Increased risk of major congenital malformations in early pregnancy use of angiotensin-converting-enzyme inhibitors and angiotensin-receptor-blockers: a meta-analysis.

AIMS: To evaluate the risk of adverse fetal outcomes after exposure to angiotensin converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) in first trimester of pregnancy, by conducting a systematic review and meta-analysis. MATERIALS AND METHODS: A systematic literature search was conducted using Medline, Embase, Cochrane and PubMed from inception to 25 November 2019. Studies were included if they evaluated pregnancies exposed to ACE-Is or ARBs, reported fetal outcomes, and compared these outcomes with a control group. Pooled odds ratios (ORs) were estimated using inverse variance-weighted random effects model. The protocol was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42020160566). RESULTS: Studies reporting on 6234 pregnancies exposed to ACE-Is or ARBs, 4104 pregnancies exposed to other oral antihypertensives, and 1,872,733 pregnancies without exposure were included in the meta-analysis. ACE-I or ARB exposed pregnancies, compared to non-exposed controls, had higher risk of major congenital malformations (OR 1.82; 95% confidence interval [CI]: 1.42-2.34), cardiovascular malformations (OR 2.50; 95% CI: 1.62-3.87) and stillbirths (OR 1.75; 95% CI: 1.21-2.53). There was no difference in congenital malformations observed between pregnancies exposed to other antihypertensives compared to non-exposed controls (OR 0.96; 95% CI: 0.69-1.33). CONCLUSIONS: Women exposed to ACE-Is or ARBs during early pregnancy had higher risk of adverse fetal outcomes, including malformations and stillbirths, than non-exposed controls. This increased risk was independent of underlying maternal hypertension, as those exposed to other antihypertensives did not exhibit a higher risk than healthy controls. Women planning for pregnancy using these medications, including those with diabetic nephropathy, should be counselled appropriately.

Epigenetic Dysregulation of the Dynamin-Related Protein 1 Binding Partners MiD49 and MiD51 Increases Mitotic Mitochondrial Fission and Promotes Pulmonary Arterial Hypertension: Mechanistic and Therapeutic Implications.

BACKGROUND: Mitotic fission is increased in pulmonary arterial hypertension (PAH), a hyperproliferative, apoptosis-resistant disease. The fission mediator dynamin-related protein 1 (Drp1) must complex with adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here, we examine the role of 2 recently discovered, poorly understood Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51), in normal vascular cells and explore their dysregulation in PAH. METHODS: Immunoblots of pulmonary artery smooth muscle cells (control, n=6; PAH, n=8) and immunohistochemistry of lung sections (control, n=6; PAH, n=6) were used to assess the expression of MiD49 and MiD51. The effects of manipulating MiDs on cell proliferation, cell cycle, and apoptosis were assessed in human and rodent PAH pulmonary artery smooth muscle cells with flow cytometry. Mitochondrial fission was studied by confocal imaging. A microRNA (miR) involved in the regulation of MiD expression was identified using microarray techniques and in silico analyses. The expression of circulatory miR was assessed with quantitative reverse transcription-polymerase chain reaction in healthy volunteers (HVs) versus patients with PAH from Sheffield, UK (plasma: HV, n=29, PAH, n=27; whole blood: HV, n=11, PAH, n=14) and then confirmed in a cohort from Beijing, China (plasma: HV, n=19, PAH, n=36; whole blood: HV, n=20, PAH, n=39). This work was replicated in monocrotaline and Sugen 5416-hypoxia, preclinical PAH models. Small interfering RNAs targeting MiDs or an miR mimic were nebulized to rats with monocrotaline-induced PAH (n=4-10). RESULTS: MiD expression is increased in PAH pulmonary artery smooth muscle cells, which accelerates Drp1-mediated mitotic fission, increases cell proliferation, and decreases apoptosis. Silencing MiDs (but not other Drp1 binding partners, fission 1 or mitochondrial fission factor) promotes mitochondrial fusion and causes G1-phase cell cycle arrest through extracellular signal-regulated kinases 1/2- and cyclin-dependent kinase 4-dependent mechanisms. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased miR-34a-3p expression. Circulatory miR-34a-3p expression is decreased in both patients with PAH and preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH. CONCLUSIONS: In health, MiDs regulate Drp1-mediated fission, whereas in disease, epigenetic upregulation of MiDs increases mitotic fission, which drives pathological proliferation and apoptosis resistance. The miR-34a-3p-MiD pathway offers new therapeutic targets for PAH.

