Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome.

BACKGROUND: The gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis, and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition. RESULTS: In this study, we integrated and interrogated multi-omics data from different organs with fecal 16S rRNA sequences and systemic metabolic phenotypic data using a Transkingdom Network Analysis. By incorporating cell type information from single-cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reduced levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo. CONCLUSIONS: Our findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes of diet-induced obesity and metabolic syndrome. TXN primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in white adipose tissue. Video Abstract.

Replicability in measures of attentional set-shifting task performance predicting chronic heavy drinking in rhesus monkeys.

This study was designed to replicate and extend a previous report that the increase in performance of an attentional set-shifting task (ASST) in rhesus monkeys predicted their future alcohol drinking status as a heavy drinker (HD) or non-heavy drinker (NHD). A cohort of 6 young adult male monkeys was trained and tested under the same ASST and then underwent a alcohol self-administration protocol that maintained open-access (22 hours/day) choice of alcohol or water 7 days/week for approximately 6 months. The average improvement in performance in the ASST, as measured by a performance index, was replicated in the cohort of 6 monkeys when compared to the increase in the task performance in a previous cohort of 9 male monkeys. The alcohol self-administration protocol was then used to determine the drinking status (HD: n = 4 or NHD: n = 2) of the replicate cohort, which was accurately predicted by the performance on the ASST. Finally, individuals from both cohorts could be combined based on future drinking status of HD (n = 8) or NHD (n = 7), and the association with pre-alcohol ASST performance remained. Specifically, monkeys that had lower rates of PI improvement were more likely to become HDs. To our knowledge, this is the first study to replicate that deficits in the set-shifting performance can predict chronic heavy alcohol drinking in primates.

One-stage oblique lateral corridor antibiotic-cement reconstruction for Candida spondylodiscitis in patients with major comorbidities: Preliminary experience.

Fungal spondylodiscitis is rare (0.5%-1.6% of spondylodiscitis) and mainly caused by Candida albicans. Surgical intervention in spondylodiscitis patients is indicated for compression of neural elements, spinal instability, severe kyphosis, failure of conservative management and intractable pain. However, there is no evidence-based optimal surgical approach for spondylodiscitis. There have been only case reports of surgical treatment for Candida spondylodiscitis. We evaluated the preliminary results of the efficacy and safety of one-stage debridement via oblique lateral corridor with interbody fusion (OLIF) using stand-alone cement reconstruction after debridement for the treatment of Candida spondylodiscitis in patients with major co-morbidities. Five patients (4 males, 1 female, mean age: 64.2 years) suffering from Candida albicans lumbar spondylodiscitis who underwent this procedure were studied. Their predominant symptoms were unremitting back and leg pain and all had pre and postoperative anti-fungal therapy under microbiologist supervision. The operative time ranged from 137minutes to 260minutes (mean: 213.4minutes). The mean blood loss was 160mL (range: 100-200mL). There were no perioperative complications. At follow-up all showed major improvement in pain and ambulatory status. CT scan showed radiological stability for all patients at 6-12 months. Our preliminary results showed stand-alone anterior debridement and spinal re-construction with cement through mini-open OLIF approach might be a safe and effective option for patients with spinal fungal infection and major comorbidities.

Long-term complications of minimally-open anterolateral interbody fusion for L5-S1.

BACKGROUND: Multiple surgical techniques and approaches exist to obtain lumbar interbody fusion. Anterolateral (oblique) is a relatively recent technique. Controversy exists for its use at the L5-S1 level. We performed this study in order to show the safety and efficacy of this technique. The aim of this study was to report the long-term complications and fusion rates of minimally-open (mini-open) anterolateral interbody fusion at the L5-S1 level. METHODS: We retrospectively analyzed all patients who underwent mini-open anterolateral interbody fusion for L5-S1 level in our department. The data collected were the following: age, sex, surgical indication, acute (less than four weeks) and long-term complications (>3 months), fusion at six months and length of follow-up. RESULTS: Seventeen patients (8M/9F) underwent mini-open anterolateral interbody fusion at L5-S1. The mean age was 64.5 years. The surgical indication was scoliosis in 10 cases, flat back in 4 cases, and spondylolisthesis in 3 cases. All patients underwent a complementary posterior procedure that included fixation. Mean blood loss was 252.9mL for the anterior procedure. Eight acute and minor complications occurred (anemia, delirium, and psoas paresis). Two acute complications required surgical intervention (cage displacement and hematoma). Long-term complications were observed in 2 cases and included proximal junction kyphosis and non-union. The fusion rate was evaluated at 88%. The mean follow-up period was 28.3 months. CONCLUSIONS: Mini-open anterolateral interbody fusion at the L5-S1 level is safe and results in fusion at the same rate as anterior interbody fusion. Most acute complications are minor and resolve spontaneously.

