Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma.

Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.

Incidental finding of a true human tail in an adult: a case report.

True human tails are rare vestigial structures that are typically removed in childhood. Here a case is presented in which an inconspicuous sacrococcygeal tail was incidentally discovered in late adulthood. A 56-year-old man with no significant past medical history presented to a dermatology clinic with a chief complaint of a hyperpigmented lesion on his central back. However, on full body skin exam, a separate flesh-colored 0.7 cm × 0.5 cm appendage was discovered in the midline sacrococcygeal region. This lesion had been present and unchanged since childhood. This particular lesion was removed via shave biopsy. Microscopic exam found it to be consistent with a diagnosis of a true human tail. There were no apparent involved spinal cord structures, and no further treatment was thought to be necessary. Human tails are congenital anomalies associated with occult spinal lesions in about 50% of cases. Therefore, it is in these patients' best interest to thoroughly evaluate for spinal cord involvement prior to biopsy. There is a relative lack of literature published on the topic, and a greater awareness of human tails would be helpful to ensure their inclusion in a differential diagnosis for persistent sacrococcygeal lesions in patients of any age.

Cutaneous infection caused by a novel Francisella sp.

A 69-year-old patient presented with a tender, thickly crusted skin lesion of 1 week's duration. A bacterial culture swab taken from the underlying granular tissue yielded a pure isolate of a Gram-negative coccobacillus, presumptively identified as a novel Francisella species via 16S rRNA and multilocus gene sequence analysis.

Dropout associated with osteopathic manual treatment for chronic noncancerous pain in randomized controlled trials.

CONTEXT: Reviews exploring harm outcomes such as adverse effects (AE), all cause dropouts (ACD), dropouts due to inefficacy, and dropouts due to AE associated with osteopathic manipulative treatment (OMT) or osteopathic manual therapy (OMTh) are scant. OBJECTIVES: To explore the overall AE, ACD, dropouts due to inefficacy, and AE in chronic noncancerous pain (CNCP) patients receiving OMTh through a systematic review of previous literature. METHODS: For this systematic review and meta-analysis, the authors searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Physiotherapy Evidence Database (PEDro), EMCare, and Allied and Complementary Medicine Database (AMED), and Ostmed.Dr, as well as the bibliographical references of previous systematic reviews evaluating OMTh for pain severity, disability, quality of life, and return to work outcomes. Randomized controlled trials with CNCP patients 18 years or older with OMTh as an active or combination intervention and the presence of a control or combination group were eligible for inclusion. In this sub-study of a previous, larger systematic review, 11 studies (n=1,015) reported data that allowed the authors to perform meta-analyses on ACD and dropouts due to AE. The risk of bias (ROB) was assessed with the Cochrane ROB tool and the quality of evidence was determined with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: The pooled analysis showed that ACD was not significantly different for visceral OMTh (vOMTh) vs. OMTh control (odds ratio [OR]=2.66 [95% confidence interval [[CI]], 0.28, 24.93]) or for OMTh vs. standard care (OR=1.26 [95% CI, 0.84, 1.89]; I2=0%). Single study analysis showed that OMTh results were nonsignificant in comparison with chemonucleolysis, gabapentin, and exercise. OMTh in combination with gabapentin (vs. gabapentin alone) and OMTh in combination with exercise (vs. exercise alone) showed nonsignificant ACD. Dropouts due to AE were not significantly different, but the results could not be pooled due to an insufficient number of studies. CONCLUSIONS: Most articles did not explicitly report AEs, ACD rates, or dropouts due to AEs and inefficacy. The limited data available on dropouts showed that OMTh was well tolerated compared with control interventions, and that the ACD and dropouts due to AEs were not significantly different than comparators. Future trials should focus on explicit reporting of dropouts along with beneficial outcomes to provide a better understanding of OMTh efficacy.

Transitional cell neoplasm of the nasolacrimal duct associated with human papillomavirus type 11.