MicroRNA-138 and MicroRNA-25 Down-regulate Mitochondrial Calcium Uniporter, Causing the Pulmonary Arterial Hypertension Cancer Phenotype.

RATIONALE: Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis resistance. This cancer-like phenotype is promoted by increased cytosolic calcium ([Ca2+]cyto), aerobic glycolysis, and mitochondrial fission. OBJECTIVES: To determine how changes in mitochondrial calcium uniporter (MCU) complex (MCUC) function influence mitochondrial dynamics and contribute to PAH's cancer-like phenotype. METHODS: PASMCs were isolated from patients with PAH and healthy control subjects and assessed for expression of MCUC subunits. Manipulation of the pore-forming subunit, MCU, in PASMCs was achieved through small interfering RNA knockdown or MCU plasmid-mediated up-regulation, as well as through modulation of the upstream microRNAs (miRs) miR-138 and miR-25. In vivo, nebulized anti-miRs were administered to rats with monocrotaline-induced PAH. MEASUREMENTS AND MAIN RESULTS: Impaired MCUC function, resulting from down-regulation of MCU and up-regulation of an inhibitory subunit, mitochondrial calcium uptake protein 1, is central to PAH's pathogenesis. MCUC dysfunction decreases intramitochondrial calcium ([Ca2+]mito), inhibiting pyruvate dehydrogenase activity and glucose oxidation, while increasing [Ca2+]cyto, promoting proliferation, migration, and fission. In PAH PASMCs, increasing MCU decreases cell migration, proliferation, and apoptosis resistance by lowering [Ca2+]cyto, raising [Ca2+]mito, and inhibiting fission. In normal PASMCs, MCUC inhibition recapitulates the PAH phenotype. In PAH, elevated miRs (notably miR-138) down-regulate MCU directly and also by decreasing MCU's transcriptional regulator cAMP response element-binding protein 1. Nebulized anti-miRs against miR-25 and miR-138 restore MCU expression, reduce cell proliferation, and regress established PAH in the monocrotaline model. CONCLUSIONS: These results highlight miR-mediated MCUC dysfunction as a unifying mechanism in PAH that can be therapeutically targeted.

An interesting case of profound hypoxemia.

A 58 year old male with a history of cirrhosis (hepatitis B and C), a long smoking history, and a recently diagnosed high-grade transitional cell carcinoma of the bladder wall presented three days after a biopsy procedure with abdominal pain, nausea, and new hypoxemia on room air. The chest radiograph was clear and the CT angiogram showed only a borderline large pulmonary artery, two small nodules (3mm and 4mm) in the right middle lobe of the lung, and emphysematous changes throughout the lung parenchyma. There was no evidence of pulmonary embolism. A wide range of diagnostic possibilities were entertained, including pneumonia (community or aspiration related to the procedure), COPD exacerbation, pulmonary emboli, porto-pulmonary syndrome, pulmonary hypertension with right to left shunt, tumor emboli, allergic reaction to a medication or chemotherapeutic agent, or lymphangitic/hematogenous spread of tumor to the lungs. The diagnosis was only established on a post mortem examination. The progressive hypoxia was due to diffuse spread of tumor within alveolar capillaries.

Bone mineral density in patients with alopecia areata treated with long-term intralesional corticosteroids.

BACKGROUND: Intralesional corticosteroid injections are a common treatment for patchy alopecia areata, the most prevalent subtype of this autoimmune hair disorder. To date, no studies have examined the potential adverse effects of this therapy on bone mineral density (BMD). METHODS: In this retrospective, cross-sectional case series, 18 patients with patchy alopecia areata treated at 4- to 8-week intervals with intralesional triamcinolone acetonide for at least 20 months were evaluated for BMD using dual-energy x-ray absorptiometry (DXA). Follow-up DXA measurements were obtained in those with abnormal findings. RESULTS: Nine out of 18 patients (50%) had abnormal DXA results. Patients with the following risk factors were more likely to have abnormal BMD: age older than 50 years, body mass index less than 18.5 kg/m2, lack of weight-bearing exercise, smoking history, postmenopausal status, past stress fracture, family history of osteopenia or osteoporosis, and a cumulative intralesional triamcinolone acetonide dose of greater than 500 mg. CONCLUSION: Patients with patchy alopecia areata who receive chronic intralesional triamcinolone acetonide therapy should be counseled on preventive measures for osteoporosis and monitored for effects on BMD.