Differing presenting features of idiopathic intracranial hypertension in the UK and US.

AIM: Demographic factors potentially influencing the presentation and severity of idiopathic intracranial hypertension (IIH) in the US vs. UK populations include obesity and ethnicity. We aimed to compare the presenting features of IIH between populations in the UK and US tertiary referral centres, to assess what population differences exist and whether these cause different presentations and impact on visual function. METHODS: Clinical data were collected on 243 consecutive UK IIH patients and 469 consecutive US IIH patients seen after 2012 in two tertiary centres. Visual function was defined as severe visual loss when Humphrey visual field mean deviation was <-15 dB, when Goldmann visual fields showed constriction or when visual acuity was <20/200. RESULTS: US patients were more commonly of self-reported black race (58.9% vs. 7.1%) than UK patients, but had a similar mean body mass index (38.3 ± 0.63kg/m2 UK vs. 37.7 ± 0.42kg/m2 US; p = 0.626). The UK cohort had lower presenting Frisén grade (median 1 vs. 2; p < 0.001) and severe visual loss less frequently (15.4% vs. 5%; p = 0.014), but there was no difference in mean cerebrospinal fluid-opening pressure (CSF-OP) (35.8 ± 0.88cmH2O UK vs. 36.3 ± 0.52cmH2O US; p = 0.582). African Americans had poorer visual outcomes compared with US whites (19.4% vs. 10% severe visual loss; p = 0.011). Visual function was weakly associated with CSF-OP (R2 = 0.059; p = 0.001), which was similar between UK and US patients. CONCLUSIONS: The UK and the US cohorts had a similar average presenting BMI. However, the worse presenting visual function in the US IIH cohort was partially attributable to differences in the black populations in the two countries.

Noninvasive Assessment of Intracranial Pressure Status in Idiopathic Intracranial Hypertension Using Displacement Encoding with Stimulated Echoes (DENSE) MRI: A Prospective Patient Study with Contemporaneous CSF Pressure Correlation.

BACKGROUND AND PURPOSE: Intracranial pressure is estimated invasively by using lumbar puncture with CSF opening pressure measurement. This study evaluated displacement encoding with stimulated echoes (DENSE), an MR imaging technique highly sensitive to brain motion, as a noninvasive means of assessing intracranial pressure status. MATERIALS AND METHODS: Nine patients with suspected elevated intracranial pressure and 9 healthy control subjects were included in this prospective study. Controls underwent DENSE MR imaging through the midsagittal brain. Patients underwent DENSE MR imaging followed immediately by lumbar puncture with opening pressure measurement, CSF removal, closing pressure measurement, and immediate repeat DENSE MR imaging. Phase-reconstructed images were processed producing displacement maps, and pontine displacement was calculated. Patient data were analyzed to determine the effects of measured pressure on pontine displacement. Patient and control data were analyzed to assess the effects of clinical status (pre-lumbar puncture, post-lumbar puncture, or control) on pontine displacement. RESULTS: Patients demonstrated imaging findings suggesting chronically elevated intracranial pressure, whereas healthy control volunteers demonstrated no imaging abnormalities. All patients had elevated opening pressure (median, 36.0 cm water), decreased by the removal of CSF to a median closing pressure of 17.0 cm water. Patients pre-lumbar puncture had significantly smaller pontine displacement than they did post-lumbar puncture after CSF pressure reduction (P = .001) and compared with controls (P = .01). Post-lumbar puncture patients had statistically similar pontine displacements to controls. Measured CSF pressure in patients pre- and post-lumbar puncture correlated significantly with pontine displacement (r = 0.49; P = .04). CONCLUSIONS: This study establishes a relationship between pontine displacement from DENSE MR imaging and measured pressure obtained contemporaneously by lumbar puncture, providing a method to noninvasively assess intracranial pressure status in idiopathic intracranial hypertension.

Confounding factors associated with oral mucositis assessment in patients receiving chemoradiotherapy for head and neck cancer.

