Analysis of Intravenous Insulin Dosing Requirements for Treatment of Severe Hypertriglyceridemia.

Purpose: Insulin infusion therapy is commonly utilized for treatment of severe hypertriglyceridemia, however, data supporting a standardized dosing approach is lacking. This study aimed to determine the average initial insulin dose utilized for treatment of hypertriglyceridemia and the associated reduction in serum triglycerides. Methods: This single-center, retrospective, descriptive analysis conducted at an academic medical center included adult hospitalized patients with serum triglyceride levels greater than 1000 mg/dL receiving treatment with an intravenous insulin infusion between November 2017 and August 2020. Data was extracted from the electronic medical record. The primary outcome was the mean weight-based intravenous insulin dose resulting in resolution of hypertriglyceridemia. Secondary outcomes included time to resolution of hypertriglyceridemia, adverse events associated with insulin treatment, incidence of rebound hypertriglyceridemia, and use of additional lipid-lowering therapies. Results: Data from 32 hospital encounters was analyzed. The mean initial triglyceride level was 3229 mg/dL. The average insulin doses observed on days 1 and 2 of therapy were 0.07 and 0.05 units/kg/hour, respectively. The mean percent triglyceride reduction at 48 hours was 40%. Mean time to resolution of hypertriglyceridemia, discontinuation of insulin infusion, or discharge was 5.7 days. Hypoglycemia and hypokalemia were observed in 9% and 29% of patients, respectively. Conclusion: The results of this study provide new guidance for insulin dosing for hypertriglyceridemia. Serum potassium levels and blood glucose should be monitored closely during therapy.

Vulval lichen sclerosus: An Australasian management consensus.

BACKGROUND/OBJECTIVES: Vulval lichen sclerosus (VLS) is a chronic inflammatory skin condition predominantly affecting the anogenital region in women and children. To date, there is lack of agreement amongst experts on a severity scale to aid assessment, research and treatment stratification on VLS. Furthermore, literature on best practice for long-term management of VLS is lacking. The aim of this consensus is to provide broad guidelines on the short and long-term management of VLS. METHODS: An initial focus group of Australasian experts in vulval dermatology developed a draft consensus statement for the management of VLS. Based on the results of the draft statement, a consensus panel of 22 Australasian experts, comprised of the initial and additional members, participated in an anonymous four-stage eDelphi process. Round 1 involved generation and voting on statements from the draft consensus statement developed by the focus group. In Rounds 2, 3 & 4, panel members were presented formal feedback from previous rounds and asked to indicate their level of agreement. Consensus was reached if there was ≥70% agreement on the importance of an item in the 4 (agree) to 5 (strongly agree) range. RESULTS: The expert panel, with a total of 504 collective years of experience in the field of VLS, reached consensus on a core set of 51 management statements related to diagnosis, severity, initial and long-term management, follow-up, and complications of VLS. CONCLUSIONS: This study has identified a set of management statements for VLS that may be useful in clinical practice in the Australasian population.

Cyproterone acetate in the treatment of oestrogen hypersensitivity vulvovaginitis.

Oestrogen hypersensitivity vulvovaginitis is a rare chronic cyclical vulvovaginitis responsive to oestrogen suppression or antagonism. We present a case series of 16 patients with refractory cyclical vulvovaginitis, all of whom responded to oestrogen suppression with cyproterone acetate.

Lichen sclerosus in pregnancy: A review of 33 cases.

Vulval lichen sclerosus (VLS) is a chronic inflammatory skin condition affecting the anogenital area in women. Serious long-term consequences of VLS include the risk of developing squamous cell carcinoma of the vulva as well as of scarring and alteration of vulval architecture. The treatment of choice for genital lichen sclerosus in females is potent to very potent topical corticosteroids. There are few published data on the course of VLS in pregnancy. We present our experience of managing 33 pregnancies in 29 women with VLS.

The aetiology of chronic vulval pain and entry dyspareunia: a retrospective review of 525 cases.

