Background and Purpose
Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, ...the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate.
Experimental Approach
Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross‐over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT‐qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions.
Key Results
We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24‐h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium‐dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes.
Conclusions and Implications
Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP.
Single nucleotide polymorphisms (SNPs) in insulin and insulin receptor genes may influence the interaction between the two molecules, as may anti-insulin antibodies (IAs), commonly found in patients ...with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) treated with exogenous insulin. We examined the impact of two SNPs in the human insulin gene (INS), rs3842752 and rs689, and two in the insulin receptor gene (INSR) rs2245649 and rs2229429, on disease susceptibility, glycaemic control, and IAs formation in 100 T1D patients and 101 T2D patients treated with insulin. 79 individuals without diabetes were typed as healthy controls. The minor alleles of rs3842752 and rs689 in INS protected against T1D (OR: 0.50, p = 0.01 and OR: 0.44; p = 0.002, respectively). The minor alleles of both rs2245649 and rs2229429 in INSR were risk factors for poor glycaemic control (HbA1c ≥ 80 mmol/mol) in T1D (OR: 5.35, p = 0.009 and OR: 3.10, p = 0.01, respectively). Surprisingly, the minor alleles of rs2245649 and rs2229429 in INSR associated strongly with the absence of IAs in T1D (OR = 0.28, p = 0.008 and OR = 0.30, p = 0.002, respectively). In conclusion, the minor alleles of the investigated INS SNPs protect against T1D, and the minor alleles of the investigated INSR SNPs are associated with poor glycaemic control and the absence of IAs in T1D.
Thyroid eye disease (TED) is a serious condition that can cause proptosis and strabismus and, in rare cases, lead to blindness. Incidence data for TED and strabismus and surgical interventions after ...TED are sparce.
To investigate the nationwide incidence of TED, strabismus, and surgical interventions associated with TED.
A Danish nationwide registry-based cohort study between 2000, which marks the beginning of uniform coding for the decompression surgery nationwide, and 2018. The cohort consisted of a mean 4.3 million people aged 18 to 100 years with no prior TED diagnosis each year. Total observation time was 8.22 × 107 person-years (women, 4.18 × 107 person-years; men, 4.04 × 107 person-years).
The annual numeric and age-standardized incidence of hospital-treated TED and cumulative incidence of strabismus, strabismus surgery, and orbital decompression surgery in patients with TED. The incidence was stratified by sex, thyroid diagnosis, and age.
A total of 4106 incident diagnoses of TED were identified during 19 years among 3344 women (81.4%) and 762 men (18.6%). The mean numeric annual nationwide incidence rate of TED was 5.0 per 100 000 person-years overall, 8.0 per 100 000 person-years in women, and 1.9 per 100 000 person-years in men, resulting in a 4:1 ratio of women to men with TED. The age-standardized incidence was similar. The mean (SD) age at onset was 51.3 (14.5) years. At the time of TED diagnosis, 611 patients (14.9%) were euthyroid, 477 (11.6%) were hypothyroid, and 3018 (73.5%) were hyperthyroid. In patients with TED who were euthyroid, the 4-year cumulative incidence was 41% for antithyroid medication and 13% for L-thyroxine. In patients with TED, the 4-year cumulative incidence for strabismus was 10%. The 4-year cumulative incidence of surgical interventions after TED was 8% for strabismus surgery and 5% for orbital decompression. At 4 years, strabismus surgery was more common in men (13.3%; 95% CI, 10.75-15.86) than in women (7.2%; 95% CI, 6.24-8.08), and the absolute difference was 6.1% (95% CI, 3.42-8.14; P < .001).
This study in Denmark provides nationwide empirical incidence of TED and strabismus and surgical interventions after TED that required inpatient or outpatient hospital treatment, and might be used for patient information and health care planning.
Large studies investigating clinical presentation and treatment in primary conjunctival melanoma (CM) are rare. Clinicopathological characteristics of BRAF-mutated CM have not been studied ...thoroughly.
To determine the associations of clinicopathological tumor features and treatment with local recurrence, metastasis, and mortality and to determine the association of BRAF mutations with these features.
Population-based cohort study at the Eye Pathology Institute, Copenhagen, Denmark. Participants included 139 patients with primary CM in Denmark from January 1, 1960, to December 31, 2012. For BRAF analysis, all patients with available formalin-fixed, paraffin-embedded tumor samples from January 1, 1994, to December 31, 2012, were included.
BRAF mutations, local recurrence, regional and distant metastasis, melanoma-related mortality, and all-cause mortality were examined.
