High imperforate transverse vaginal septum with vaginal cicatrisation: a surgical tribulation.

An early adolescent girl was referred to us with cryptomenorrhoea, and pelvic pain consistent with obstructed menstruation. Originally presumed to be a case of imperforate hymen, she was referred to our centre after two failed surgical misadventures at correcting the obstruction. MRI revealed a haematometrocolpos, high transverse complete vaginal septum and an occluded vagina. She underwent a laparoscopic drainage of the collection, septal resection and a vaginoplasty with an absorbable Interceed graft. Postoperative recovery was smooth and she was sent with instructions to use a vaginal mould daily. Successful surgical treatment requires precise preoperative planning with MRI. A vaginal-assisted laparoscopic approach turned out to be advantageous in resecting the septum to a large extent due to the associated cicatrised vagina. The use of Interceed, a novel mould and harnessing system, ensured a favourable postoperative outcome by bolstering patient motivation due to its less challenging technique of use.

Inflammatory pain resolution by mouse serum-derived small extracellular vesicles.

Chronic pain is a significant public health issue. Current treatments have limited efficacy and significant side effects, warranting research on alternative strategies for pain management. One approach involves using small extracellular vesicles (sEVs) to transport beneficial biomolecular cargo to aid pain resolution. Exosomes are 30-150 nm sEVs that can carry RNAs, proteins, and lipid mediators to recipient cells via circulation. Exosomes can be beneficial or harmful depending on their source and contents. To investigate the short and long-term effects of mouse serum-derived sEVs in pain modulation, sEVs from naïve control or spared nerve injury (SNI) model donor mice were injected intrathecally into naïve recipient mice. Basal mechanical thresholds transiently increased in recipient mice. This effect was mediated by opioid signaling as this outcome was blocked by naltrexone. Mass Spectrometry of sEVs detected endogenous opioid peptide leu-enkephalin. A single prophylactic intrathecal injection of sEVs two weeks prior to induction of the pain model in recipient mice delayed mechanical allodynia in SNI model mice and accelerated recovery from inflammatory pain after complete Freund's adjuvant (CFA) injection. ChipCytometry of spinal cord and dorsal root ganglion (DRG) from sEV treated mice showed that prophylactic sEV treatment reduced the number of natural killer (NK) and NKT cells in spinal cord and increased CD206+ anti-inflammatory macrophages in (DRG) after CFA injection. Further characterization of sEVs showed the presence of immune markers suggesting that sEVs can exert immunomodulatory effects in recipient mice to promote the resolution of inflammatory pain. Collectively, these studies demonstrate multiple mechanisms by which sEVs can attenuate pain.

Accuracy of 3-D Surface Rendering of 2-D Ultrasound Images of the Uterus Using a Novel Software in Mapping Uterine Fibroids.

OBJECTIVE: Three-dimensional surface rendering of 2-D ultrasound images of the uterus in mapping uterine fibroids is a fast-evolving imaging technique that holds great potential for gynecology. The purpose of this study was to assess the accuracy of 3-D surface rendering of 2-D ultrasound images of the uterus using a new Fibroid Mapping Reviewer Application (FMRA) software for mapping uterine fibroids as compared with the pathological evaluation of uterine fibroids in pre-menopausal women undergoing hysterectomy. METHODS: We enrolled women aged 35-55 y scheduled for hysterectomy for symptomatic fibroids at a tertiary care hospital from 2019 to 2021. Per pre-set guidelines, we recorded 2-D images and videos of the uterus with fibroids during the transvaginal ultrasound. The recordings were transferred through USB, loaded in the FMRA software and post-processed to generate a 3-D rendered uterus model. An experienced pathologist assessed and documented the gross examination details per a set protocol. We compared the pre-specified dimensions related to the size (L1, L2) and location (X, Y) of fibroids between the 3-D model and the pathologist's assessment of the hysterectomy specimen. RESULTS: A total of 25 fibroids in 25 women, the single largest per woman, were considered for analysis. The two methods had good correlation with respect to size (for L1, R² = 0.9723, and for L2, R² = 0.9784) and location (for X, R² = 0.9618, and for Y, R² = 0.9753). Inter-observer analysis revealed that measurements from two sonologists were reproducible (Cronbach's α = 0.9 for the L1, L2 and L3 dimensions of fibroids from the 3-D model). CONCLUSION: The FMRA is a novel tool for mapping fibroids. With its proven accuracy, it will be helpful in planning surgeries and during guided procedures for managing uterine fibroids.