BACKGROUND: There are few published data about the incidence of diagnoses or treatment outcomes, for chronic vulval pain. AIMS: To document diagnoses and treatment outcomes in a cohort of chronic vulval pain presentations. MATERIALS AND METHODS: A retrospective case review of the patient database of a private vulval clinic between January 2011 and March 2015. RESULTS: Five hundred and twenty-five out of 3360 patients (15.6%) met the criterion of vulval pain alone. Mean age was 47.1 years (range 17-86). Average duration of symptoms was 60 months (range 3-432). Overall, 277/525 (52.7%) patients had satisfactory responses to appropriate treatment and 90/525 (17%) had partial improvement. A dermatosis was identified in 322/525 (61.3%) patients and of these, 211/322 (65.5%) had satisfactory responses to appropriate dermatological treatment. In the remaining 203/525 (38.7%) the skin was normal. These patients were questioned around the possibility of a neuromuscular cause for their pain, including pre-existing dysfunction, trauma or previous operations involving the spine, hips or lower limbs. There were 181/203 (89%) patients considered to have a neuromuscular cause for their pain and considered suitable for physiotherapy and/or neuromodulating medications. Of these patients, 63/182 (34.6%) had satisfactory responses to this treatment. One hundred and sixty-six out of 525 (31.6%) described vulval pain only during sexual intercourse. There was no statistically significant difference between different diagnoses and responses to treatment between patients reporting dyspareunia only and those sexually active women who did not experience dysparenunia (29/525, 5.5%). CONCLUSIONS: The majority of this cohort with chronic vulval pain had a dermatological disease with a smaller proportion caused by neuromuscular dysfunction. Both groups are potentially treatable.

Ovulatory disorders are an independent risk factor for pregnancy complications in women receiving assisted reproduction treatments.

BACKGROUND: Conception using assisted reproduction treatments (ART) has been associated with an increased risk of pregnancy complications. It is uncertain if this is caused by ART directly, or is an association of the underlying factors causing infertility. AIMS: We assessed the relationship between assisted conception (AC) and maternal or fetal complications in a large retrospective cohort study. In a nested cohort of women receiving infertility treatment, we determined if such risk rests predominantly with certain causes of infertility. MATERIALS AND METHODS: Retrospective database analysis of 50 381 women delivering a singleton pregnancy in four public hospital obstetric units in western Sydney, and a nested cohort of 508 women receiving ART at a single fertility centre, in whom the cause of infertility was known. RESULTS: A total of 1727 pregnancies followed AC; 48 654 were spontaneous conceptions. Adjusted for age, body mass index and smoking, AC was associated with increased risk of preterm delivery (OR 1.73, 95% CI 1.50-2.02), hypertension (OR 1.55, 95% CI 1.34-1.82) and diabetes (OR 1.51, 95% CI 1.30-1.75). In the nested cohort, ovulatory dysfunction was present in 145 women and 336 had infertility despite normal ovulatory function. Ovulatory dysfunction was associated with increased risk of diabetes (OR 2.94, 95% CI 1.72-5.02) and hypertension (OR 2.40, 95% CI 1.15-5.00) compared to women with normal ovulatory function. CONCLUSIONS: Assisted conception is associated with increased risk of pregnancy complications. This risk appears greatest for women whose underlying infertility involves ovulatory dysfunction. Such disorders probably predispose towards diabetes and hypertension, which is then exacerbated by pregnancy.

A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia.

Four hundred and twenty-one adult allogeneic haematopoietic stem cell transplant (HSCT) survivors participated in a cross-sectional study to assess sexual dysfunction and infertility post-transplant. Survey instruments included the Sydney Post-Blood and Marrow Transplant (BMT) Survey, Functional Assessment of Cancer Treatment (FACT) - BMT, the Depression, Anxiety, Stress Scales (DASS 21), the Chronic Graft-versus-Host Disease (cGVHD) Activity Assessment- Patient Self Report (Form B), the Lee cGVHD Symptom Scale and The Post-Traumatic Growth Inventory. Most HSCT survivors reported sexual difficulties (51% of males; 66% of females). Men reported erectile dysfunction (79%) and decreased libido (61·6%) and women reported loss of libido (83%), painful intercourse (73%) and less enjoyment of sex (68%). Women also commonly reported vaginal dryness (73%), vaginal narrowing (34%) and vaginal irritation (26%). Woman had much higher rates of genital cGvHD than men (22% vs. 5%). Age and cGVHD were significantly associated with sexual dysfunction. Few survivors had children following transplant (3·3%). However, for those of reproductive age at HSCT, 22% reported trying to conceive, with 10·3% reporting success. This study is the largest to date exploring sexual function in survivors of allo-HSCT. This data provides the basis for health service reform to better meet the needs of HSCT survivors, including evidence to support counselling and education both pre- and post-transplant.

