Citations

Abstract Objective: The need for effective nonhormonal treatments for hot flash management without unwanted side effects continues. The primary aim of this pilot study was to evaluate the effect of combining a nonhormonal pharmacologic agent with a behavioral treatment for hot flash reduction. Methods: Seventy-one postmenopausal women were randomized to one of four groups: venlafaxine 75 mg + hypnosis (VH) versus venlafaxine 75 mg + sham hypnosis (VSH) versus a placebo pill + hypnosis (PH) versus placebo pill + sham hypnosis (PSH). Women recorded hot flash severity and frequency in a daily diary, in real time. The intrapatient difference in hot flash score (frequency × severity) at 8 weeks was analyzed using a General Estimating Equation model, using VSH as the referent arm, controlling for baseline hot flashes. Results: The active arms including PH or VH were not statistically significantly different than VSH (P = 0.34, P = 0.05, respectively). Women in each active arm reported hot flash reductions of about 50%, with the PSH group reporting a 25% reduction. Women receiving the PSH reported statistically significantly smaller reductions in hot flash score than women in the referent VSH arm (P = 0.001). There were no significant negative side effects during the course of the study. Conclusions: Hypnosis alone reduced hot flashes equal to venlafaxine alone, but the combination of hypnosis and venlafaxine did not reduce hot flashes more than either treatment alone. More research is needed to clarify whether combining hypnosis with a different antidepressant would provide synergistic benefits.

Background: Giant cell tumor (GCT) of bone is a benign, though locally aggressive tumor, classically described as an eccentric lytic lesion, often with cortical expansion and destruction. It typically involves the metaphysis or epiphysis of long bones in skeletally mature patients, with a slight female predominance. The incidence in the small bones of the hand has been reported to be 2% to 5%. Methods: Treatment options have evolved in recent years, and currently include intralesional curettage with or without adjuvant therapy, wide resection, and occasionally amputation. Results: In this report, we present a long-term follow-up (10 years) of a patient with GCT involving a metacarpal, who was initially reconstructed with a metacarpal head allograft, which was eventually revised to a metacarpophalangeal (MCP) total joint arthroplasty. Conclusions: To our knowledge, this is the only report of pyrocarbon being used for tumor reconstruction and the only report of late MCP allograft salvage.

Background: Oblique injuries are known to be a common cause of time out of play for professional baseball players, and prior work has suggested that injury rates may be on the rise in Major League Baseball (MLB). Purpose: To better understand the current incidence of oblique injuries, determine their impact based on time out of play, and to identify common injury patterns that may guide future injury prevention programs. Study Design: Descriptive epidemiological study. Methods: Using the MLB Health and Injury Tracking System, all oblique injuries that resulted in time out of play in MLB and Minor League Baseball (MiLB) during the 2011 to 2015 seasons were identified. Player demographics such as age, position/role, and handedness were included. Injury-specific factors analyzed included the following: date of injury, timing during season, days missed, mechanism, side, treatment, and reinjury status. Results: A total of 996 oblique injuries occurred in 259 (26%) MLB and 737 (74%) MiLB players. Although the injury rate was steady in MiLB, the MLB injury rate declined ( P = .037). A total of 22,064 days were missed at a mean rate of 4413 days per season and 22.2 days per injury. The majority of these occurred during batting (n = 455, 46%) or pitching (n = 348, 35%), with pitchers losing 5 days more per injury than batters ( P < .001). The leading side was injured in 77% of cases and took 5 days longer to recover from than trailing side injuries ( P = .009). Seventy-nine (7.9%) players received either a corticosteroid or platelet-rich plasma injection, and the mean recovery time was 11 days longer compared with those who did not receive an injection ( P < .001). Conclusion: Although the rate of abdominal oblique injuries is on the decline in MLB, this is not the case for MiLB, and these injuries continue to represent a significant source of time out of play in professional baseball. The vast majority of injuries occur on the lead side, and these injuries result in the greatest amount time out of play. The benefit of injections for the treatment of oblique injuries remains unknown.