The life course perspective of gestational diabetes: An opportunity for the prevention of diabetes and heart disease in women.

Gestational diabetes mellitus (GDM), which has traditionally been defined as glucose intolerance of varying severity with first onset in pregnancy, is rising in prevalence with maternal hyperglycemia currently affecting one in every six pregnancies worldwide. Although often perceived as a medical complication of pregnancy, GDM is actually a chronic cardiometabolic disorder that identifies women who have an elevated lifetime risk of ultimately developing type 2 diabetes and cardiovascular disease. In identifying high-risk women early in the natural history of these conditions, the diagnosis of GDM raises the tantalizing possibility of early intervention and risk modification. However, before such promise can be realized in practice, a series of clinical challenges/obstacles (reviewed herein) must be overcome. Ultimately, the coupling of this life course perspective of GDM with concerted efforts to overcome these challenges may enable fulfilment of this unique opportunity for the primary prevention of diabetes and heart disease in women.

Gestational weight gain in women with type 2 diabetes and perinatal outcomes: A secondary analysis of the metformin in women with type 2 diabetes in pregnancy (MiTy) trial.

AIMS: Our study assesses perinatal outcomes among women with type 2 diabetes, with gestational weight gain (GWG) within and outside of US Institute of Medicine (IOM) guidelines, by conducting a secondary analysis of the Metformin in Type 2 Diabetes in Pregnancy (MiTy) trial. METHODS: 460 participants were classified into three cohorts by total and weekly GWG (excessive, appropriate vs. restricted according to IOM). The primary outcome was birthweight z score, and secondary outcomes included both maternal and fetal outcomes. RESULTS: Women with restricted (total and weekly) GWG had lower birthweight z score, lower fetal birthweight, and lower neonatal body fat mass. Women with restricted weekly GWG had fewer LGA, extreme LGA, and lower neonatal body fat mass infants, but more SGA and preterm births. Women with excessive (total and weekly) GWG had higher maternal total insulin doses in the third trimester. Women with excessive weekly GWG had more preeclampsia and higher SGA. CONCLUSIONS: Restricted GWG among women with type 2 diabetes is associated with both benefits and harms. Both must be considered when counseling patients.

Opiate Exposure State Controls a D2-CaMKIIα-Dependent Memory Switch in the Amygdala-Prefrontal Cortical Circuit.

The mammalian basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) comprise a functionally interconnected circuit that is critical for processing opiate-related associative memories. In the opiate-naïve state, reward memory formation in the BLA involves a functional link between dopamine (DA) D1 receptor (D1R) and extracellular signal-related kinase 1/2 (ERK1/2) signaling substrates, but switches to a DA D2 (D2R)/Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα)-dependent memory substrate following chronic opiate exposure and spontaneous withdrawal. Using conditioned place preference (CPP) in rats paired with molecular analyses, we examined the role of intra-mPFC CaMKII, ERK and DAergic activity during the formation of opiate associative memories, and how opiate exposure state may regulate the functions of these molecular memory pathways. We report that the role of CaMKIIα signaling is functionally reversed within the BLA-mPFC pathway depending on opiate exposure state. Thus, in the opiate-naïve state, intra-mPFC but not intra-BLA blockade of CaMKII signaling prevents formation of opiate reward memory. However, following chronic opiate exposure and spontaneous withdrawal, the role of CaMKII signaling in the BLA-mPFC is functionally reversed. This behavioral memory switch corresponds to a selective increase in the expression of D2R and CaMKIIα, but not other calcium/calmodulin-related molecules, nor D1R expression levels within the mPFC.

Lung cancer in women: analysis of the national Surveillance, Epidemiology, and End Results database.