Epigenetic regulation in opioid induced hyperalgesia.

About 25 million American adults experience pain daily and one of the most commonly prescribed drugs to treat pain are opioids. Prolonged opioid usage and dose escalations can cause a paradoxical response where patients experience enhanced pain sensitivity. This opioid induced hyperalgesia (OIH) is a major hurdle when treating pain in the clinic because its underlying mechanisms are still not fully understood. OIH is also commonly overlooked and lacks guidelines to prevent its onset. Research on pain disorders and opioid usage have recognized potential epigenetic drivers of disease including DNA methylation, histone modifications, miRNA regulation, but their involvement in OIH has not been well studied. This article discusses epigenetic changes that may contribute to pathogenesis, with an emphasis on miRNA alterations in OIH. There is a crucial gap in knowledge including how multiple epigenetic modulators contribute to OIH. Elucidating the epigenetic changes underlying OIH and the crosstalk among these mechanisms could lead to the development of novel targets for the prevention and treatment of this painful phenomena.

Stress incontinence combined score (SICS): A novel combined grading system to assess the severity of stress urinary incontinence in women.

INTRODUCTION: Natural history of urinary incontinence (UI) in women is a less understood domain. Stratifying severity of stress urinary incontinence (SUI) can be an important tool to understand the natural history, prognosticate the disease and plan optimal management. Present study was aimed to test a novel score (Stress Incontinence Combined score: SICS) with the currently popular tools International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) and Incontinence Symptom Index (ISI) scores. MATERIAL AND METHODS: This was a prospective study conducted at a university teaching hospital, over a period of 2 years. After screening women for SUI, SICS was administered. The novel SICS score was then compared with ICIQ-UI SF and ISI. RESULTS: A total of 1750 women, attending various OPDs in a tertiary care hospital, were screened for urinary incontinence. The prevalence of UI and SUI was 26.6% and 12.8% respectively. The agreement between ISI and SICS was 81.7%, while the ICIQ- UI SF agreed with the SICS in 80.8% of the cases. AUROC analysis done showed that a score of 10 or more on the SICS (total score 16) could diagnose high-grade SUI with a sensitivity of 97%, specificity of 96% (Reference: ISI), and a sensitivity of 100%, and specificity of 93% (Reference: ICIQ- UI SF) CONCLUSION: SICS is the first of its kind tool, developed to specifically grade the severity of SUI, while incorporating both subjective and objective measures, with excellent reliability and reproducibility.

High-fat food biases hypothalamic and mesolimbic expression of consummatory drives.

Maintaining healthy body weight is increasingly difficult in our obesogenic environment. Dieting efforts are often overpowered by the internal drive to consume energy-dense foods. Although the selection of calorically rich substrates over healthier options is identifiable across species, the mechanisms behind this choice remain poorly understood. Using a passive devaluation paradigm, we found that exposure to high-fat diet (HFD) suppresses the intake of nutritionally balanced standard chow diet (SD) irrespective of age, sex, body mass accrual and functional leptin or melanocortin-4 receptor signaling. Longitudinal recordings revealed that this SD devaluation and subsequent shift toward HFD consumption is encoded at the level of hypothalamic agouti-related peptide neurons and mesolimbic dopamine signaling. Prior HFD consumption vastly diminished the capacity of SD to alleviate the negative valence associated with hunger and the rewarding properties of food discovery even after periods of HFD abstinence. These data reveal a neural basis behind the hardships of dieting.

NK cell enteropathy: a case report with 10 years of indolent clinical behaviour.