PurposeIn diffusion MRI (dMRI), fractional anisotropy derived from the single‐tensor model (FADTI) is the most widely used metric to characterize white matter (WM) microarchitecture, despite known limitations in regions with crossing fibers. Due to time constraints when scanning patients in clinical settings, high angular resolution diffusion imaging acquisition protocols, often used to overcome these limitations, are still rare in clinical population studies. However, the tensor distribution function (TDF) may be used to model multiple underlying fibers by representing the diffusion profile as a probabilistic mixture of tensors.MethodsWe compared the ability of standard FADTIand TDF‐derived FA (FATDF), calculated from a range of dMRI angular resolutions (41, 30, 15, and 7 gradient directions), to profile WM deficits in 251 individuals from the Alzheimer's Disease Neuroimaging Initiative and to detect associations with 1) Alzheimer's disease diagnosis, 2) Clinical Dementia Rating scores, and 3) average hippocampal volume.ResultsAcross angular resolutions and statistical tests, FATDFshowed larger effect sizes than FADTI, particularly in regions preferentially affected by Alzheimer's disease, and was less susceptible to crossing fiber anomalies.ConclusionThe TDF “corrected” form of FA may be a more sensitive and accurate alternative to the commonly used FADTI, even in clinical quality dMRI data. Magn Reson Med 78:2322–2333, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition signifying the presence of a B-cell lymphoproliferative disorder. By connotation, it should not meet the definition of multiple myeloma, Waldenström macroglobulinemia, or lymphoma. In addition, it cannot be responsible for any end-organ damage. Similar to polyclonal immunoglobulins (Ig), monoclonal gammopathy has been increasingly recognized as an important cause of kidney disease. The recent introduction of the term “monoclonal gammopathy of renal significance” (MGRS) highlights this importance. MGRS is similar to MGUS in which the B-cell lymphoproliferative disorder has not reached a state considered to be malignant, but differentiates itself by the presence of a monoclonal gammopathy related kidney disease. This distinction is important since it separates MGRS, which is not benign, from the MGUS condition, which is benign. It also allows for a better classification of kidney diseases caused by monoclonal gammopathies. There are many renal diseases and lesions that have been identified to be secondary to MGRS. In addition, MGRS-associated renal diseases can mimic polyclonal Ig mediated kidney diseases. Kidney biopsy with immunofluorescence is the key for diagnosing MGRS-related kidney diseases. Once the diagnosis is made, a specific evaluation is needed for the diagnosis and treatment of MGRS-related kidney diseases that differs from the polyclonal Ig counterparts.

ABSTRACTHuman cerebral malaria (HCM) is a serious complication ofPlasmodium falciparuminfection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology.

Abstract Background: Epidemiologic associations of leukocyte telomere length (LTL) and pancreatic ductal adenocarcinoma (PDAC) have been inconsistent owing, in part, to variation in telomere length (TL) assessment across studies. To overcome this limitation and address concerns of potential reverse causation, we used carriage of telomere-related alleles to genetically predict TL and examined its association with PDAC. Methods: A case–control study of 1,500 PDAC cases and 1,500 controls, frequency-matched on age and sex was performed. Eight of nine polymorphisms previously associated with variation in LTL were analyzed. Genetic risk scores (GRS) consisting of the TL-related polymorphisms were computed as the number of long TL alleles carried by an individual scaled to published kilobase pairs of TL associated with each allele. Participants were further categorized on the basis of the number of short TL alleles they carry across all eight SNPs. Associations were examined in additive and dominant models using logistic regression to calculate ORs and 95% confidence intervals (CI). Results: In age- and sex-adjusted models, one short TL allele (rs10936599, T) was associated with reduced risk, whereas another short TL allele (rs2736100, A) was associated with increased risk, with per-allele ORs of 0.89 (95% CI, 0.79–0.99) and 1.13 (95% CI, 1.01–1.24), respectively. No association was observed with GRS or short TL allele counts, and no associations were observed in the dominant models. Conclusions: Findings suggest that genetically predicted short TL is not associated with PDAC risk. Impact: Common genetic determinants of short TL do not appear to influence PDAC risk. Cancer Epidemiol Biomarkers Prev; 26(6); 971–4. ©2017 AACR.

Background Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. Methods 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. Results For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. Conclusions Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.