BACKGROUND: Tumors of the lacrimal sac are rare but noteworthy because of their significant potential to become malignant or life-threatening if treatment is delayed. Dermatologists may be the first to encounter such neoplasms. OBSERVATIONS: We report a case of a 53-year-old Caucasian woman who presented with a seven-year history of an asymptomatic, subcutaneous nodule near her right medial canthus. Histology of the lesion revealed transitional epithelium in a papillary growth pattern with numerous goblet cells, scattered mitoses and focal full-thickness atypia. The patient was diagnosed with transitional cell neoplasm (inverted papilloma-type) of the nasolacrimal duct. PCR evaluation identified HPV type 11 in the lesion. CONCLUSION: Our report is one of a growing number of case reports and series detecting HPV DNA in these tumors which further supports HPV as an etiologic agent in epithelial lacrimal sac tumors. We believe that dermatopathologists need to be aware of this entity, as dermatologists may be the first to encounter these neoplasms. LIMITATIONS: The association of HPV with this tumor does not prove causality.

A firm plaque on the back of a newborn.

We report a case of subcutaneous fat necrosis of the newborn (SCFN), a rare disorder in term or post-term neonates. Although it is often associated with hematological abnormalities such as anemia and hypercalcemia, SCFN in this patient presented with hyperbilirubinemia. The course of SCFN is generally benign and self-limiting, though may be associated with complications secondary to hypercalcemia.

Osteopathic Manual Treatment for Pain Severity, Functional Improvement, and Return to Work in Patients With Chronic Pain.

CONTEXT: Chronic non-cancer pain (CNCP) is associated with disability, poor quality of life (QOL), and failure to return to work (RTW). Osteopathic manipulative treatment (OMT) or osteopathic manual therapy (OMTh) are increasingly offered to patients with CNCP; however, the existing systematic reviews and meta-analyses in the literature that explore the effectiveness of OMTh have major limitations. OBJECTIVE: To systematically evaluate the quality of evidence documenting the effectiveness of OMTh for patients with CNCP using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and to evaluate the efficacy of OMTh in patients with CNCP through a meta-analysis of pooled data from previous studies. METHODS: We searched online the databases Ovid, MEDLINE, Embase, OSTMED.DR, EMCare, Allied and Complementary Medicine Database (AMED), Physiotherapy Evidence Database (PEDro), and Cochrane Central Register of Controlled Trials (CENTRAL), as well as the bibliographic references of previous systematic review articles evaluating OMTh for pain severity, disability, QOL, or RTW outcomes. Eligibility included randomized controlled trials methodology, CNCP patients 18 years or older, use of previously validated assessment tools, use of OMTh as an active or combination intervention, and presence of a control or comparison group. We pooled studies based on the homogeneity between OMT comparator treatment and outcomes. Risk of bias was assessed with the Cochrane risk of bias tool and the quality of evidence was determined with GRADE. RESULTS: Sixteen randomized controlled trials (n=1158 patients) were eligible for data extraction. Moderate quality evidence showed that OMTh vs. standard care was significantly associated with a reduction in pain [standardized mean difference (95% CI)=[-.37 (-.58, -.17)] and disability [-.28 (-.46, -.10)], as well as improved QOL [.67 (.29, 1.05)]. Moderate quality evidence showed that OMTh plus exercise vs. exercise only was significantly associated with reduction in pain severity [-1.25 (-1.67, -.83)] and disability [-1.15 (-1.57, -.74)]. Moderate quality evidence showed that using visceral OMTh vs. general OMTh was significantly associated with reduction in pain severity [-.74 (-1.09, -.39)] and disability [-.52 (-.91, -.13)]. In comparison to physiotherapy, gabapentin, and OMTh plus gabapentin, OMTh did not show any significant effect for any of the outcomes. OMTh vs. standard care did not show significant improvement in RTW at 12 weeks, although the effect was significant at 8 weeks after OMTh. CONCLUSION: Moderate quality evidence suggests that OMTh is effective for CNCP patients. There was a significant association between visceral OMTh and reduced pain severity and disability. More robust, high-quality randomized controlled trials with larger sample sizes are required to further explore the effectiveness of the OMTh in the management of CNCP.

Lymphatic invasion detected by D2-40/S-100 dual immunohistochemistry does not predict sentinel lymph node status in melanoma.