AIMS: Natural killer (NK) cell enteropathy is a recently described clinically indolent condition characterised by atypical NK cell infiltrates in the gastrointestinal mucosa that mimics malignant lymphoma. We report a case that highlights the indolent clinical behaviour by documenting absence of clinical progression over 10 years. METHODS AND RESULTS: We report the case of a 69-year old female who had clinically long-standing abdominal pain and recurrent mucosal ulcerations associated with atypical NK cell infiltrates. The clinical, morphologic and immunophenotypical findings in this case were diagnostic of NK cell enteropathy. Review of the patient's prior biopsies demonstrated that this persisted without clinical progression for 10 years, confirming the clinical indolent course. CONCLUSION: Recognition of NK cell enteropathy is important to avoid over-diagnosing this benign condition as an aggressive lymphoma.

Induction of colon and cervical cancer cell death by cinnamic acid derivatives is mediated through the inhibition of Histone Deacetylases (HDAC).

Recent studies from our group and many others have shown the ability of histone deacetylase (HDAC) inhibitors for retarding the growth of carcinomas of cervix, colon and rectum in vitro. A search for naturally occurring HDAC inhibitors continues due to the adverse effects associated with known HDAC inhibitors like SAHA and TSA. Therefore in the current study, naturally occurring cinnamic acids derivatives were screened for HDAC inhibitory effect using in silico docking method which identified cinnamic acids as potential candidates. Cinnamic acids (CA) are naturally occurring phenolic compounds known to exhibit anticancer properties. However, it is not clearly known whether the anticancer properties of CA derivatives are due to the inhibition of oncogenic HDACs, if so how the efficacy varies among various CA derivatives. Hence, the HDAC inhibitory potential of CA derivatives containing increasing number of hydroxylic groups or methoxy moieties was determined using Discovery Studio software and the most potent CA derivatives tested ex vivo (biochemical assay) as well as in vitro (using cell based assay). Among CA derivatives tested, dihydroxy cinnamic acid (DHCA, commonly known as caffeic acid) exhibited better interactions with HDAC2 (compared to other isoforms) in silico and inhibited its activity ex vivo as well as in vitro. Targeted reduction of HDAC activity using DHCA induced death of cancer cells by (a) generating reactive oxygen species, (b) arresting cells in S and G2/M phases; and (c) induction of caspase-3 mediated apoptosis. In conclusion, we demonstrated that DHCA inhibited cancer cell growth by binding to HDAC followed by the induction of apoptosis.

High-risk human papillomavirus in HIV-infected women undergoing cervical cancer screening in Lilongwe, Malawi: a pilot study.

Rates of abnormal visual inspection with acetic acid and prevalence of high-risk human papillomavirus (HPV) subtypes have not been well characterized in HIV-infected women in Malawi. We performed a prospective cohort study of visual inspection with acetic acid (N = 440) in HIV-infected women aged 25--59 years, with a nested study of HPV subtypes in first 300 women enrolled. Of 440 women screened, 9.5% (N = 42) had abnormal visual inspection with acetic acid with 69.0% (N = 29) having advanced disease not amenable to cryotherapy. Of 294 women with HPV results, 39% (N = 114) of women were positive for high-risk HPV infection. Only lower CD4 count (287 cells/mm(3) versus 339 cells/mm(3), p = 0.03) and high-risk HPV (66.7% versus 35.6%, p < 0.01) were associated with abnormal visual inspection with acetic acid. The most common high-risk HPV subtypes in women with abnormal visual inspection with acetic acid were 35 (33.3%), 16 (26.7%), and 58 (23.3%). Low CD4 cell count was associated with abnormal visual inspection with acetic acid and raises the importance of early antiretroviral therapy and expanded availability of visual inspection with acetic acid. HPV vaccines targeting additional non-16/18 high-risk HPV subtypes may have greater protective advantages in countries such as Malawi.

Citizens in the commons: blood and genetics in the making of the civic.

