EED and EZH2 constitutive variants: A study to expand the Cohen‐Gibson syndrome phenotype and contrast it with Weaver syndrome

Overgrowth‐intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen‐Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.

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Okamoto syndrome has features overlapping with Au–Kline syndrome and is caused by HNRNPK mutation

Okamoto syndrome is characterized by severe intellectual disability, generalized hypotonia, stenosis of the ureteropelvic junction with hydronephrosis, cardiac anomalies, and characteristic facial gestalt. Several patients have been reported. The basic mechanism of Okamoto syndrome has not been clarified. Au–Kline syndrome is a new syndrome due to loss‐of‐function variants in the HNRNPK (heterogeneous nuclear ribonucleoprotein K) gene. A new patient with Okamoto syndrome visited our hospital. We noticed that the patient had features overlapping with Au–Kline syndrome. We studied the HNRNPK gene by Sanger sequencing, and identified a novel splicing variant. We suggest that Okamoto syndrome is identical to Au–Kline syndrome.

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Clinical Infectious Diseases

The Association of Antibiotic Stewardship With Fluoroquinolone Prescribing in Michigan Hospitals: A Multi-hospital Cohort Study Abstract Background Fluoroquinolones increase the risk of Clostridioides difficile infection and antibiotic resistance. Hospitals often use pre-prescription approval or prospective audit and feedback to target fluoroquinolone prescribing. Whether these strategies impact aggregate fluoroquinolone use is unknown. Methods This study is a 48-hospital, retrospective cohort of general-care, medical patients hospitalized with pneumonia or positive urine culture between December 2015–September 2017. Hospitals were surveyed on their use of pre-prescription approval and/or prospective audit and feedback to target fluoroquinolone prescribing during hospitalization (fluoroquinolone stewardship). After controlling for hospital clustering and patient factors, aggregate (inpatient and post-discharge) fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin) exposure was compared between hospitals with and without fluoroquinolone stewardship. Results There were 11 748 patients (6820 pneumonia; 4928 positive urine culture) included at 48 hospitals. All hospitals responded to the survey: 29.2% (14/48) reported using pre-prescription approval and/or prospective audit and feedback to target fluoroquinolone prescribing. After adjustment, fluoroquinolone stewardship was associated with fewer patients receiving a fluoroquinolone (37.1% vs 48.2%; P = .01) and fewer fluoroquinolone treatment days per 1000 patients (2282 vs 3096 days/1000 patients; P = .01), driven by lower inpatient prescribing. However, most (66.6%) fluoroquinolone treatment days occurred after discharge, and hospitals with fluoroquinolone stewardship had twice as many new fluoroquinolone starts after discharge as hospitals without (15.6% vs 8.4%; P = .003). Conclusions Hospital-based stewardship interventions targeting fluoroquinolone prescribing were associated with less fluoroquinolone prescribing during hospitalization, but not at discharge. To limit aggregate fluoroquinolone exposure, stewardship programs should target both inpatient and discharge prescribing.