BACKGROUND: Sentinel lymph node biopsy provides important prognostic information with controversial therapeutic advantages. D2-40 is a novel immunohistochemical stain specific for lymphatic endothelium often utilized to study tumor lymphangiogenesis and lymphatic invasion. OBJECTIVE: To increase the detection of lymphatic invasion in primary cutaneous melanomas with D2-40/S-100 dual immunohistochemistry, and then apply the technique to melanomas with known sentinel lymph node status. The primary aim was to assess whether the presence or absence of lymphatic invasion could predict sentinel lymph node status. The secondary aims were to assess whether lymphatic invasion and/or sentinel lymph node involvement were associated with clinicopathologic parameters commonly studied in melanomas. METHODS: Twenty-seven biopsy specimens of primary cutaneous melanoma from 27 patients with known sentinel lymph node status were retrospectively reviewed and labeled with D2-40/S-100 dual immunohistochemistry. The following clinicopathologic variables were evaluated: age, gender, histologic type, Breslow thickness, Clark level, ulceration, mitoses, lymphovascular invasion by routine staining and D2-40/S-100 dual immunohistochemistry, and overall survival. Statistical analyses were performed to assess for associations. RESULTS: D2-40/S-100 dual immunohistochemistry showed unequivocal lymphatic invasion in 10 of 27 melanomas compared with 1 of 27 with routine histology. Eight of 10 melanomas with lymphatic invasion were sentinel lymph node negative. There was no statistical association between the presence or absence of lymphatic invasion and sentinel lymph node status. LIMITATIONS: The major limitation was the small sample size. CONCLUSION: D2-40/S-100 dual immunohistochemistry increases the sensitivity of detection of lymphatic invasion in melanoma but does not predict sentinel lymph node involvement.

Differential Effect of Patient Weight on Pain-Related Judgements About Male and Female Chronic Low Back Pain Patients.

Compared with men, women report more pain and are at increased risk for having pain discounted or misattributed to psychological causes. Overweight individuals experience high rates of pain and may receive suboptimal care because of provider bias. Research suggests the social consequences of being overweight are worse for women than men, and that gender and weight uniquely and interactively affect pain experience and care. Healthy participants (n = 616) viewed 6 videos of back pain patients (1 female and 1 male of normal weight, overweight, and obese categories) performing a functional task. Participants provided judgements/ratings regarding patient pain (intensity, interference, exaggeration), potential sources of patient pain (medical, psychological), and treatment recommendations (opioids, psychological therapy, seek workplace accommodations). Results suggest that the pain of normal and overweight women and obese men was discounted (judged as less intense, less interfering, more exaggerated, and less attributable to medical factors) and judged as less in need of treatment (treated with less opioids and workplace accommodations). Across all weight categories, women's pain was attributed more to psychological factors and was more likely to receive recommendations for psychological therapy than men's pain. These findings highlight the differential effect of patient weight on pain-related judgements about women and men. PERSPECTIVE: This article examines the relationships among patient weight, patient gender, and observers' pain appraisals and treatment recommendations. These findings highlight the differential effect of patient weight on pain-related judgements about women and men and indicate the need for research to determine how these judgements affect treatment decisions in clinical settings.

Ginseng: Cardiotonic in adult rat cardiomyocytes, cardiotoxic in neonatal rat cardiomyocytes.

Ginsengs are widely used to improve cardiac health and circulation. Loosely termed as ginsengs, Asian (Panax), Siberian and Ashwagandha (Indian Ginseng) Indian ginsengs are prepared from different plants. We tested the popular belief of cardiotonic effects of ginsengs using both neonatal and adult rat cardiomyocytes, comparing extracts from the three ginsengs. Addition of 10% v/v of extract (100 microl of extract/ml of culture medium) of each of the ginsengs resulted in a rapid (<10 s) cessation of beating in neonatal cardiomyocytes due to calcium overload, while sequential dilutions revealed that treatment with a low dose (0.01% v/v, 0.1 microl/ml of the medium) resulted in constant, regular beats (transients), and a slight elevation of diastolic calcium without overload. Addition of extracts to sparking, calcium-tolerant adult cardiomyocytes resulted in initiation of calcium transients, and adult cells were able to tolerate exposure to high concentrations of extract. Cardiotonic effects in adult cells (cardiotoxicity in neonatal cells) were most profound with Asian ginseng (2.6 times that of Siberian ginseng, 1.6 times that of Indian ginseng) probably due to the active ingredients (ginsenosides in Asian, eleutherosides in Siberian and withanolides in Indian) being structurally different. We conclude that fully developed cardiomyocytes are able to accommodate higher doses of ginseng than neonatal cells, and that the effects of ginseng on newly formed, developing myocytes, could be extremely deleterious to the fetus. However, for adults, ginseng might well be a 'tonic' in its ability to increase beating and intramyocytic calcium levels.