Vulvovaginal candidiasis as a chronic disease: diagnostic criteria and definition.

OBJECTIVE: Although recurrent vulvovaginal candidiasis is defined as 4 or more discrete attacks of vulvovaginal candidiasis per year, there is no diagnostic nomenclature or definition for the many women who are chronically symptomatic. This study aims to establish and propose a definition and a set of diagnostic criteria, which would enable clinicians to promptly identify and treat women with chronic vulvovaginal candidiasis (CVVC). DESIGN: Prospective cohort study. SETTING: Public and private vulvar dermatology outpatient clinics in Sydney, Australia. PARTICIPANTS: Data were obtained prospectively from 50 women with presumptive CVVC and 42 controls. Historical and clinical features of CVVC identified by expert consensus were compared between the 2 groups. Diagnostic criteria were then prospectively applied to a further 163 patients to verify their accuracy. OUTCOME MEASURES: Signs and symptoms diagnostic of CVVC. RESULTS: The following characteristics were found to be significantly more common in women with CVVC compared to controls (p ≤ .001): a history of positive vaginal Candida swab, discharge, dyspareunia, soreness, swelling, cyclicity, and exacerbation of symptoms with antibiotics. CONCLUSIONS: We propose that CVVC can be confidently diagnosed using the major criteria of a chronic nonspecific and nonerosive vulvovaginitis that includes at least 5 or more properties from the following criteria: soreness, dyspareunia, positive vaginal swab either at presentation or in the past, previous response to antifungal medication, exacerbation with antibiotics, cyclicity, swelling, and discharge. This condition responds reliably to oral antifungal medication.

Management of nonsexually acquired genital ulceration using oral and topical corticosteroids followed by doxycycline prophylaxis.

BACKGROUND: Data regarding the treatment of nonsexually acquired genital ulceration (NSAGU) are limited. OBJECTIVE: We sought to provide evidence for the safety and efficacy of topical and systemic corticosteroids followed by doxycycline prophylaxis for acute and recurrent NSAGU. METHODS: A retrospective chart review was conducted of patients with NSAGU treated in a private dermogynecology practice. RESULTS: A total of 26 girls and women with NSAGU were identified and divided into 2 groups: group A = 17 patients with moderate to severe ulceration treated in the acute stage with oral corticosteroid; and group B = 9 patients with mild ulceration treated in the acute stage with topical corticosteroid. Patients in group A, with a mean age of 27.9 years (range, 11-62 years), were treated with oral prednisolone commencing with 15 to 50 mg per day depending on severity. Sixteen (94%) achieved rapid pain relief and complete healing of ulcers within 16 days. Eight (47%) commenced doxycycline prophylaxis. Women in group B, with a mean age of 42.5 years (range, 26-67 years) were treated with topical corticosteroids. Eight (89%) had a history of recurrent ulcers and 6 (66%) commenced doxycycline prophylaxis. Of all 14 patients on doxycycline prophylaxis, none reported any recurrences during a mean follow-up of 18.3 months. There were no adverse effects caused by prednisolone. One patient experienced mild photosensitivity from doxycycline but continued to take it. LIMITATIONS: This was a retrospective case series from a single private practice-based population. CONCLUSION: Topical or oral corticosteroids followed by prophylactic doxycycline can be effective in rapidly resolving acute flareups and preventing recurrences of NSAGU. All patients responded to therapy without treatment-limiting side effects.

Surgical division of labial adhesions in vulvar lichen sclerosus and lichen planus.