Prevalence, Predictors, and Successful Treatment Outcomes of Xpert MTB/RIF–identified Rifampicin-resistant Tuberculosis in Post-conflict Eastern Democratic Republic of the Congo, 2012–2017: A Retrospective Province-Wide Cohort Study Abstract Background Multidrug-resistant tuberculosis (MDR-TB) jeopardizes global TB control. The prevalence and predictors of Rifampicin-resistant (RR) TB, a proxy for MDR-TB, and the treatment outcomes with standard and shortened regimens have not been assessed in post-conflict regions, such as the South Kivu province in the eastern Democratic Republic of the Congo (DRC). We aimed to fill this knowledge gap and to inform the DRC National TB Program. Methods of adults and children evaluated for pulmonary TB by sputum smear microscopy and Xpert MTB/RIF (Xpert) from February 2012 to June 2017. Multivariable logistic regression, Kaplan–Meier estimates, and multivariable Cox regression were used to assess independent predictors of RR-TB and treatment failure/death. Results Of 1535 patients Xpert-positive for TB, 11% had RR-TB. Independent predictors of RR-TB were a positive sputum smear (adjusted odds ratio [aOR] 2.42, 95% confidence interval [CI] 1.63–3.59), retreatment of TB (aOR 4.92, 95% CI 2.31–10.45), and one or more prior TB episodes (aOR 1.77 per episode, 95% CI 1.01–3.10). Over 45% of RR-TB patients had no prior TB history or treatment. The median time from Xpert diagnosis to RR-TB treatment initiation was 12 days (interquartile range 3–60.2). Cures were achieved in 30/36 (83%) and 84/114 (74%) of patients on 9- vs 20/24-month MDR-TB regimens, respectively (P = .06). Predictors of treatment failure/death were the absence of directly observed therapy (DOT; adjusted hazard ratio [aHR] 2.77, 95% CI 1.2–6.66) and any serious adverse drug event (aHR 4.28, 95% CI 1.88–9.71). Conclusions Favorable RR-TB cure rates are achievable in this post-conflict setting with a high RR-TB prevalence. An expanded Xpert scale-up; the prompt initiation of shorter, safer, highly effective MDR-TB regimens; and treatment adherence support are critically needed to optimize outcomes. The Association of Antibiotic Stewardship With Fluoroquinolone Prescribing in Michigan Hospitals: A Multi-hospital Cohort Study Abstract Background Fluoroquinolones increase the risk of Clostridioides difficile infection and antibiotic resistance. Hospitals often use pre-prescription approval or prospective audit and feedback to target fluoroquinolone prescribing. Whether these strategies impact aggregate fluoroquinolone use is unknown. Methods This study is a 48-hospital, retrospective cohort of general-care, medical patients hospitalized with pneumonia or positive urine culture between December 2015–September 2017. Hospitals were surveyed on their use of pre-prescription approval and/or prospective audit and feedback to target fluoroquinolone prescribing during hospitalization (fluoroquinolone stewardship). After controlling for hospital clustering and patient factors, aggregate (inpatient and post-discharge) fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin) exposure was compared between hospitals with and without fluoroquinolone stewardship. Results There were 11 748 patients (6820 pneumonia; 4928 positive urine culture) included at 48 hospitals. All hospitals responded to the survey: 29.2% (14/48) reported using pre-prescription approval and/or prospective audit and feedback to target fluoroquinolone prescribing. After adjustment, fluoroquinolone stewardship was associated with fewer patients receiving a fluoroquinolone (37.1% vs 48.2%; P = .01) and fewer fluoroquinolone treatment days per 1000 patients (2282 vs 3096 days/1000 patients; P = .01), driven by lower inpatient prescribing. However, most (66.6%) fluoroquinolone treatment days occurred after discharge, and hospitals with fluoroquinolone stewardship had twice as many new fluoroquinolone starts after discharge as hospitals without (15.6% vs 8.4%; P = .003). Conclusions Hospital-based stewardship interventions targeting fluoroquinolone prescribing were associated with less fluoroquinolone prescribing during hospitalization, but not at discharge. To limit aggregate fluoroquinolone exposure, stewardship programs should target both inpatient and discharge prescribing. Prevalence, Predictors, and Successful Treatment Outcomes of Xpert MTB/RIF–identified Rifampicin-resistant Tuberculosis in Post-conflict Eastern Democratic Republic of the Congo, 2012–2017: A Retrospective Province-Wide Cohort Study Abstract Background Multidrug-resistant tuberculosis (MDR-TB) jeopardizes global TB control. The prevalence and predictors of Rifampicin-resistant (RR) TB, a proxy for MDR-TB, and the treatment outcomes with standard and shortened regimens have not been assessed in post-conflict regions, such as the South Kivu province in the eastern Democratic Republic of the Congo (DRC). We aimed to fill this knowledge gap and to inform the DRC National TB Program. Methods of adults and children evaluated for pulmonary TB by sputum smear microscopy and Xpert MTB/RIF (Xpert) from February 2012 to June 2017. Multivariable logistic regression, Kaplan–Meier estimates, and multivariable Cox regression were used to assess independent predictors of RR-TB and treatment failure/death. Results Of 1535 patients Xpert-positive for TB, 11% had RR-TB. Independent predictors of RR-TB were a positive sputum smear (adjusted odds ratio [aOR] 2.42, 95% confidence interval [CI] 1.63–3.59), retreatment of TB (aOR 4.92, 95% CI 2.31–10.45), and one or more prior TB episodes (aOR 1.77 per episode, 95% CI 1.01–3.10). Over 45% of RR-TB patients had no prior TB history or treatment. The median time from Xpert diagnosis to RR-TB treatment initiation was 12 days (interquartile range 3–60.2). Cures were achieved in 30/36 (83%) and 84/114 (74%) of patients on 9- vs 20/24-month MDR-TB regimens, respectively (P = .06). Predictors of treatment failure/death were the absence of directly observed therapy (DOT; adjusted hazard ratio [aHR] 2.77, 95% CI 1.2–6.66) and any serious adverse drug event (aHR 4.28, 95% CI 1.88–9.71). Conclusions Favorable RR-TB cure rates are achievable in this post-conflict setting with a high RR-TB prevalence. An expanded Xpert scale-up; the prompt initiation of shorter, safer, highly effective MDR-TB regimens; and treatment adherence support are critically needed to optimize outcomes. Glycocalyx Breakdown is Associated with Severe Disease and Fatal Outcome in Plasmodium falciparum Malaria Abstract Background Interactions between the endothelium and infected erythrocytes, microvascular dysfunction and parasite sequestration play major roles in the pathogenesis of severe falciparum malaria. The glycocalyx is a carbohydrate-rich layer lining the endothelium mediating NO production and vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity is not known. Methods We prospectively enrolled Indonesian inpatients (≥18 years old) with severe (SM) or moderately-severe (MSM) falciparum malaria and healthy controls (HCs). Glycocalyx breakdown products were measured in enrolment samples of urine (glycosaminoglycans; dimethylmethylene blue [GAG-DMMB] and liquid chromatography-tandem mass spectrometry [GAG-MS] assays) and plasma (syndecan-1; ELISA), and related to vascular NO bioavailability (reactive hyperemia-peripheral arterial tonometry). Results A total of 129 subjects (SM=43, MSM=57, HC=29) were recruited. Syndecan-1 (µg/ml), GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM [median (range) 332.4 (85-3-1913), 3.16 (0.04-27.9) and 4.73 (2.02-27.13)] compared to MSM [99.1 (19.9-767.6), 1.28 (0.03-9.3) and 4.44 (1.19-13.87)], and HCs [48.9 (32.3-88.3), 0.11 (0.02-1.9) and 2.55 (0.73-10.19)]; P<0.001. In SM, GAG-DMMB and GAG-MS were increased in non-survivors (n=3) [median (IQR): 6.72 (3.80-27.87) and 12.15 (7.88-17.20)] compared to survivors n=39 [(3.10 (0.46-4.5) and 4.64 (2.02-15.20)]; P=0.03. Glycocalyx degradation was associated with parasite biomass in MSM (r=0.31, P=0.03 [syndecan-1]; r=0.48 [GAG-DMMB] and r=0.43 [GAG-MS], P<0.001), and SM patients (r=0.29, P=0.04, r=0.47; P=0.002 and r=0.33, P=0.04), and inversely associated with endothelial NO bioavailability. Conclusions Increased endothelial glycocalyx breakdown is associated with impaired vascular NO, severe disease and fatal outcome in adults with falciparum malaria, likely contributing to pathogenesis. Impact of rotavirus vaccine introduction in children less than 2 years of age presenting for medical care with diarrhea in rural Matlab, Bangladesh Abstract Background Following the conclusion of a Rotarix vaccine (HRV) cluster-randomized controlled trial (CRT) in Matlab, Bangladesh, HRV was included in Matlab's routine immunization program. We describe the population-level impact of programmatic rotavirus vaccination in Bangladesh in children <2 years of age Methods Interrupted time series were used to estimate the impact of HRVintroduction. Diarrheal surveillance collected between 2000 and 2014 within the two service delivery areas (icddr,b service area [ISA] and government service area [GSA]) of the Matlab Health and Demographic Surveillance System administered by icddr,b was used. Age-group specific incidence rates were calculated for both rotavirus-positive (RV+) and rotavirus-negative (RV-) diarrhea of any severity presenting to the hospital. Two models were used to assess impact within each service area: Model 1 used the pre-vaccine time period in all villages (HRV- and control-only) and Model 2 combined the pre-vaccine time period and the CRT time period using outcomes from control-only villages. Results Both models demonstrated a downward trend in RV+ diarrheal incidence in the ISA villages during 3.5 years of routine HRV use, though only Model 2 was statistically significant. Significant impact of HRV on RV+ diarrhea incidence in GSA villages was not observed in either model. Differences in population-level impact between the two delivery areas may be due to varied rotavirus vaccine coverage and presentation rate to the hospital. Conclusions This study provides initial evidence of the population-level impact of rotavirus vaccines in children <2 years of age in Matlab, Bangladesh. Further studies of rotavirus vaccine impact after nationwide introduction in Bangladesh are needed. Transmission-blocking effects of primaquine and methylene blue suggest P. falciparum gametocyte sterilisation rather than effects on sex ratio Abstract Gametocyte density and sex-ratio can predict the proportion of mosquitoes that become infected after feeding on blood of patients receiving non-gametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex-ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects. Principal Controversies in Vaccine Safety in the United States Abstract Concerns about vaccine safety can lead to decreased acceptance of vaccines and resurgence of vaccine-preventable diseases. We summarize the key evidence on some of the main current vaccine safety controversies in the United States, including: 1) MMR vaccine and autism; 2) thimerosal, a mercury-based vaccine preservative, and the risk of neurodevelopmental disorders; 3) vaccine-induced Guillain-Barré Syndrome (GBS); 4) vaccine-induced autoimmune diseases; 5) safety of HPV vaccine; 6) aluminum adjuvant-induced autoimmune diseases and other disorders; and 7) too many vaccines given early in life predisposing children to health and developmental problems. A possible small increased risk of GBS following influenza vaccination has been identified, but the magnitude of the increase is less than the risk of GBS following influenza infection. Otherwise, the biological and epidemiologic evidence does not support any of the reviewed vaccine safety concerns. Insertion as resistance mechanism against integrase inhibitors in several retroviruses Birth Cohort Studies Assessing Norovirus Infection and Immunity in Young Children: A Review Abstract Globally, noroviruses are among the foremost causes of acute diarrheal disease, yet there are many unanswered questions on norovirus immunity, particularly following natural infection in young children during the first 2 years of life when the disease burden is highest. We conducted a literature review on birth cohort studies assessing norovirus infections in children from birth to early childhood. Data on infection, immunity, and risk factors are summarized from 10 community-based birth cohort studies conducted in low- and middle-income countries. Up to 90% of children experienced atleast one norovirus infection and up to 70% experienced norovirus-associated diarrhea, most often affecting children 6 months of age and older. Data from these studies help to fill critical knowledge gaps for vaccine development, yet study design and methodological differences limit comparison between studies, particularly for immunity and risk factors for disease. Considerations for conducting future birth cohort studies on norovirus are discussed. In the Literature Saddle Nose Deformity in an Immunosuppressed Patient Cover News Ebola's Curse: 2013–2016 Outbreak in West Africa By OldstoneMichael and OldstoneMadeleine. Elsevier, 2017. 126 pp. $89.95 (hardcover). ISBN: 9780128138885. Cost-effectiveness and Cost-utility of the Adherence Improving Self-management Strategy in Human Immunodeficiency Virus Care: A Trial-based Economic Evaluation Abstract Background Several promising human immunodeficiency virus (HIV) treatment adherence interventions have been identified, but data about their cost-effectiveness are lacking. This study examines the trial-based cost-effectiveness and cost-utility of the proven-effective Adherence Improving Self-Management Strategy (AIMS), from a societal perspective, with a 15-month time horizon. Methods Treatment-naive and treatment-experienced patients at risk for viral rebound were randomized to treatment as usual (TAU) or AIMS in a multicenter randomized controlled trial in the Netherlands. AIMS is a nurse-led, 1-on-1 self-management intervention incorporating feedback from electronic medication monitors, delivered during routine clinical visits. Main outcomes were costs per reduction in log10 viral load, treatment failure (2 consecutive detectable viral loads), and quality-adjusted life-years (QALYs). Results Two hundred twenty-three patients were randomized. From a societal perspective, AIMS was slightly more expensive than TAU but also more effective, resulting in an incremental cost-effectiveness ratio (ICER) of €549 per reduction in log10 viral load and €1659 per percentage decrease in treatment failure. In terms of QALYs, AIMS resulted in higher costs but more QALYs compared to TAU, which resulted in an ICER of €27759 per QALY gained. From a healthcare perspective, AIMS dominated TAU. Additional sensitivity analyses addressing key limitations of the base case analyses also suggested that AIMS dominates TAU. Conclusions Base case analyses suggests that over a period of 15 months, AIMS may be costlier, but also more effective than TAU. All additional analyses suggest that AIMS is cheaper and more effective than TAU. This trial-based economic evaluation confirms and complements a model-based economic evaluation with a lifetime horizon showing that AIMS is cost-effective. Clinical Trials Registration NCT01429142 First Human Case of Metacestode Infection Caused by Versteria sp. in a Kidney Transplant Recipient Abstract Cestodes are emerging agents of severe opportunistic infections among immunocompromised patients. We describe the first case of human infection, with the recently-proposed genus Versteria causing an invasive, tumor-like hepatic infection with regional and distant extension in a 53-year-old female kidney transplant recipient from Atlantic Canada. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus–1 Infection: Week 48 Results of the DRIVE-AHEAD Trial Abstract Background Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. Methods DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment–naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). Results Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) (-3.83 vs +13.26 mg/dL) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (−1.6 vs +8.7 mg/dL and −3.8 vs +13.3 mg/dL, respectively). Conclusions In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non–HDL-C compared with EFV/FTC/TDF. Clinical Trials Registration NCT02403674 A 44-Year-Old Female With Overwhelming Sepsis sepsisaspleniaRPSA geneHowell-Jolly bodiesStreptococcus pneumonia Concurrent Seroprevalence of Antibodies to Toxoplasma gondii and Toxocara Species in the United States, 2011–2014 To the Editor—We report supplemental findings incorporating Toxoplasma gondii serology results from our study of risk factors for Toxocara seropositivity in the United States [1] using stored serum samples collected from the National Health and Nutrition Examination Survey (NHANES), 2011–2014. Whereas T. gondii is a protozoan parasite and Toxocara is an intestinal nematode, both share ingestion of contaminated soil as means of exposure in humans. Both parasites can contaminate soil when environmentally resistant T. gondii oocysts or Toxocara cati eggs are shed in the feces of infected cats [2, 3].

Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection Abstract Recognizing the importance of timely guidance regarding the rapidly evolving field of hepatitis C management, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) developed a web-based process for the expeditious formulation and dissemination of evidence-based recommendations. Launched in 2014, the hepatitis C virus (HCV) guidance website undergoes periodic updates as necessitated by availability of new therapeutic agents and/or research data. A major update was released electronically in September 2017, prompted primarily by approval of new direct-acting antiviral agents and expansion of the guidance's scope. This update summarizes the latest release of the HCV guidance and focuses on new or amended recommendations since the previous September 2015 print publication. The recommendations herein were developed by volunteer hepatology and infectious disease experts representing AASLD and IDSA and have been peer reviewed and approved by each society's governing board.

Correction to: Effects of Carbohydrate Mouth Rinse on Cycling Time Trial Performance: A Systematic Review and Meta-Analysis

Section 3.2, Fig. 2: The wording on the x-axis which previously read.

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Sphingosine‐1‐phosphate activates mouse vagal airway afferent C‐fibres via S1PR3 receptors

Key points

Sphingosine‐1‐phosphate (S1P) strongly activates mouse vagal C‐fibres in the airways. Airway‐specific nodose and jugular C‐fibre neurons express mRNA coding for the S1P receptor S1PR3. S1P activation of nodose C‐fibres is inhibited by a S1PR3 antagonist. S1P activation of nodose C‐fibres does not occur in S1PR3 knockout mice.

Abstract

We evaluated the effect of sphingosine‐1‐phosphate (S1P), a lipid that is elevated during airway inflammatory conditions like asthma, for its ability to stimulate vagal afferent C‐fibres in mouse lungs. Single cell RT‐PCR on lung‐specific vagal afferent neurons revealed that both TRPV1‐expressing and TRPV1‐non‐expressing nodose neurons express mRNA coding for the S1P receptor S1PR3. TRPV1‐expressing airway‐specific jugular ganglion neurons also express S1PR3 mRNA. S1PR1 and S1PR2 mRNAs were also found to be expressed but only in a limited subset (32% and 22%, respectively) of airway‐specific vagal sensory neurons; whereas S1PR4 and S1PR5 were rarely expressed. We used large scale two‐photon imaging of the nodose ganglia from our ex vivo preparation isolated from Pirt‐Cre;R26‐GCaMP6s transgenic mice, which allows for simultaneous monitoring of calcium transients in ∼1000 neuronal cell bodies in the ganglia during tracheal perfusion with S1P (10 μM). We found that S1P in the lungs strongly activated 81.5% of nodose fibres, 70% of which were also activated by capsaicin. Single fibre electrophysiological recordings confirmed that S1P evoked action potential (AP) generation in a concentration‐dependent manner (0.1–10 μM). Action potential generation by S1P in nodose C‐fibres was effectively inhibited by the S1PR3 antagonist TY 52156 (10 μM). Finally, in S1PR3 knockout mice, S1P was not able to activate any of the airway nodose C‐fibres analysed. These results support the hypothesis that S1P may play a role in evoking C‐fibre‐mediated airway sensations and reflexes that are associated with airway inflammatory diseases.

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Chronic fetal hypoxia disrupts the peri‐conceptual environment in next‐generation adult female rats

Key points

Exposure to chronic hypoxia during gestation influences long‐term health and development, including reproductive capacity, across generations. If the peri‐conceptual environment, in the developing oviduct, is affected by gestational hypoxia, then this could have implications for later fertility and the health of future generations. In this study, we show that the oviducts of female rats who were exposed to chronic hypoxia whilst in utero, have reduced telomere length, decreased mitochondrial DNA biogenesis, and increased oxidative stress Our results show that exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in early adulthood, and help us understand how exposure to hypoxia during development could influence reproductive health across generations.

Abstract

Exposure to chronic hypoxia during fetal development has important effects on immediate and long‐term outcomes in offspring. Adverse impacts in adult offspring include impairment of cardiovascular function, metabolic derangement, and accelerated ovarian ageing. However, it is not known whether other aspects of the female reproductive system may be similarly affected. In this study, we examine the impact of chronic gestational hypoxia on the developing oviduct. Wistar rat dams were randomized to either normoxia (21%) or hypoxia (13%) from day 6 post‐mating until delivery. Post‐delivery female offspring were maintained in normoxia until 4 months of age. Oviductal gene expression was assayed at the RNA (q‐rtPCR) and protein (Western blotting) levels. Oviductal telomere length was assayed using Southern blotting. Oviductal telomere length was reduced in the gestational hypoxia‐exposed animals compared to the normoxic controls (p<0.01). This was associated with a specific post‐transcriptional reduction in the KU70 subunit of DNA‐pk in the gestational hypoxia‐exposed group (p<0.05). Gestational hypoxia‐exposed oviducts also showed evidence of decreased mitochondrial DNA biogenesis; reduced mtDNA copy number (p<0.05), and reduced gene expression of Tfam (p<0.05) and Pgc1α (p<0.05). In the hypoxia‐exposed oviducts there was up‐regulation of mitochondrial‐specific antioxidant defense enzymes (MnSOD; p<0.01). Exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in adulthood. The oviduct plays a central role in early development as the site of gamete transport, syngamy, and early development, hence accelerated ageing of the oviductal environment could have important implications for fertility and the health of future generations.

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MEDEX 2015: The key role of cardiac mechanics to maintain biventricular function at high altitude

New Findings

What is the central question of this study? This study is the first investigating the effects of high‐altitude trekking on biventricular mechanics including measurements of left ventricular (LV) subendocardial and subepicardial function. What is the main finding and its importance? We provide new evidence that an increased contractility and untwisting efficiency, a key element of diastolic function, probably play a key role to preserve cardiac function during high‐altitude trekking. Persistent increased loading conditions during several weeks at high altitude may have a key role in the apparition of LV or RV dysfunctions.

Abstract

Aims

Cardiac responses to acute hypoxic exposure have been deeply investigated. We analyzed the effects of high‐altitude trekking (i.e. prolonged hypoxic exposure) on the biventricular function including the evaluation of subendocardial and subepicardial functions in the left ventricle (LV).

Methods and results

Resting evaluations of LV and right ventricular (RV) function and mechanics were assessed by Speckle Tracking Echocardiography on twenty subjects at sea level and at high altitude (5085 m, after a 10‐day ascent). Pulmonary artery systolic pressure (PASP) was increased at high altitude (sea level: 13.1 ± 5.9 mmHg; high altitude: 26.6 ± 10.8 mmHg, p < 0.001). LV volumes were decreased whereas RV volumes were increased at high altitude. Alterations in PASP and cardiac volumes were correlated to hypoxemia. We observed neither RV nor LV systolic dysfunction, including analysis of LV subendocardial and subepicardial function. LV systolic strain rates were enhanced at high altitude. Transmitral and transtricuspid diastolic filling ratios were decreased at high altitude. Diastolic apical rotational rate, untwisting rate and untwisting rate/peak twist ratio (i.e. untwisting efficiency) were enhanced at high altitude.