A poor prognosis of tumors involving the extrabulbar conjunctiva and adjacent tissue structures was confirmed in multivariable Cox proportional hazards regression models. Patients undergoing incisional biopsy more frequently developed metastasis (hazard ratio HR, 2.46; 95% CI, 1.08-5.58; P = .03). Excision without adjuvant treatment was associated with local recurrence (HR, 1.97; 95% CI, 0.11-3.48; P = .02), metastatic disease (HR, 2.51; 95% CI, 1.07-5.91; P = .03), and all-cause mortality (HR, 1.80; 95% CI, 1.05-3.08; P = .03). BRAF mutations were identified in 19 of 47 primary CMs (40.4%) and were more frequent in younger patients (P = .005), less frequent in the extrabulbar conjunctiva (P = .05), more frequently classified as T1 tumors (P = .03), and rarely manifested with primary acquired melanosis (P = .001) or with a uniformly pigmented lesion (P = .006). Distant metastases developed in 6 of 19 BRAF-mutated CMs (31.6%) as opposed to 1 of 28 BRAF wild-type CMs (3.6%). No definitive association with distant metastasis was seen in multivariable Cox proportional hazards regression models.
Incisional biopsy and excision without adjuvant therapy were associated with a poor outcome in patients with CM. Extrabulbar location was also associated with a poor outcome in multivariable analysis. BRAF-mutated CMs were frequent in younger patients and were rare in tumors involving the extrabulbar conjunctiva. Despite a more favorable location, BRAF-mutated tumors may be associated with more frequent distant metastasis.
Purpose Increasing evidence indicates that statin use may reduce mortality from prostate cancer. In this work, we examined whether postdiagnosis statin use was associated with reduced cancer-specific ...mortality or all-cause mortality among patients with prostate cancer in Denmark. Material and Methods From nationwide Danish registries, we identified all patients with incident prostate adenocarcinoma from 1998 to 2011 and retrieved data on tumor and patient characteristics, drug use, and primary treatment. We defined postdiagnosis use (two or more prescriptions) of statins as a time-varying covariate with 1-year lag. Cox proportional hazards regression models used to compute hazard ratios (HRs) for prostate cancer-specific mortality and all-cause mortality through 2013 associated with postdiagnosis statin use. In secondary and sensitivity analyses, we assessed statin use within exposure periods of 1 year or 5 years after prostate cancer diagnosis and evaluated the influence of prediagnosis statin use. Results Among 31,790 patients, 7,365 died of prostate cancer and 11,811 died from other causes during a median follow-up of 2.8 years (interquartile range, 1.3 to 5.1 years) from 1 year after diagnosis. Postdiagnosis statin use was associated with adjusted HRs of 0.83 (95% CI, 0.77 to 0.89) for prostate cancer mortality and 0.81 (95% CI, 0.76 to 0.85) for all-cause mortality. Similar results were observed in 1-year and 5-year sensitivity analyses. No substantial effect measure modification was found with estimated dose or type of statin, clinical stage, Gleason score, or with prediagnosis statin use; however, patients who were diagnosed early in the study period or who underwent radical prostatectomy or endocrine therapy exhibited slightly lower HRs for prostate cancer mortality with postdiagnosis statin use than did those in the overall analyses. Conclusion Postdiagnosis statin use was associated with reduced mortality from prostate cancer; however, it remains to be established whether this association is causal.
Fluorescence spectroscopy of gas-phase ions generated through electrospray ionization is an emerging technique able to probe intrinsic molecular photophysics directly without perturbations from ...solvent interactions. While there is ample scope for the ongoing development of gas-phase fluorescence techniques, the recent expansion into low-temperature operating conditions accesses a wealth of data on intrinsic fluorophore photophysics, offering enhanced spectral resolution compared with room-temperature measurements, without matrix effects hindering the excited-state dynamics. This perspective reviews current progress on understanding the photophysics of anionic fluorone dyes, which exhibit an unusually large Stokes shift in the gas phase, and discusses how comparison of gas- and condensed-phase fluorescence spectra can fingerprint structural dynamics. The capacity for temperature-dependent measurements of both fluorescence emission and excitation spectra helps establish the foundation for the use of fluorone dyes as fluorescent tags in macromolecular structure determination. We suggest ideas for technique development.
The ion motion in a quadrupole ion trap of hyperbolic geometry is well described by the Mathieu equations. A simpler cylindrical ion trap has also gained significance and has been used by us for ...fluorescence-spectroscopy experiments. This design allows for the easy replacement of the end-cap with a mesh, enhancing the photon collection. It is crucial to obtain a firm understanding of the ion motion in cylindrical ion traps and their capability as mass spectrometers. We present here an empirical method of calibrating a cylindrical ion trap based on fluorescence detection. This can be done nearly background-free in a pulsed experiment. The ions are located at the center of the trap, where the field is primarily quadrupolar, and here an effective Mathieu description is found through an effective geometry parameter. In spectroscopy experiments, high buffer-gas pressures are needed to efficiently cool the ions, which complicates the ions’ motion and hence their stability. Still, simulations show that the stability diagram closely aligns with the Mathieu diagram, albeit shifted due to collisions. We map the stability diagram for six molecular ions by fluorescence collection from four cations and two anions spanning m/z from 212 to 647. The stability diagram is parametrized through the Mathieu functions with an m/z-dependent effective geometry parameter and a q-dependent shrinkage of the diagram. Based on the calibration, we estimate the mass resolution to be +7/–3 Da for ions with masses in the hundreds of Da.