OBJECTIVE: Vulvar lichen sclerosus (LS) and lichen planus (LP) may cause persistent symptomatic labial adhesions. In the scant literature on this topic, there is no agreement about which operation is suitable, or the role of suppressive medical therapy. We report on simple perineotomy in the context of careful preoperative and postoperative medical suppressions. MATERIALS AND METHODS: Thirty-five patients were identified within a referral vulvar practice, with symptomatic labial adhesions due to LS or LP. After sharp dissection of adhesions and injection of anesthesia, patients doubled the frequency of their preoperative therapy and underwent close surveillance until complete healing had occurred. Suppression of the inflammatory process was continued indefinitely with regular review. RESULTS: Mean age was 57 years. Of the patients, 27 had LS and 8 had LP. Of the 35 patients, 28 (80%) had dyspareunia or apareunia. Mean symptom duration was 9 years. Of the 35 patients, 21 had posterior fusion, 11 had anterior fusion, and 3 had both anterior and posterior fusions. Of the 35 patients, 17 had mild fusion, 11 had moderate fusion, and 7 had severe introital stenosis. At the 3-month review, 31 of the 35 patients had no refusion. Mean duration of follow-up was 2 years (range = 3 months to 7.5 years). Of the 35 patients, 29 had no late refusion during this time. Of the 18 patients with dyspareunia, 8 had no pain, and 9 had less pain. Of the 10 patients with apareunia, 1 could have sex without pain, and 6 could have sex but with pain. CONCLUSION: Simple perineotomy is adequate to treat persistent labial adhesions, provided that the inflammatory process is carefully suppressed.

Management of vulvovaginal lichen planus: a new approach.

OBJECTIVE: This study aimed to report on a novel approach to therapy in a large private dermatogynecology practice using multimodal therapies with adjunctive use of systemic agents where necessary. MATERIALS AND METHODS: This was a retrospective audit of the presentation and management of 131 patients with a clinical diagnosis of vulvovaginal lichen planus. RESULTS: The most frequently presenting symptoms were genital soreness, itch, and burning. Of the 131 patients, 39 (30%) had extragenital disease, mainly oral. Eighty-four (64%) had no external disease. Twenty-two (17%) had introital erosions as the only visible abnormality. Fifty-five (42%) had some degree of labial fusion. Two had full-thickness vulval intraepithelial neoplasia (VIN). Remission induction was achieved in most patients with superpotent topical steroids, but 53 (40%) of 131 patients used oral prednisolone either as an adjunct therapy or alone. All compliant patients achieved symptomatic and objective disease control in a mean of 7.5 weeks. Of the 131 patients, 48 (37%) required multimodal therapy to maintain their initial improvement. Forty-five (34.3%) patients used topical tacrolimus, usually with topical corticosteroids, for maintenance. Eleven (8.5%) required low-dose weekly methotrexate. Fourteen patients experienced adverse reactions severe enough to lead to the cessation of that treatment. The mean length of follow-up was 6.4 years (range = 1 mo to 15 y). The 2 patients with VIN at presentation have had no recurrence. No other patient has yet developed VIN or carcinoma. CONCLUSIONS: Long-term symptomatic and objective control of vulvovaginal lichen planus is possible but requires multimodal therapies, flexible treatment programs, and the judicious use of oral agents.

Production of a p65fl/fl/LysMCre mouse model with dysfunctional NF-κB signaling in bone marrow-derived macrophages.

Here, we describe the production and characterization of a novel p65fl/fl/LysMCre mouse model, which lacks canonical nuclear factor-kappaB member RelA/p65 (indicated as p65 hereafter) in bone marrow-derived macrophages. Cultured bone marrow-derived macrophages that lack p65 protein reveal NF-κB signaling deficiencies, a reduction in phagocytic ability, and reduced ability to produce nitrites. Despite abnormal bone marrow-derived macrophage function, p65fl/fl/LysMCre mice do not exhibit differences in naïve systemic immune profiles or colony forming units and time to death following Salmonella infection as compared to controls. Additionally, p65fl/fl/LysMCre mice, especially females, display splenomegaly, but no other obvious physical or behavioral differences as compared to control animals. As bone marrow-derived macrophages from this transgenic model are almost completely devoid of canonical nuclear factor-kappaB pathway member p65, this model has the potential for being very useful in investigating bone marrow-derived macrophage NF-kappaB signaling in diverse biological and biomedical studies.