Conclusion

We observed no echocardiographic signs of LV and RV pathological dysfunctions at rest at high altitude. In contrast, our data highlighted major changes in the LV mechanics with an increased LV contractility and a higher untwisting efficiency at high altitude. Biventricular interaction, alterations in loading conditions and an increase in plasma catecholamine concentration may partly explain these modifications. Thus, we demonstrated that LV mechanics (i.e. increased strain rates and untwisting efficiency) have a key role to preserve cardiac function during high‐altitude trekking.

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Bone marrow mononuclear cell transplantation rescue glomerular filtration barrier and epithelial cellular junctions in renovascular hypertension model

New Findings

What is the central question of this study? To determine whether a single BMMC transplant into subcapsular region of kidney could improve cellular communication and adhesion, while restoring renal tissue cytoarchitecture and function during renovascular hypertension. What is the main finding and its importance? It was possible to observe that BMMC transplantation can restore connexin 40 expression and also recover N‐ and E‐cadherin levels within 15 days. It was observed for the first time that BMMC transplantation restores nephrin expression, a glomerular filtration barrier component, related to podocytes and glomerular basal membrane.

Abstract

Stem cell therapy has emerged as a potential treatment for renal diseases due to their regenerative potential. However, a better understanding of damaged renal cells morphofunctional changes in the presence of transplanted stem cells is needed. This study aimed to investigate cell‐cell communication and adhesion in renal parenchyma along with fibrosis analysis, to evaluate renal morphology and function after bone marrow mononuclear cell (BMMC) transplantation in 2 Kidneys–1 Clip (2K1C) rats. BMMC therapy significantly decreased blood pressure and renin expression, also improved renal morphology and restored glomerular filtration barrier with remodeling of podocytes. In addition, there was fibrosis reduction while connexin 40 and nephrin expression was significantly increased after 7 and 15 days of transplantation. Plasma creatinine, urea and total protein levels were restored while proteinuria was reduced. Furthermore, N‐ and E‐cadherin expression was increased soon after BMMC therapy. GFP⁺ BMMC were found in the renal cortex after 24 and 48 hours of transplantation into renal subcapsule, while 7 and 15 days after, these cells were observed throughout renal medulla, indicating cellular migration. Therefore, these data suggest that transplanted BMMC improve cell‐cell communication and adhesion between damaged cells, accompanied by renal morphology and function recovery.

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NAEMSP president discusses impact of ET3 model

Our co-hosts sit down with the NAEMSP president to discuss how the new reimbursement model will transform all aspects of the industry

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A new way to determine correct depth of central venous catheter insertion using a real‐time ultrasound‐guided insertion technique in pediatric patients

Abstract

Background

Several formulae or methods are reported to predict the ideal central venous catheter (CVC) insertion depth. However, they are complicated and often unsuitable in cases requiring rapid management.

Aim

This study aimed to determine a simple and practical method to predict the ideal CVC insertion depth after ultrasound‐guided right internal jugular, or left or right supraclavicular puncture in pediatric patients.

Method

Pediatric patients with congenital heart diseases who underwent cardiovascular surgery between July 2015 and February 2018 in the German Pediatric Heart Center Sankt Augustin were enrolled. Body height, body weight, patient age (months), and CVC insertion depth were retrieved from the anesthesia records. Ideal CVC insertion depth was calculated by measuring the distance between the level of the carina tracheae and the CVC tip on the first postoperative chest radiograph. The relationships of body height, body weight, and patient age (months) to ideal CVC insertion depth for the right internal jugular, left supraclavicular, and right supraclavicular approaches were investigated.

Results

Body height was the best parameter, providing the best coefficients of determination as well as the simplest relationship. Based on analysis for ideal CVC insertion depth for every 10‐cm increase in body height, there was an ideal CVC insertion depth for each body height, independent of the anesthesiologist's experience with the approach used. Whereas ideal CVC insertion depths for the right internal jugular vein approach and the left supraclavicular approach showed no significant difference, ideal CVC insertion depth for the right supraclavicular approach was significantly shorter than that of the other two approaches.

Conclusion

This study successfully determined a visually simple and practical bar graph to predict the ideal CVC depth inserted using only the real‐time ultrasound‐guided insertion technique for the right internal jugular vein, left supraclavicular, and right supraclavicular approaches.

This article is protected by copyright. All rights reserved.

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The heart rate variability derived Newborn Infant Parasympathetic Evaluation (NIPE™) Index in paediatric surgical patients from 0‐2 years under sevoflurane anaesthesia ‐ a prospective observational pilot study

Summary

Background

The heart rate variability derived Newborn Infant Parasympathetic Evaluation (NIPE^™) Index is a continuous non‐invasive tool to assess pain and discomfort in infants < 2 years. Initial studies focused on pain monitoring in the neonatal intensive care unit environment.

Aim

To investigate the performance of the NIPE in infants under sevoflurane anaesthesia. The primary objective of this study was to compare the NIPE and heart rate as tools to help recognise the need for additional opioid drugs. Secondary objectives were the course of the NIPE and heart rate around specific standardized noxious procedural mile‐stones.

Methods

NIPE and heart rate values recorded during a 120 sec. interval before the anaesthetist's decision to administer additional opioid due to perceived insufficient anti‐nociception and during a 120 sec. interval after drug administration were analysed by means of a repeated measures ANOVA. The same analyses were performed for datasets around per protocol administration of morphine for postoperative analgesia, performance of a caudal block and surgical incision.

Results

In patients with a NIPE value <50, additional opioid drug administration resulted in a rise of NIPE values, reaching a maximum increase of 5.1 (95% CI 0.22 to 9.99) units 120 sec. after drug administration (p= 0.041). There was no evidence of a change in heart rate during these two 120 sec. periods. Per protocol administration of morphine, caudal block and surgical incision did not result in changes of the NIPE, which was around 65 units on these occasions, and heart rate.

Conclusions

In infants anaesthetised with sevoflurane, NIPE values <50 might be indicative of insufficient anti‐nociception. The results of this observational pilot study might suggest that the NIPE could be a better measure of the nociception / anti‐nociception balance than heart rate.

This article is protected by copyright. All rights reserved.