OBJECTIVES: In order to further characterize the effect of gender on the clinicopathologic features and survival of patients with lung cancer, and to determine gender-associated differences in temporal trends, we analyzed data that had been entered into a population-based cancer database. PATIENTS AND METHODS: Data on demographics, stage at diagnosis, histology, initial therapy, and survival were obtained on all patients with primary bronchogenic carcinoma registered in the national Surveillance, Epidemiology, and End Results database from 1975 to 1999. RESULTS: Of the 228,572 eligible patients, 35.8% were female. The median age at diagnosis was 66 years for both men and women. However, women accounted for 40.9% of patients who were < 50 years of age and for 35.4% of older patients. The incidence of lung cancer in men peaked at 72.5 per 100,000 person-years in 1984 and then declined to 47 per 100,000 person-years by 1999. In women, the incidence continued to rise to a peak of 33.1 per 100,000 person-years in 1991 before reaching a plateau at 30.2 to 32.3 per 100,000 person-years from 1992 to 1999. These changes have resulted in a marked narrowing of the male/female incidence ratio from 3.56 in 1975 to 1.56 in 1999. As initial treatment, women with local disease underwent surgery more frequently than did men. Stage-specific survival rates were better for women at all stages of disease (p < 0.0001). In a multivariate analysis, male gender was an independent negative prognostic factor (p < 0.0001). CONCLUSION: The incidence rate of lung cancer in women in the United States has reached a plateau. However, women are relatively overrepresented among younger patients, raising the question of gender-specific differences in the susceptibility to lung carcinogens. At each stage of the disease, the relative survival of women is better than that of men, with the largest difference noted in patients with local disease.

Western Database of Lipid Variants (WDLV): a catalogue of genetic variants in monogenic dyslipidemias.

BACKGROUND: Next-generation sequencing (NGS) is nearing routine clinical application, especially for diagnosis of rare monogenic cardiovascular diseases. But NGS uncovers so much variation in an individual genome that filtering steps are required to streamline data management. The first step is to determine whether a potential disease-causing variant has been observed previously in affected patients. METHODS: To facilitate this step for lipid disorders, we developed the Western Database of Lipid Variants (WDLV) of 2776 variants in 24 genes that cause monogenic dyslipoproteinemias, including conditions characterized primarily by either high or low low-density lipoprotein cholesterol, high or low high-density lipoprotein cholesterol, high triglyceride, and some miscellaneous disorders. We incorporated quality-control steps to maximize the likelihood that a listed mutation was disease causing. RESULTS: The details of each mutation found in a dyslipidemia, together with a mutation map of the causative genes, are shown in graphical display items. CONCLUSIONS: WDLV will help clinicians and researchers determine the potential pathogenicity of mutations discovered by DNA sequencing of patients or research participants with lipid disorders.

Disruption of urogenital biofilms by lactobacilli.

The process that changes a relatively sparse vaginal microbiota of healthy women into a dense biofilm of pathogenic and potentially pathogenic bacteria is poorly understood. Likewise, the reverse step whereby an aberrant biofilm is displaced and returns to a healthy lactobacilli dominated microbiota is unclear. In order to study these phenomena, in vitro experiments were performed to examine the structure of biofilms associated with aerobic vaginosis, urinary tract infections, and bacterial vaginosis (BV). Uropathogenic Escherichia coli were able to form relatively thin biofilms within five days (6 µm height), while Atopobium vaginae and Gardnerella vaginalis formed thicker biofilms 12 µm in height within two days. Challenge of E. coli biofilms with lactobacilli did not result in pathogen displacement. However, the resulting thicker lactobacilli infused biofilms, caused significant E. coli killing. E. coli biofilms challenged with secreted products of L. rhamnosus GR-1 caused a marked decrease in cell density, and increased cell death. Similarly challenge of BV biofilms with lactobacilli infiltrated BV biofilms and caused bacterial cell death. Metronidazole produced holes in the biofilm but did not eradicate the organisms. The findings provide some evidence of how lactobacilli probiotics might interfere with an aberrant vaginal microbiota, and strengthen the position that combining probiotics with antimicrobials could better eradicate pathogenic biofilms.

Approach to hair loss in women of color.

Hair loss in women of color represents a unique diagnostic challenge that requires a systematic approach. In women of color, clinical examination of the hair and scalp is most helpful when performed first and used to guide subsequent history-taking to arrive at a clinical assessment. The most common hair problems in women of color are hair breakage, traction alopecia, and central centrifugal cicatricial alopecia. A careful detailed clinical examination and history will guide the clinician to appropriate counseling and management. It is important to recognize that a patient may have more than one of these 3 diagnoses and each requires separate attention. Traction alopecia is completely preventable with appropriate education of the public and medical establishment.