Purpose
To investigate incidence, clinicopathological features and prognosis of BRAF‐mutated conjunctival melanoma in Denmark. Furthermore, to determine BRAF mutations in paired premalignant lesions ...and evaluate immunohistochemical BRAF V600E oncoprotein detection.
Methods
Data from 139 patients with conjunctival melanoma (1960–2012) were collected. Archived conjunctival melanoma samples and premalignant lesions were analysed for BRAF mutations using droplet digital polymerase chain reaction (PCR). Results were associated with clinicopathological features and compared with BRAF V600E oncoprotein stainings.
Results
The overall incidence of conjunctival melanoma (0.5 cases/1 000 000/year) increased during the study period with 0.13 cases/1 000 000/10 years. The increase comprised a higher proportion of patients aged >65 years, epibulbar tumours and tumours developed from a primary acquired melanosis with atypia. BRAF mutations were identified in 39 of 111 (35%) cases. The rate ratio of BRAF‐mutated versus BRAF‐wild‐type melanoma did not change over time. BRAF mutations were associated with T1 stage (p = 0.007), young age (p = 0.001), male gender (p = 0.02), sun‐exposed location (p = 0.01), mixed/non‐pigmented tumour colour (p = 0.02) and nevus origin (p = 0.005), but did not associate with prognosis. BRAF status in conjunctival melanoma and paired premalignant lesions corresponded in 19 of 20 cases. Immunohistochemistry detected BRAF V600E mutations with a sensitivity of 0.94 and a specificity of 1.00 in newer conjunctival melanoma samples (2000–2012, n = 47).
Conclusion
The incidence of conjunctival melanoma increased in Denmark over 50 years. The proportion of BRAF‐mutated conjunctival melanoma was constant. BRAF mutations were identified as early events in conjunctival melanoma, associated with a distinct clinicopathological profile, similar to BRAF‐mutated cutaneous melanoma. Immunohistochemical detection of BRAF can be used to assess BRAF V600E mutations.
Abstract
REQUIEM-2D (Resolving Quiescent Magnified Galaxies with 2D Grism Spectroscopy) comprises a sample of eight massive (
log
(
M
∗
/
M
⊙
)
>
10.6
) strongly lensed quiescent galaxies at
z
∼ 2. ...REQUIEM-2D combines the natural magnification from strong gravitational lensing with the high-spatial-resolution grism spectroscopy of the Hubble Space Telescope through a spectrophotometric fit to study spatially resolved stellar populations. We show that quiescent galaxies in the REQUIEM-2D survey have diverse formation histories with age gradients at the 1
σ
–3
σ
level, including examples of (1) a younger central region supporting outside-in formation, (2) flat age gradients that show evidence for both spatially uniform early formation and inside-out quenching, and (3) regions at a fixed radial distance having different ages (such asymmetries cannot be recovered when averaging stellar population measurements azimuthally). The typical dust attenuation curve for the REQUIEM-2D galaxies is constrained to be steeper than Calzetti’s law in the UV and generally consistent with
A
V
< 1. Combined together and accounting for the different physical radial distances and formation timescales, we find that the REQUIEM-2D galaxies that formed earlier in the universe exhibit slow and uniform growth in their inner core, whereas the galaxies that formed later have rapid inner growth in their inner core with younger ages than the outskirts. These results challenge the currently accepted paradigm of how massive quiescent galaxies form, where the earliest galaxies are thought to form most rapidly. Significantly larger samples close to the epoch of formation with similar data quality and higher spectral resolution are required to validate this finding.
Abstract
In this Letter, we reconstruct the formation pathway of MRG-S0851, a massive,
log
M
*
/
M
⊙
=
11.02
±
0.04
, strongly lensed, red galaxy at
z
= 1.883 ± 0.001. While the global photometry and ...spatially resolved outskirts of MRG-S0851 imply an early formation scenario with a slowly decreasing or constant star formation history, a joint fit of 2D grism spectroscopy and photometry reveals a more complex scenario: MRG-S0851 is likely to be experiencing a centrally concentrated rejuvenation in the inner ∼1 kpc in the last ∼100 Myr of evolution. We estimate 0.5 ± 0.1% of the total stellar mass is formed in this phase. Rejuvenation episodes are suggested to be infrequent for massive galaxies at
z
∼ 2, but as our analyses indicate, more examples of complex star formation histories may yet be hidden within existing data. By adding an FUV color criterion to the standard
U–V
/
V–J
diagnostic—thereby heightening our sensitivity to recent star formation—we show that we can select populations of galaxies with similar spectral energy distributions to that of MRG-S0851, but note that deep follow-up spectroscopic observations and/or spatially resolved analyses are necessary to robustly confirm the rejuvenation of these candidates. Using our criteria with MRG-S0851 as a prototype, we estimate that ∼1% of massive quiescent galaxies at 1 <
z
< 2 are potentially rejuvenating.
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