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Safe Paediatric Procedural Sedation and Anagesia by Anaesthesiologists for elective procedures: a Clinical Practice Statement from the European Society for Pediatric Anaesthesiology

Abstract

The growing number of medical procedures performed in children that require cooperation of patients, lack of movement, anxiolysis or/and analgesia triggers the increased need for procedural sedation. This document presents the consensus statement of the European Society for Paediatric Anaesthesiology about the principles connected with the safe management of procedural sedation and analgesia (PSA) by anaesthesiologists for elective procedures in children. It does not aim to provide a legal statement on how and by whom PSA should be performed. The National Societies of Pediatric Anesthesiology and Ministries of Health could use this document to facilitate decision‐making on how and by whom PSA in children should be performed in their countries.

This article is protected by copyright. All rights reserved.

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NAEMSP president discusses impact of the ET3 model

Our co-hosts sit down with the NAEMSP president to discuss how the new reimbursement model will transform all aspects of the industry

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Random Chromosome Partitioning in the Polyploid Bacterium Thermus thermophilus HB27

Little is known about chromosome segregation in polyploid prokaryotes. In this study, whether stringent or variable chromosome segregation occurs in polyploid thermophilic bacterium Thermus thermophilus was analyzed. A stable heterozygous strain (HL01) containing two antibiotic resistance markers at one gene locus was generated. The inheritance of the two alleles in the progeny of the heterozygous strain was then followed. During incubation without selection pressure, the fraction of heterozygous cells decreased and that of homozygous cells increased, while the relative abundance of each allele in the whole population remained constant, suggesting chromosome segregation had experienced random event. Consistently, in comparison with Bacillus subtilis in which the sister chromosomes were segregated equally, the ratios of DNA content in two daughter cells of T. thermophilus had a broader distribution and a larger standard deviation, indicating that the DNA content in the two daughter cells was not always identical. Further, the protein homologs (i.e. ParA and MreB) which have been suggested to be involved in bacterial chromosome partitioning did not actively participate in the chromosome segregation in T. thermophilus. Therefore, it seems that protein-based chromosome segregation machineries are less critical for the polyploid T. thermophilus, and chromosome segregation in this bacterium are not stringently controlled but tend to be variable, and random segregation can occur.

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Comparative Analysis of Brain and Fat Body Gene Splicing Patterns in the Honey Bee, Apis mellifera

RNA-seq has proven to be a powerful tool to unravel various aspects of the transcriptome, especially the quantification of alternative splicing (AS) that leads to isoform diversity. The honey bee (Apis mellifera) is an important model organism for studying the molecular underpinnings of behavioral plasticity and social behavior, and recent RNA-seq studies of honey bees have revealed AS patterns and their regulation by DNA methylation. However, tissue-specific AS patterns have not been fully explored. In this paper, we characterized AS patterns in two different honey bee tissue types, and also explored their conservation and regulation. We used the RNA-seq data from brain and fat body to improve the existing models of honey bee genes and identified tissue-specific AS patterns. We found that AS genes show high conservation between honey bee and Drosophila melanogaster. We also confirmed and extended previous findings of a correlation between gene body DNA methylation and AS patterns, providing further support for the role of DNA methylation in regulating AS. In addition, our analysis suggests distinct functional roles for tissue-specific alternatively spliced genes. Taken together, our work provides new insights into the conservation and dynamics of AS patterns across different tissue types

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Paramedic - Knox County, TN - Priority Ambulance

**Location: Knox County, TN** Priority Ambulance is seeking paramedics to serve in Knox County serving hospital and medical facility clients. Our business is expanding is Knox County, and we need additional team members that share our mission of exceptional patient care and friendly customer service. Flexible full- and part-time schedules are available. Our team is a supportive family that works together ...

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Paramedic - Priority Ambulance

**Job Summary** Functions as Paramedic on 911 response ambulance operating in Loudon County, Tennessee. Safely operates vehicle to/from pick up and drop off locations. Provides ALS patient care and movement. Documents all transports completely per company SOP. Adheres to all company policies and procedures. **Qualifications** • High School Diploma or GED • Valid Driver's License • State of Tennessee ...

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On the origin of “indolent” and “aggressive” non-functioning pancreatic neuroendocrine tumour… genetically unrelated or close relative?

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EMS Today 2019 Quick Take: Medical ethics algorithms

Learn how to train EMS providers in the four pillars of medical ethics, how to make difficult decisions in EMS and what ethics is not

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10 reasons we are on the cusp of Peak EMS

A bold prediction that EMS patient transport to the hospital by ambulance is sure to peak, level off and decline as we near 2020

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Prehospital providers shouldn't be cautionary tales of why knowing your stroke risk matters

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Limited supply: How drug shortages are impacting EMS

Rotating pharmaceutical stock, and exploring alternative pain management and expired drug options can mitigate EMS drug shortages

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Limited supply: How drug shortages are impacting EMS

Rotating pharmaceutical stock, and exploring alternative pain management and expired drug options can mitigate EMS drug shortages

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Comparison of intracellular responses between HBV genotype A and C infection in human hepatocyte chimeric mice

Abstract

Background and aims

The clinical course and responsiveness to antiviral treatments differs among hepatitis B virus (HBV) genotypes. However, the cause of these differences is unclear. In the present study, we compared mRNA expression profiles in human hepatocyte chimeric mice infected with HBV genotypes A and C.

Methods

Fifteen chimeric mice were prepared and divided into the following three groups: uninfected control mice, HBV genotype A-infected mice, and HBV genotype C-infected mice. Human hepatocytes were collected from these mouse livers and gene expression analyses were performed using next-generation RNA sequencing.

Results

Although similar pathways were influenced by HBV infection, including inflammation mediated by chemokine and cytokine signaling, p53, and integrin signaling pathways, expression levels of up-regulated genes by HBV genotype A or C infection were quite different. In HBV genotype A-infected hepatocytes, 172 genes, including KRT23 and C10orf54, were significantly more highly expressed than in HBV genotype C-infected cells, whereas 10 genes, including SPX and IER3, were expressed at significantly lower levels. Genes associated with the p53 pathway and the inflammation mediated by chemokine and cytokine signaling pathway were more highly expressed in cells with HBV genotype A infection, whereas genes associated with CCKR signaling map and oxidative stress response were more highly expressed in cells with HBV genotype C infection.

Conclusion

Several differences in gene expression with respect to HBV genotype A and C infection were detected in human hepatocytes. These differences might be associated with genotypic difference in the clinical course or responsiveness to treatment.