This essay is based on ethnographic fieldwork conducted with the Indian community in Houston, as part of a NIH/NHGRI-sponsored ethics study and sample collection initiative entitled 'Indian and Hindu Perspectives on Genetic Variation Research.' Taking a cue from my Indian interlocutors who largely support and readily respond to such initiatives on the grounds that they will undoubtedly serve 'humanity' and the common good, I explore notions of the commons that are created in the process of soliciting blood for genetic research. How does blood become the stuff of which a civic discourse is made? How do idealistic individual appeals to donate blood, ethics research protocols, open-source databases, debates on approaches to genetic research, patents and Intellectual Property regulations, markets and the nation-state itself variously engage, limit or further ideas of the common good? Moving much as my interlocutors do, between India and the United States, I explore the nature of the commons that is both imagined and pragmatically reckoned in both local and global diasporic contexts.

Oral sampling and human papillomavirus genotyping in HIV-infected patients.

BACKGROUND: Oral human papillomavirus (HPV) is associated with several health complications especially in combination with HIV infections. Screening may be useful, but methodologies and results have varied widely in previous studies. We conducted a pilot study in an HIV-positive population to evaluate HPV detection in four different oral sample types. METHODS: Upon enrollment, an oral-rinse (OR) sample was collected in 10 ml saline. Additional samples of the buccal mucosa, tonsils, and oral lesion if present were collected with cytology brushes. DNA was extracted using LC-MagNAPure, and the Linear Array HPV genotyping Assay (Roche) was used for HPV genotyping. RESULTS: In samples from 100 HIV-positive participants, HPV was detected in 39 (%) of the oral rinses, 13 (%) mucosal and 11 (12.9%) tonsil brushings. Of seven lesion brushings collected, four were HPV positive. All participants with HPV detected in mucosal, tonsil, or lesion brushings were also positive in the OR sample. Among the rinse samples, 27 different genotypes were detected with HPV84 (n = 6), HPV55 (n = 5), and HPV83 (n = 5) being the most common. Multiple infections were detected in 17 samples (range 2-9, mean 1.9 types). As potential cofactors, only receptive oral sex was significantly associated with HPV (P = 0.018, odds ratio 2.9, 95% CI 1.2-6.9). CONCLUSION: Sampling is a significant factor for oral prevalence studies. Oral rinse provides the best representation for HPV in the oral cavity. To evaluate associated cofactors other than receptive oral sex, larger studies with case-control design are necessary.

HIV-associated multicentric Castleman disease.

PURPOSE OF REVIEW: HIV-associated multicentric Castleman disease (HIV MCD) is a rare lymphoproliferative disorder, the incidence of which appears to be increasing in the highly active antiretroviral therapy era. Current knowledge of the disease is limited and this review will discuss what is known about the pathophysiology, diagnosis, management, and prognosis of HIV MCD. RECENT FINDINGS: HIV MCD has been shown to be associated with infection with human herpesvirus-8. Vascular endothelial growth factor and the cytokine interleukin-6 (IL-6) are also thought to play a role in the pathogenesis of MCD. Currently, rituximab is often used alone or in combination with chemotherapy for treatment of MCD. Novel monoclonal antibodies targeting IL-6 and the IL-6 receptor are also being studied for the management of this disease. SUMMARY: Because HIV MCD is an uncommon diagnosis, comprehensive clinical studies have not been done, and understanding of the disease is incomplete. Further studies are needed to make definitive conclusions regarding optimal treatment of HIV MCD.

Targeted therapies for metastatic esophagogastric cancer.

The prognosis and long-term survival for patients with metastatic esophagogastric cancer (EGC) is poor. Historically, the mainstay of treatment has been combination chemotherapy. More recently, a number of targeted therapies have been developed and are being studied with the goal of improving response rate and survival in patients with metastatic EGC. To date, the only targeted therapy which has been clinically approved is trastuzumab which targets the HER2/Neu oncogene. However, only a small group of patients with EGCs are HER2 amplified, and there are other important targets/pathways which play a role in the development of these cancers that are currently being studied. With the identification of these other clinically relevant pathways, it is anticipated that several other therapies will be approved in the future.

Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes.

BACKGROUND: There are few studies that describe the medical treatment and colitis response rates among patients with a severe relapse of inflammatory bowel disease (IBD) during pregnancy, and few studies of the effect of such a relapse on birth outcomes in these patients. OBJECTIVES: To describe the treatment and response rates of severe colitis in pregnancy, and to assess the effects of a severe relapse of colitis during pregnancy on birth outcomes. METHODS: We performed a case control study of pregnant patients with IBD hospitalized for a disease relapse at two large treatment centers between 1989 and 2001. Details of management of disease relapse and maternal and fetal outcomes were recorded. RESULTS: Eighteen patients (11 ulcerative colitis, 6 Crohn's disease, 1 indeterminate colitis), mean age 28.6 yr (range 19-38) formed the study group; 41 age-matched pregnant IBD patients without disease relapse formed the control group. Study patients were hospitalized at a mean of 15.9-wk gestation (range 8-35) for a mean of 10.4 days (range 3-31). All 18 patients received IV hydrocortisone (mean dose 199 mg/day) and 7 patients (39%) either continued taking or were commenced on immunomodulators: IV cyclosporine (5 patients) and azathioprine/6-MP (3 patients). Fifteen patients (83%) had a clinical response to these medical treatments, 3 patients required colectomy. There were significant differences between study and control groups in gestation period (35.0 wk vs 38.7 wk, respectively, P= 0.0001) and birth weight (2,001 g vs 3,018 g, respectively, P < 0.0001). CONCLUSIONS: Treatment with IV hydrocortisone and IV cyclosporine appears effective at inducing remission of colitis but their use must continue to be confined to severely ill patients being treated at specialized centers. Severe relapses of colitis during pregnancy increase the risk of preterm birth and low birth weight.

Hormonal replacement therapy after menopause is protective of disease activity in women with inflammatory bowel disease.

BACKGROUND AND AIMS: The nature of inflammatory bowel disease (IBD) following menopause has not been previously studied. The aim of this study was to characterize the effect of menopause on disease activity and identify possible modifiers of disease activity. METHODS: This was a retrospective study of women followed at the University of Chicago IBD Clinic. Disease activity was assessed using clinical scoring systems during the pre- and postmenstrual periods of subjects. Variables of interest included: history of smoking, use of oral contraceptives (OCP) prior to onset of menopause, and use of hormone replacement therapy (HRT). RESULTS: Sixty-five women were included, 20 with ulcerative colitis and 45 with Crohn's disease. The median age of menopause was similar to historical controls. Twenty-three patients (35%) experienced active symptoms in the premenopausal time period and 25 patients (38%) had disease indices consistent with a flare within the first 2 yr after menopause (P > 0.05). There was no relation between those who had a pre- versus postmenstrual flare as a group (P > 0.05). However, there was a significant protective effect on disease activity with postmenopausal HRT use (hazard ratio [HR] 0.18, 95% confidence interval [CI] 0.04-0.72). There was also a dose-response effect noted with an HR with longer duration of use (0.20, 0.07-0.65). CONCLUSIONS: The likelihood of having a flare postmenopause is not different from having it premenopause. HRT, however, may provide a protective effect for disease activity in the postmenopausal period. The anti-inflammatory effects of estrogen may be the mechanism for this observation.

Higher incidence of abnormal Pap smears in women with inflammatory bowel disease.