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms.

Huntington disease (HD) is an inherited neurological disorder caused by a polyglutamine expansion in the protein huntingtin and is characterized by selective neurodegeneration that preferentially occurs in striatal medium spiny neurons. Because the medium spiny neurons are innervated abundantly by glutamatergic axons from cortical neurons, the preferential degeneration in the striatal neurons supports the glutamate excitotoxicity theory for HD pathogenesis. Thus, glutamate uptake by glia may be particularly important for preventing glutamate excitotoxicity in HD. Although mutant huntingtin is expressed ubiquitously in various types of cells, it accumulates and forms aggregates in fewer glial cells than in neuronal cells. It remains largely unknown whether and how mutant huntingtin in glia can contribute to the neurological symptoms of HD. We generated transgenic mice that express N-terminal mutant huntingtin in astrocytes, a major type of glial cell that remove extracellular glutamate in the brain. Although transgenic mutant huntingtin in astrocytes is expressed below the endogenous level, it can cause age-dependent neurological phenotypes in transgenic mice. Mice expressing mutant huntingtin show body weight loss, have motor function deficits, and die earlier than wild-type or control transgenic mice. We also found that mutant huntingtin in astrocytes decreases the expression of glutamate transporter by increasing its binding to Sp1 and reducing the association of Sp1 with the promoter of glutamate transporter. These results imply an important role for glial mutant huntingtin in HD pathology and suggest possibilities for treatment.

Vulvar psoriasis in adults and children: a clinical audit of 194 cases and review of the literature.

OBJECTIVE: There are limited data on psoriasis as it affects the vulva in the medical literature. This observational study aimed to describe the symptoms, signs, and management of vulvar psoriasis in adults and children in a private vulvar disease referral practice. MATERIALS AND METHODS: A review of the existing literature on vulvar psoriasis was used to generate inclusion criteria of a chronic noninfective erythematous vulvitis without vaginal involvement. Between January 2009 and October 2011, 201 patients presenting with these criteria were coded as having psoriasis in a computerized database where standardized data were collected. In 194 of these patients, adequate data were available to include in the study. RESULTS: Only 12.3% of the patients presented with psoriasis as a provisional diagnosis with a mean symptom duration of 4.5 years (range = 6 weeks to 35 years). The most common presentation was a pruritic, bilaterally symmetrical, erythematous, nonscaly, well-demarcated macular eruption or slightly raised plaque (82.5%). Of the remaining patients, 9.2% presented with only diffuse symptomatic erythema, whereas 8.2% were symptomatic without erythema. In 64.9% of the patients, evidence of psoriasis was found on other parts of the skin. Initial induction treatment with potent topical corticosteroid followed by a maintenance treatment with less potent topical steroids and other psoriasis-specific treatment such as tar creams and calcipotriol resulted in a suppression of disease in 93.8% of the patients during a mean follow-up duration of 8.9 months (range = 1 month to 7.25 years). CONCLUSIONS: Vulvar psoriasis is a difficult diagnosis that should be considered in patients presenting with a chronic erythematous vulvitis without vaginitis. It is a chronic relapsing skin condition that requires long-term management.

Development of a novel purification protocol to isolate and identify brain microglia.

Microglia, the tissue-resident macrophage of the central nervous system (CNS), play a paramount role in brain health and disease status. Here, we describe a novel method for enriching and isolating primary microglia from mouse brain tissue. This isolation method yields a high number of cells from either young or adult mice, and importantly, maintains the health and function of the cells for subsequent cell culture. We also describe flow cytometry methods using novel cell surface markers, including CX3CR1 and Siglec-H, to specifically label microglia while avoiding other bone marrow and/or non-CNS derived macrophages and monocytes, which has been historically difficult to achieve. As microglia are crucial in multiple aspects of biology, such as in normal brain development/function, immune response, neurodegeneration, and cancer, this isolation technique could greatly benefit a wide range of studies in human CNS biology, health, and disease mechanisms. Being able to isolate a largely pure population of microglia could also allow for a more comprehensive understanding of their functional dynamics and role in disease mechanisms, advancement of potential biomarkers, and development of novel therapeutic targets to improve prognosis and quality of life in multiple diseases.

Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice.

Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) repeat (>37Q) in huntingtin (htt), and age of onset is inversely correlated with the length of the polyQ repeat. Mutant htt with expanded polyQ is ubiquitously expressed in various types of cells, including glia, but causes selective neurodegeneration. Our recent study demonstrated that expression of the N-terminal mutant htt with a large polyQ repeat (160Q) in astrocytes is sufficient to induce neurological symptoms in mice (Bradford, J., Shin, J. Y., Roberts, M., Wang, C. E., Li, X.-J., and Li, S. H. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 22480-22485). Because glia-neuron interactions are critical for maintaining the normal function and survival of neurons in the brain and because mutant htt is more abundant in neurons than in glial cells, it is important to investigate whether glial htt can still contribute to HD pathology when mutant htt is abundantly expressed in neuronal cells. We generated transgenic mice that express mutant htt with 98Q in astrocytes. Unlike our recently generated htt-160Q transgenic mice, htt-98Q mice do not show obvious neurological phenotypes, suggesting that the length of the polyQ repeat determines the severity of glial dysfunction. However, htt-98Q mice show increased susceptibility to glutamate-induced seizure. Mice expressing mutant htt in astrocytes were mated with N171-82Q mice that express mutant htt primarily in neuronal cells. Double transgenic mice expressing mutant htt in both neuronal and glial cells display more severe neurological symptoms and earlier death than N171-82Q mice. These findings indicate a role of glial mutant htt in exacerbating HD neuropathology and underscore the importance of improving glial function in treating HD.

Vulvovaginal candidiasis in postmenopausal women: the role of hormone replacement therapy.

OBJECTIVE: : This study aimed to explore the role of hormone replacement therapy (HRT) in susceptibility to vulvovaginal candidiasis (VVC) in a private vulval disease referral practice. METHODS: : Between January 2009 and December 2010, 149 healthy, nondiabetic patients with vulvar conditions were compared for significant differences in vaginal swab result, age, and diagnosis between those using and not using HRT. Detailed clinical data were collected from those with VVC. RESULTS: : The mean ages of the HRT (n = 70) and non-HRT (n = 79) groups were 62.5 and 62.5 years, respectively. Positive cultures for Candida were found in 34 (48.5%) of 70 patients on HRT and in 2 (3%) of 79 subjects not on HRT (p < .001). Culture-positive, clinical VVC was identified in 34 (49%) of 70 patients on HRT and in 1 (1%) of 79 patients not on HRT (p < .001). Candida species (32 Candida albicans and 2 Candida glabrata) were isolated from the 34 VVC patients, and of these, 23 (67%) had a history of recurrent or chronic candidiasis before menopause. All 34 had been previously treated with antifungal therapy without ceasing HRT and had been unresponsive to treatment or had relapse after treatment. In 27 (79%) of 34 patients, HRT was suspended during treatment. Of those who remained on HRT during treatment or resumed it after treatment, prophylactic antifungal treatment was initiated in 15 (44%) to prevent recurrence. All patients responded to the antifungal treatment provided HRT was suspended or prophylactic treatment was used. CONCLUSIONS: : Postmenopausal women taking HRT are significantly more prone to develop VVC than women who are not and those with VVC are likely to have been susceptible to it before menopause.

Interactions between vulvovaginal disorders and urinary disorders: The case for an integrated view of the pelvis.

Lower urinary tract symptomatology is often difficult to categorize if history and investigation focus only on the urinary tract. Disease and dysfunction in organs more posteriorly can often cause or influence such bladder and urethral symptoms. Vulvovaginal skin diseases are an important but often missed influence on lower urinary tract symptomatology.