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Limited supply: how drug shortages are impacting EMS

Rotating pharmaceutical stock, and exploring alternative pain management and expired drug options can mitigate EMS drug shortages

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Limited supply: how drug shortages are impacting EMS

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Pneumocephalus and pneumoventricle

CASE REPORT

Year : 2019  |  Volume : 14  |  Issue : 1  |  Page : 325-328

Delayed pneumoventricle following endonasal cerebrospinal fluid rhinorrhea repair with thecoperitoneal shunt

Shyam Sundar Krishnan, Adarsh Manuel, Madabhushi Chakravarthy Vasudevan
Department of Neurosurgery, Achanta Lakshmipathi Neurosurgical Centre, Voluntary Health Services Hospital, Chennai, Tamil Nadu, India

Date of Web Publication

21-Feb-2019

Correspondence Address:
Dr. Shyam Sundar Krishnan
Department of Neurosurgery, Achantha Lakshmipathy Neurosurgical Centre, Voluntary Health Services, TTTI Post, Taramani, Chennai - 600 113, Tamil Nadu 
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/ajns.AJNS_224_18

Abstract

Pneumocephalus and pneumoventricle are well-documented in neurosurgical practice. Although both are common posttraumatic sequelae, iatrogenic causes are also well recognized. Iatrogenic causes may be seen after intracranial surgical procedures or cerebrospinal fluid (CSF) diversion procedures. Small amount of pneumoventricle postshunt procedure is usually a self-limiting condition. Rarely, the patient may develop tension pneumoventricle which requires emergency intervention. The occurrence of delayed tension pneumoventricle/pneumatocele following surgery for CSF rhinorrhea with CSF diversion procedures is very rare. We report one case of late presentation of delayed tension pneumoventricle with temporal pneumatocele in a patient who underwent transnasal endoscopic repair of CSF fistula followed by thecoperitoneal shunt. This condition is potentially lethal that requires prompt recognition and surgical treatment.

Keywords: Cerebrospinal fluid rhinorrhea, pneumatocele, pneumocephalus, tension pneumoventricle, thecoperitoneal shunt

How to cite this article: Krishnan SS, Manuel A, Vasudevan MC. Delayed pneumoventricle following endonasal cerebrospinal fluid rhinorrhea repair with thecoperitoneal shunt. Asian J Neurosurg 2019;14:325-8

How to cite this URL: Krishnan SS, Manuel A, Vasudevan MC. Delayed pneumoventricle following endonasal cerebrospinal fluid rhinorrhea repair with thecoperitoneal shunt. Asian J Neurosurg [serial online] 2019 [cited 2019 Feb 21];14:325-8. Available from: http://www.asianjns.org/text.asp?2019/14/1/325/250010

Introduction

The occurrence of pneumoventricle as a delayed complication of cerebrospinal fluid (CSF), rhinorrhea repair with thecoperitoneal shunt is a rare presentation. Tension pneumocephalus is a known and common entity as compared to tension pneumoventricle. The presence of pneumatocele in the temporal lobe in association with the above condition makes it a unique clinical presentation.

Case Report

This 48-year-old female presented with complaints of CSF rhinorrhea since 2 months. There was no history or clinical finding suggestive of trauma or meningitis. Her neurological examination otherwise was unremarkable. Computed tomography (CT) face/skull base followed by magnetic resonance imaging (MRI) brain and diagnostic nasal endoscopy were done which showed the defect in the cribriform plate and left a lateral wall of the sphenoid sinus [Figure 1]. Lumbar puncture done showed the CSF opening pressure of 35 cm of water and no evidence of infection.

Figure 1: Magnetic resonance images of the patient showing cerebrospinal fluid fistula in cribriform plate (short arrow) and lateral wall of sphenoid sinus (long arrow) and computed tomography paranasal sinuses bone window showing defect (long arrow) in the sphenoid bone with cerebrospinal fluid filling into the left sphenoid sinus (long arrow) Click here to view

She underwent transnasal endoscopic repair of CSF fistula along with placement of thecoperitoneal shunt with no anti-siphon device. The bath-plug technique was used to seal the defects by introducing a fat plug with a specifically secured vicryl suture into the intradural space, followed by applying traction on the suture to seal the defect much like a bathplug seals a bath. Rectus abdominis fascia graft was harvested from the same abdominal wound used for shunt placement. The defect was further reinforced by fascia, fat and surgical, and fibrin sealant. It was decided to place thecoperitoneal shunt as the CSF opening pressure was very high to prevent the recurrent CSF leak. Postoperatively, she was symptom-free and discharged to home.

After 1 month, she presented with memory disturbances, multiple episodes of vomiting and headache. There was no recurrence of CSF rhinorrhea or postnasal drip. MRI brain showed pneumoventricle with right temporal pneumatocele [Figure 2]. Diagnostic endoscopy was done which showed dislodged fascia graft. She underwent emergency repacking of the CSF fistula with the removal of thecoperitoneal shunt and aspiration of pneumoventricle underwater seal which was under high pressure. Fasica graft was repositioned to cover the defect after sealing it with fat using the bath-plug technique as in the previous surgery. Fat and fascia packing was reinforced with a pedicled Hadad flap and fibrin sealant. She improved in her symptoms postoperatively. Postoperative CT brain showed good resolution of pneumoventricle with reduced size of ventricular system [Figure 3]. She remained symptom free at 6-month follow-up.

Figure 2: Magnetic resonance imaging brain showing pneumatocele (long arrow) in the right temporal lobe and pneumoventricle (short arrow) Click here to view

Figure 3: Postoperative computed tomography brain showing good resolution of tension pneumoventricle and right temporal pneumatocele Click here to view

Discussion

Pneumocephalus is defined as the presence of air in the intracranial compartment due to communication between intracranial and extracranial compartments.^[1],[2],[3] Tension pneumocephalus is a rarer form of pneumocephalus in which the air is under high pressure.^{[1],[2],[4],[5],[6],[7]}Pneumocephalus occur most commonly in head injuries.^[1],[2],[3] Intra- and post-operative pneumocephalus/pneumoventricle is well-documented, especially, in sitting position surgeries, nitrous oxide anesthesia, and CSF diversion surgeries.^[1],[2],[3] Other conditions causing pneumocephalus are CNS infections caused by gas-producing organisms, congenital neurenteric cysts, and postradiotherapy for nasopharyngeal carcinoma.^{[1],[2],[4],[5],[6],[7]} Small amounts of pneumoventricle alone are common after shunt surgeries, ventricular tumor surgeries.^{[1],[2],[3],[8]} Sometimes, wound breakdown following the shunt surgeries may cause influx of air peritubally and cause pneumoventricle.^[9] Delayed tension pneumoventricle is an extremely rare complication and <50 cases have been described in the literature.^[1]Pneumocephalus/pneumoventricle is usually benign which does not require any treatment, and it decreases at a rate of 25% per week.^{[4],[9],[10],[11],[12]}