BACKGROUND AND AIMS: Immunosuppression results in a higher incidence of cervical dysplasia compared with healthy controls. We examined the relationship between immunomodulator use and the presence of abnormal cervical histology in women with inflammatory bowel disease (IBD). METHODS: Women with IBD and serial Pap smears were recruited. Patients were compared to age-, race-, and parity-matched controls. Pap smears were recorded in relation to exposure to immunomodulators. Variables included diagnosis, type and duration of immunosuppressant, and smoking. RESULTS: Forty patients (8 UC, 32 CD) with 134 Pap smears were included. The incidence of any abnormal Pap in a woman with IBD was 42.5%versus 7% of controls (P < 0.001). Women with IBD were more likely to have higher-grade lesions than controls (P < 0.001). Those women with a history of exposure to immunosuppression were more likely to have an abnormal Pap smear (P < 0.001) than controls. Pap smears done with > 6 months exposure to an immunosuppressant resulted in increased risk (OR 1.5, 1.2-4.1, P= 0.021). Cytopathology of abnormal lesions revealed either HPV serotype 16 or 18 in all specimens. Multivariate analysis did not reveal any differences between the groups when controlled for other variables. CONCLUSIONS: Women with IBD have a higher risk of an abnormal Pap smear compared with healthy controls. Patients with immunomodulator use have a higher risk of an abnormal Pap smear associated with HPV infection. Women with IBD should be included in the American College of Obstetrics and Gynecology screening guidelines for immunocompromised individuals.

Rheumatoid arthritis: current pharmacologic treatment and anesthetic considerations.

A diagnosis of rheumatoid arthritis carries with it a lifelong progressive disease; however twenty percent of patients enjoy periods of partial to total remission. After remission, the disease will frequently plague previously unaffected joints. Life expectancy is reduced by an average of three to seven years. Complications of RA include vasculitis and amyloidosis affecting any vessel, including the aorta. Additionally, complications of therapy such as chronic NSAID use leading to GI bleeding and infections associated with long term steroid use, can add to the difficulties of the disease. The recent discovery and use of anticytokines and DMARDs has lead to greatly reduced symptomology associated with RA and greater patient comfort. Side effects of drugs should be well understood including the risk of bleeding from NSAIDs. Management and surgical intervention of problems that arise from this disease vary dramatically. The anesthesiologist must be aware of airway pathologies, pain management techniques, and available pharmacology parameters.

GOOD GIFTS FOR THE COMMON GOOD: Blood and Bioethics in the Market of Genetic Research.

This article is based on ethnographic fieldwork conducted with the Indian community in Houston, as part of a NIH-NHGRI-sponsored ethics study and sample collection initiative entitled "Indian and Hindu Perspectives on Genetic Variation Research." At the heart of this research is one central exchange-blood samples donated for genetic research-that draws both the Indian community and a community of researchers into an encounter with bioethics. I consider the meanings that come to be associated with blood donation as it passes through various hands, agendas, and associated ethical filters on its way to the lab bench: how and why blood is solicited, how the giving and taking of blood is rationalized, how blood as material substance is alienated, processed, documented, and made available for the promised ends of basic science research. Examining corporeal substances and asking what sorts of gifts and problems these represent, I argue, sheds some light on two imbricated tensions expressed by a community of Indians, on the one hand, and of geneticists and basic science researchers, on the other hand: that gifts ought to be free (but are not), and that science ought to be pure (but is not). In this article, I explore how experiences of bioethics are variously shaped by the histories and habits of Indic giving, prior sample collection controversies, commitments to "good science" and the common "good of humanity," and negotiations of the sites where research findings circulate.

Digoxin therapy for heart failure: an update.

Digoxin therapy has long been used to treat heart failure; however, its effectiveness was not completely known until recently. Results of the Digitalis Investigation Group trial showed that adding digoxin to standard heart failure therapy had no effect on mortality. However, adding digoxin decreased hospitalizations related to heart failure and improved symptoms in patients treated for heart failure. Reanalyses of the trial's findings have raised new questions about the role of digoxin in heart failure treatment. These new analyses showed that low serum digoxin concentrations used in patients with more severe disease offered the most benefit. Digoxin use in women was associated with increased mortality risk. This finding should be interpreted with caution, however, because it was based on retrospective data, and the cause of this phenomenon has not been fully elucidated. Prospective clinical trials are needed to determine the serum digoxin concentration that is associated with the most clinical benefit and to determine the role of digoxin therapy for women. Digoxin generally does not have a role in the treatment of diastolic heart failure and is not a first-line therapy for managing atrial fibrillation in patients with heart failure.