and all applicators, and completed an exit interview. Emptied applicators were tested by UVA and then DSA, and scored by 2 blinded readers. Positive and negative controls were randomly included in applicator batches. RESULTS: Among 42 women enrolled, 39 completed the study. Both DSA and UVA yielded similar sensitivity (97% and 95%) and specificity (79% and 79%). Two participants had fully inoperable Wisebags, and 9 had partially inoperable Wisebags. The proportion of participants considered to have high adherence (≥80%) varied: 43% (Wisebag), 46% (UVA), 49% (DSA), and 62% to 82% (self-reports). For estimating high adherence, Wisebag had a sensitivity of 76% (95% confidence interval, 50%-93%) and a specificity of 85% (95% confidence interval, 62%-97%) compared with DSA. Although 28% of participants reported forgetting to open the Wisebag daily, 59% said that it helped them remember gel use. CONCLUSIONS: Dye stain assay and UVA performed similarly. Compared with these tests, self-reports overestimated and Wisebag underestimated adherence. Although Wisebag may encourage gel use, the applicator tests currently seem more useful for measuring use in clinical trials.

HSV activates Akt to trigger calcium release and promote viral entry: novel candidate target for treatment and suppression.

HSV triggers intracellular calcium release to promote viral entry. We hypothesized that Akt signaling induces the calcium responses and contributes to HSV entry. Exposure of human cervical and primary genital tract epithelial, neuronal, or keratinocyte cells to HSV serotype 2 resulted in rapid phosphorylation of Akt. Silencing of Akt with small interfering RNA prevented the calcium responses, blocked viral entry, and inhibited plaque formation by 90% compared to control siRNA. Susceptibility to infection was partially restored if Akt was reintroduced into silenced cells with an Akt-expressing plasmid. HSV-2 variants deleted in glycoproteins B or D failed to induce Akt phosphorylation, and coimmunoprecipitation studies indicated that Akt interacts with glycoprotein B. Cell-surface expression of Akt was rapidly induced in response to HSV exposure. Miltefosine (50 µM), a licensed drug that blocks Akt phosphorylation, inhibited HSV-induced calcium release, viral entry, and plaque formation following infection with acyclovir-sensitive and resistant clinical isolates. Miltefosine blocked amplification of HSV from explanted ganglia to epithelial cells; viral yields were significantly less in miltefosine compared to control-treated cocultures (P<0.01). Together, these findings identify a novel role for Akt in viral entry, link Akt and calcium signaling, and suggest a new target for HSV treatment and suppression.

Morbidity and prostate-specific antigen control of external beam radiation therapy plus low-dose-rate brachytherapy boost for low, intermediate, and high-risk prostate cancer.

PURPOSE: Dose escalation has been shown beneficial in prostate cancer. Brachytherapy (BT) provides an opportunity for dose escalation beyond what can be safely delivered using only teletherapy methods. The purpose of this study was to determine cancer control and morbidity of external beam radiation therapy (EBRT) plus low-dose-rate (LDR) BT boost in patients with prostate cancer treated at Duke University Health System. METHODS: Between June 1997 and August 2007, 199 patients were consecutively treated at our facility with 46Gy EBRT followed by 100Gy palladium-103 ((103)Pd) or 120Gy iodine-125 ((125)I) LDR prostate implant. Treatment characteristics and followup data were retrospectively analyzed. Intermediate risk was defined as T2b-c, Gleason score 7 (GS 7), or prostate-specific antigen (PSA) of 10.1-19.9ng/mL. High risk was defined as GS 8-10, PSA>20, T3+, or two intermediate risk factors. The Radiation Therapy Oncology Group toxicity scale was used to report morbidity for gastrointestinal (GI) and genitourinary (GU) effects. PSA recurrence was defined as nadir+2ng/mL. RESULTS: Median followup was 4.2 years for all patients, 4.8 years for high-risk patients. Risk categories were as follows: 20% low risk, 47% intermediate risk, and 33% high risk. Forty five percent of patients received adjuvant androgen deprivation therapy (ADT). The median length of time since end of ADT to last followup was 2.7 years in all patients, 2.0 years for high-risk patients. Five-year biochemical relapse-free survival was 87% for all, 81% for high-risk patients. PSA control was similar at 92% for all and 86% for high-risk patients. Five-year actuarial risk of any and Grade 3 late GI morbidity was 38% and 7% respectively, and any and Grade 3 late GU morbidity was 21% and 3%, respectively. There were no significant differences in risk of Grade 2+GI or GU morbidity with choice of isotope. CONCLUSIONS: EBRT plus LDR BT has acceptable morbidity and, with 5-year followup, provides excellent cancer control even in high-risk patients.

Gastrointestinal toxicity of transperineal interstitial prostate brachytherapy.

PURPOSE: To characterize the severity and time course of rectal toxicity following transperineal prostate brachytherapy using prospectively recorded data, and to determine factors associated with toxicity. METHODS AND MATERIALS: One hundred thirty-four patients with prostate cancer treated with transperineal brachytherapy from 1997 to 1999 had rectal toxicity data available for analysis. Patients with Gleason score (GS) > 6, prostate-specific antigen (PSA) > 6, or stage > T2a were treated initially with external beam radiation therapy followed by brachytherapy boost; patients with none of these features were treated with brachytherapy alone. Both iodine-125 and palladium-103 sources were used, and loaded according to a modified Quimby distribution. At each follow-up, toxicity was recorded according to a modified RTOG gastrointestinal scale. RESULTS: Thirty-nine percent of patients experienced gastrointestinal toxicity, mostly Grade 1. Median duration of symptoms was 6 months. Two patients experienced Grade 3 toxicity, both of whom had minimal symptoms until their 12-month follow-up. There was no Grade 4 or 5 toxicity. The addition of external beam radiation therapy (p = 0.003), higher clinical stage (p = 0.006), and Caucasian race (p = 0.01) were associated with increased incidence of toxicity. CONCLUSION: Most patients with rectal toxicity have very mild symptoms. There is a small risk of severe late toxicity. External beam radiation, higher stage, and race are associated with toxicity.