PURPOSE: The aim of this study was to identify patient-centered, mucositis-associated adverse impact factors and events that might confound physician-assessed oral mucositis (OM) in head and neck cancer (HNC) patients receiving chemoradiotherapy. METHODS: This was a post hoc analysis of a previously conducted randomized trial to determine the efficacy of 5% phenylbutyrate mouthwash in preventing chemoradiotherapy-induced OM. This analysis identified patient-centered symptomatic, observable, and measurable factors that may confound physician scoring of the severity of OM during chemoradiotherapy. Confounding factors were then combined with physician-rated OM scores according to World Health Organization (WHO) and OM Assessment Scale (OMAS) criteria to investigate the therapeutic implications of OM treatment. RESULTS: The original analysis found no significant differences between experimental and placebo groups with respect to the cumulative incidence of physician-recorded severe OM (WHO ≥3 or OMAS ≥2), patient-reported adverse events, and opioid use. However, patients in the experimental arm had relatively lower rates of OM-associated adverse clinical issues including unplanned short radiation breaks, skipping of chemotherapy, nausea/vomiting, late loss of body weight, and early opioid use, all of which could potentially interfere with physician-assessed OM scoring. When WHO OM grade (functional impact and pain), OMAS ulceration size (organic impact), and prolonged radiation treatment time (cancer treatment impact) were combined, there were significantly fewer interruptions of chemoradiotherapy treatment in symptomatic OM patients in the experimental compared to the placebo group. The benefits conferred by reducing the amount of chemoradiotherapy-related, OM-associated adverse impacts in the experimental group were reflected by better 5-year locoregional recurrence-free survival. CONCLUSIONS: This exploratory study raises questions as to whether the severity reflected by physician-rated OM scores is in concordance with OM-induced adverse impacts on HNC patients. Further investigations are warranted to identify patient-related and cancer-associated symptom burdens that may affect tolerance, compliance, and outcome of chemoradiotherapy and confound the evaluation of therapeutic effects on chemoradiotherapy-induced OM.

Functional and simulated visual loss.

Nonorganic visual loss (NOVL) is the cause of a large number of referrals to neurologists and ophthalmologists and is a frequent area of overlap between neurologists, ophthalmologists, and psychiatrists. NOVL is the presence of visual impairment without an organic cause for disease despite a thorough and comprehensive investigation. A diagnosis of NOVL requires both the absence of any findings on examination and proof of the integrity and functioning of the visual system. Although sometimes a challenging diagnosis to make, there are a number of techniques and maneuvers which can be utilized fairly easily, either at the bedside or in the clinic, to help determine if a patient has NOVL. In some instances specialized testing, such as formal visual field testing, optical coherence tomography, visual evoked responses, electroretinogram, and various imaging modalities (magnetic resonance imaging) are performed to help determine if the cause of visual loss is organic or nonorganic. Once a diagnosis of NOVL is made, treatment centers around reassurance of the patient, close follow-up, and, if necessary, referral to a psychiatrist, as these patients may have underlying psychiatric disorders and a preceding strong emotional event leading to the current symptoms, and may be more likely to develop depression and anxiety.

Dynamics of wound healing signaling as a potential therapeutic target for radiation-induced tissue damage.

We hypothesized the histone deacetylase inhibitor phenylbutyrate (PB) has beneficial effects on radiation-induced injury by modulating the expression of DNA repair and wound healing genes. Hamsters received a radiosurgical dose of radiation (40 Gy) to the cheek and were treated with varying PB dosing regimens. Gross alteration of the irradiated cheeks, eating function, histological changes, and gene expression during the course of wound healing were compared between treatment groups. Pathological analysis showed decreased radiation-induced mucositis, facilitated epithelial cell growth, and preventing ulcerative wound formation, after short-term PB treatment, but not after vehicle or sustained PB. The radiation-induced wound healing gene expression profile exhibited a sequential transition from the inflammatory and DNA repair phases to the tissue remodeling phase in the vehicle group. Sustained PB treatment resulted in a prolonged wound healing gene expression profile and delayed the wound healing process. Short-term PB shortened the duration of inflammatory cytokine expression, triggered repeated pulsed expression of cell cycle and DNA repair-regulating genes, and promoted earlier oscillatory expression of tissue remodeling genes. Distinct gene expression patterns between sustained and short-term treatment suggest dynamic profiling of wound healing gene expression can be an important part of a biological therapeutic strategy to mitigate radiation-related tissue injury.

Evolving blood pressure dynamics for extremely preterm infants.

OBJECTIVE: To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants. STUDY DESIGN: Prospective observational study of infants 23(0/7) to 26(6/7) weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 h. RESULT: A cohort of 367 infants had 18 709 ABP measurements recorded. ABP decreased for the first 3 h, reached a nadir at 4 to 5 h and then increased at an average rate of 0.2 mm Hg h(-1). The rise in ABP from hour 4 to 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135) or dopamine (n=92). GA-specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA. CONCLUSION: ABP increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.