Two different mechanisms have been proposed in the development of delayed tension pneumoventricle/pneumocephalus.^{[1],[2],[3],[13],[14]}

1. Dandy's theory of ball valve mechanism: one-way ball valve mechanism causing air to flow into the skull through dural defect where the exit is prevented by brain or meninges sealing the leak site
2. Horowitz inverted soda-bottle effect: negative pressure develops inside the cranial cavity as a result of excessive loss of CSF. This drop in intracranial pressure (ICP) causes air to flow from the extra to the intracranial space across the pressure gradient.

In our case, the patient presented with spontaneous CSF rhinorrhea and was treated by endoscopic skull base defect repair with thecoperitoneal shunt placement. CSF rhinorrhea can be due to traumatic or nontraumatic causes. Traumatic can be either due to head injuries causing skull base fractures or due to iatrogenic causes. Spontaneous leaks could be associated with or without raised ICP. High-pressure leaks could account up to 45% of the nontraumatic CSF rhinorrhea.^[15] Sustained increase in ICP causes bony erosion and creation of an osteodural defect in pneumatized parts of the skull base such as cribriform plate, craniopharyngeal canal, sella, and spheno-occipital synchondrosis leading to CSF leak.^[7],[15] CSF leaks in these cases have been postulated to represent a manifestation of benign intracranial hypertension or pseudotumor cerebri.^{[16],[17],[18],[19]} In our case also CSF leak was associated with raised ICP with no evidence of trauma or infection. This could be an underlying benign ICP with or without congenital defect.

Normal pressure leaks represent 55% of the nontraumatic cases of the CSF rhinorrhea.^[20],[21] It is hypothesized that the spontaneous leak is due to point erosions in the skull base which occur in normal person as a result of physiologic alterations in CSF pressure with transient increase in ICP up to 80 mm of water lasting for few seconds.^[15] Other nontraumatic causes of CSF leak include congenital skull base defects, erosion of the skull base by tumors, infection, mucocele, and following radiation.

CSF diversion in patients with long-standing raised ICP may result in the pneumoventricle by air aspiration through a preexisting congenital or iatrogenic skull base erosion/fistula.^[3] These fistulous sites/erosion points are plugged by scarred meninges or gliotic brain which open up due to a drop in ICP causing inward flow of air. This air is prevented from escaping by temporarily resealing of meningeal cicatrix and this cycle repeatedly happens, resulting in tension pneumoventricle (ball valve mechanism). Shunts by their siphon effect can create significant negative ICP drop which ranges from −30 to −155 mm of water, and sometimes as low as −440 mm of water.^[2],[5] Pneumatocele is located close to the site of fistulae and more common in the temporal lobe. In our case also there might have been a sustained negative pressure caused by the thecoperitoneal shunt without anti-siphon device.

Pneumoventricle presents usually with symptoms and signs of raised ICP such as a recurrent headache with vomiting, impairment of consciousness, seizures, memory disturbances, and gait disturbance. Sometimes, patients present with acute or chronic meningitis. Intracranial splashing sounds called "bruit hydroaerique" are characteristic in some patients. Similarly, our patient also presented with memory disturbances and cognitive impairment during the second presentation.

The delay from CSF shunting to the development of pneumocephalus may vary from a week up to 5 years.^[7],[22] The usage of high-pressure shunts and antisiphon devices have been recommended by some authors to prevent this complication.^[1],[2],[23] Our routine policy is to place Chhabra standard adult thecoperitoneal shunt with no anti-siphon device. However, anti-siphon device has advantages of preventing over-drainage of CSF, and the reservoir gives access to check the patency of the shunt system. We have seen an increased risk of shunt obstruction with anti-siphon device. We had 42 cases who underwent Lumbar-peritoneal (LP) shunts without anti-siphon device in the past 5 years and none of them presented with shunt obstruction or shunt-related morbidity other than shunt migration (five patients) and abdominal pseudocyst (two patients). Programmable shunt provides the benefit of adjusting the pressure setting according to the ventricular pressure. We routinely do not use programmable LP shunts as ours is a resource-limited center with most of the patients coming from low-socioeconomic strata.

Prevention of infection, treatment of raised ICP, aspiration of pneumoventricle, closure of fistula, and removal of shunt tube are the keys to successful management of tension pneumoventricle secondary to CSF fistula.^[23] Broad-spectrum antibiotics are used after shunt removal, but its prophylactic usage is debated.^[1],[5],[23] Removal of the shunt tube relieves the sustained negative pressure which may cause recurrent pneumoventricle/pneumocephalus. Postshunt removal a temporary CSF diversion is preferred by some authors, especially, if the infection is doubted clinically or confirmed.^[1],[2],[23]

In our case, as there was dislodgement of fat-fascia graft, repacking was done followed by aspiration of pneumoventricle underwater seal and thecoperitoneal shunt was removed. We feel the tension pneumoventricle caused air to dissect into the right temporal lobe region under pressure forming the temporal pneumatocele. The shunt was removed to alleviate negative pressure gradient as it was nonprogrammable shunt with no anti-siphon device. The patient had complete resolution of symptoms after the procedure. This makes us think that we should probably reconsider the usage of anti-siphon device and also a pedicled flap to repair the skull base defects. A programmable valve may be the best choice in financially affordable patients. In patients with normal/moderately high ICP (25 cm of water), a temporary lumbar drain can be considered for few days until the defects heal thus preventing the recurrent CSF leaks.

Conclusion

Although it is a rare entity, tension pneumoventricle should be considered in patients who have undergone CSF diversion procedures along with anterior skull base repair. Sometimes, it can occur as a delayed complication which may lead to acute neurological deterioration and sudden death. Hence, prompt diagnosis is necessary for timely intervention and prevention.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 

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17.	Owler BK, Allan R, Parker G, Besser M. Pseudotumour cerebri, CSF rhinorrhoea and the role of venous sinus stenting in treatment. Br J Neurosurg 2003;17:79-83.
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Figures

  [Figure 1], [Figure 2], [Figure 3]