Evaluating retinopathy of prematurity screening guidelines for 24- to 27-week gestational age infants.

OBJECTIVE: To determine whether current retinopathy of prematurity (ROP) screening guidelines adequately identify treatable ROP in a contemporary cohort of extremely low gestation infants. STUDY DESIGN: Data from the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial were used. Inborn infants of 24 (0)/7 to 27 (6)/7 weeks gestational age (GA) with consent before delivery were enrolled in 2005 to 2009. Severe ROP (type 1 ROP or treatment with laser, cryotherapy or bevacizumab) or death was the primary outcome for the randomized trial. Examinations followed the then current AAP (American Academy of Pediatrics) screening recommendations, beginning by 31 to 33 weeks postmenstrual age (PMA). RESULT: One thousand three hundred and sixteen infants were enrolled in the trial. Nine hundred and ninety-seven of the 1121 who survived to first eye exam had final ROP outcome determined. One hundred and thirty-seven (14% of 997) met criteria for severe ROP and 128 (93%) of those had sufficient data (without missing or delayed exams) to determine age of onset of severe ROP. PMA at onset was 32.1 to 53.1 weeks. In this referral center cohort, 1.4% (14/997) developed severe ROP after discharge. CONCLUSION: Our contemporary data support the 2013 AAP screening guidelines for ROP for infants of 24 (0)/7 to 27 (6)/7 weeks GA. Some infants do not meet treatment criteria until after discharge home. Post-discharge follow-up of infants who are still at risk for severe ROP is crucial for timely detection and treatment.

Outcomes of extremely preterm infants following severe intracranial hemorrhage.

OBJECTIVE: Severe intracranial hemorrhage (ICH) is an important prognostic variable in extremely preterm (EPT) infants. We examined imaging and clinical variables that predict outcomes in EPT infants with severe ICH. STUDY DESIGN: Retrospective analysis of 353 EPT infants with severe ICH. Outcomes were compared by examining: (i) unilateral vs bilateral ICH; and (ii) presence vs absence of hemorrhagic parenchymal infarction (HPI). Regression analyses identified variables associated with death or neurodevelopmental impairment (NDI). RESULT: Bilateral ICH and HPI had higher rates of adverse outcomes and were independently associated with death/NDI. HPI was the most important variable for infants of lower birth weight, and bilateral ICH for larger infants. For infants surviving to 36 weeks, shunt placement was most associated with death/NDI. CONCLUSION: Bilateral ICH and the presence of HPI in EPT infants with severe ICH are associated with death/NDI, though the importance depends on birth weight and survival to 36 weeks.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer.

Peritoneal carcinomatosis (PC) arising from colorectal cancer (CRC) is generally considered a terminal condition with few treatment options. However, over the past few decades, new chemotherapeutic and biologic agents have improved the median overall survival of patients with unresectable metastatic disease up to 20 months. There has also been emergence of combining cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with PC. The literature supporting such an approach is significant, though not extensive, mainly consisting of small single-institution series, one international multicenter retrospective review, and one single-institution prospective randomized trial. Yet, there is remarkable homogeneity among the reported clinical outcomes, demonstrating 5-year OS rates of approximately 25-40% for patients undergoing a complete cytoreduction. These studies have fueled increasing interest in the use of CS and HIPEC for metastatic colorectal cancer over the past decade. However, despite the publication of a consensus statement on the role of CS and HIPEC for PC from CRC, there is still controversy regarding its appropriateness, effectiveness, safety, and application in this subset of patients. In this review we analyze the currently available scientific evidence supporting the clinical application of CS and HIPEC in the treatment of PC of colorectal origin.

Spinning disk for compressive imaging.

We report the first, to the best of our knowledge, experimental implementation of a spinning-disk configuration for high-speed compressive image acquisition. A single rotating mask (i.e., the spinning disk) with random binary patterns was utilized to spatially modulate a collimated terahertz (THz) or IR beam. After propagating through the sample, the THz or IR beam was measured using a single detector, and THz and IR images were subsequently reconstructed using compressive sensing. We demonstrate that a 32-by-32 pixel image could be obtained from 160 to 240 measurements in both the IR and THz ranges. This spinning-disk configuration allows the use of an electric motor to rotate the spinning disk, thus enabling the experiment to be performed automatically and continuously. This, together with its compact design and computational efficiency, makes it promising for real-time imaging applications.

Phenylbutyrate suppresses distinct skin reactions that are enhanced by blockade of epidermal growth factor receptor signaling.

BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) cause skin inflammation, and understanding the factors that mediate this reaction is fundamental for designing therapies for EGFRI-related cutaneous side effects. OBJECTIVE: We characterized EGFRI-enhanced skin reactions and evaluated the therapeutic efficacy of phenylbutyrate, a histone deacetylase inhibitor. METHODS: PD168393, an EGFRI, was applied topically to the ear skin of mice with or without mast cell deficiency. The skin was then irritated once or pre-sensitized and repeatedly challenged with 2,4-dinitrofluorobenzene (DNFB). The reaction pattern, the type and number of infiltrating cells, changes in protein, cytokine (TNF-α) and chemokine (CCL2) expression, and the immune response were analyzed. Phenylbutyrate, formulated as a gel for topical treatment or dissolved in water for intraperitoneal administration, was tested as a treatment. RESULTS: EGFRI rapidly upregulated the mast cell chemotactic factor, stem cell factor (SCF) and augmented DNFB-induced immediate contact dermatitis within hours of treatment in the presence of mast cells. Topical phenylbutyrate treatment suppressed EGFRI-induced SCF expression in the epithelium, inhibited DNFB-induced mast cell recruitment in the dermis, and ameliorated the EGFRI-enhanced acute skin reaction. EGFRI also enhanced the delayed-type DNFB-induced hypersensitive reaction that was mast-cell independent but was associated with T lymphocytes. Systemic phenylbutyrate administration suppressed EGFRI-enhanced delayed-type skin hypersensitivity by increasing the number and function of Foxp3(+) T regulatory suppressor cells, which inhibited T helper cell proliferation. CONCLUSIONS: Our data suggest that phenylbutyrate has dual beneficial therapeutic effects on EGFRI-enhanced acute (local inflammatory) and late (systemic immune) skin reactions.

Optical coherence tomography (OCT) in optic neuritis and multiple sclerosis.

Optical coherence tomography (OCT) is a non-invasive imaging technique routinely used in ophthalmology to visualize and quantify the layers of the retina. It also provides information on optic nerve head topography, peripapillary retinal nerve fiber layer thickness, and macular volume, which correlate with axonal loss. These measurements are of particular interest in optic neuropathies and in multiple sclerosis, and OCT parameters are now used as endpoints in neurologic clinical trials.

Atypical idiopathic intracranial hypertension: normal BMI and older patients.

BACKGROUND: Idiopathic intracranial hypertension (IIH) typically affects young, obese women. We examined 2 groups of atypical patients with IIH: those with a normal body mass index (BMI) and those at least 50 years of age. METHODS: A retrospective cohort study of 407 consecutive adult patients with IIH with known BMI from 3 centers was undertaken. Demographics, associated factors, visual acuity, and visual fields were collected at presentation and follow-up. RESULTS: We identified 18 IIH patients (4%) with normal BMI and 19 (5%) aged 50 years or older at the time of diagnosis who were compared with the remainder of the cohort. Medication-induced IIH was more frequent in patients with IIH with normal BMI (28 vs 7%, p = 0.008). No patient with IIH with a normal BMI had severe visual loss in either eye (0 vs 17%, p = 0.09). Older patients with IIH had a lower BMI, but were still generally obese (33 vs 38, p = 0.04). Older patients were less likely to report headache as initial symptom (37 vs 76%, p < 0.001) and more likely to complain of visual changes (42 vs 21%, p = 0.03). Treatment of any type was less likely in older patients (significant for medications: 74 vs 91%, p = 0.004), and they were more likely to have persistent disc edema at last follow-up (median Frisén grade: 1 vs 0, p = 0.002), but had similar, if not better, visual outcomes compared with younger patients. A case-control study did not identify any new medication or risk factor associations. CONCLUSIONS: Patients with normal body mass index and those 50 years or older make up a small proportion of patients with idiopathic intracranial hypertension (IIH), but appear to have better visual outcomes than more typical patients with IIH.

Suppression of the critical temperature of superconducting NdFeAs(OF) single crystals by Kondo-like defect sites induced by alpha-particle irradiation.

We report the effect of alpha-particle irradiation on the reduction of the critical temperature T{c} of a NdFeAs(OF) single crystal. Our data indicate that irradiation defects cause both nonmagnetic and magnetic scattering, resulting in the Kondo-like excess resistance Delta rho(T) proportional to lnT over 2 decades in temperatures above T{c}. The critical density of magnetic irradiation defects which suppresses T{c} is found to be much higher than those for cuprates and multiband BCS superconductors. We suggest that such anomalously weak pair breaking by irradiation defects indicates that magnetic scattering in pnictides is coupled with pairing interactions mediated by spin fluctuations.