Adenosquamous carcinoma of the skin: a case series.

BACKGROUND: Adenosquamous carcinoma is an uncommon cutaneous malignant neoplasm with mixed glandular and squamous differentiation and a propensity for aggressive clinical behavior. OBSERVATIONS: Of 27 patients diagnosed as having adenosquamous carcinoma, 19 were men and 5 were immunosuppressed. The mean age was 74 years. The majority of tumors were located on the face and scalp (19 of 27 [70%]) or upper extremity (4 of 27 [15%]). Squamous and glandular differentiation was characteristic. Thickness of the primary lesion ranged from 1.2 to 9.2 mm, with all tumors extensively invading the reticular dermis. Perineural invasion was seen in 4 of 27 primary cases (15%). Although 3 of 6 patients treated with Mohs micrographic surgery had subsequent locoregional recurrences, there was no evidence of distant metastasis after a mean of 2.3 years of patient follow-up. CONCLUSIONS: Adenosquamous carcinoma is best considered as a locally aggressive high-risk subtype of cutaneous squamous cell carcinoma. Tumor thickness and perineural invasion are high-risk histopathological attributes, and immunosuppression is an important clinical risk factor. Although Mohs micrographic surgery may be the best initial treatment, locoregional recurrence is common.

Pathology of borderline HER-2/neu breast carcinoma: a biologically distinct phenotype.

PURPOSE: The significance of HER-2/neu results obtained by immunohistochemical analyses (IHC) which are neither negative nor strongly positive is controversial. The incidence of fluorescence in situ hybridization (FISH) positivity in these tumors is small and the implication is that these borderline results represent laboratory misclassification. We analyzed the tumor characteristics of these HER-2/neu borderline tumors to determine if they represent a unique tumor type. METHODS: HER-2/neu status was determined by image analysis (IA) of IHC sections in 669 cases of invasive breast cancer. Borderline cases were reflexed to FISH to determine gene status. HER-2/neu results were compared to tumor morphology and other tumor markers. RESULTS: HER-2/neu was negative, borderline and positive in 69.5, 15.8, and 14.6% of cases, respectively. HER-2/neu amplification was present in 17.3% of borderline cases. The borderline group is significantly different from the HER-2/neu positive group for all parameters studied except Ki-67. Compared to the HER-2/neu negative group, the borderline group showed a significantly higher HER-2/neu gene copy number and a trend towards lower progesterone receptor expression (p=0.058). Compared to the HER-2/neu negative group, the HER-2/neu borderline/FISH-negative group showed significantly lower PR expression. Compared to the HER-2/neu positive group, the HER-2/neu borderline/FISH positive group showed significant differences with multiple parameters. CONCLUSION: Borderline HER-2/neu tumors are a unique tumor type and do not represent laboratory imprecision. Hormone receptor alterations are associated with early changes in HER-2/neu expression. While IA is capable of detecting these changes, current FISH methodology is not.

Sunless tanning.

BACKGROUND: Americans continue to desire and pursue the tan. Recent data indicate continued high incidence of sunburn and ultraviolet tanning despite public health skin cancer prevention messages. The rising popularity of recently available sunless tanning booths prompted this review. OBJECTIVE: To present an overview of the history of sunless tanning and the sunless tanning booth industry, and to describe the current availability and safety practices of sunless tanning booth providers. METHODS: The current literature and internet resources were reviewed. Phone surveys of 300 businesses were conducted in July, 2003. RESULTS: Sunless tanning services were offered by 43% (39/90) of businesses with tanning services of any type. Sunless tanning booths were the most commonly offered sunless tanning application modality. The safety precautions most commonly offered to sunless tanning customers were recommendations to close their eyes (100%, 17/17), hold their breath (77%, 13/17), and utilize post-sunless tanning sun protection (82%, 14/17). CONCLUSION: Uniform guidelines should be developed to address safety issues associated with sunless tanning booth use. Future investigations are warranted to assess both the medical and behavioral implications of perpetuating the aesthetic appeal of the tan.

Mature myelin basic protein-expressing oligodendrocytes are insensitive to kainate toxicity.

We examined the vulnerability to excitotoxicity of rat oligodendrocytes in dissociated cell culture at different developmental stages. Mature oligodendrocytes that express myelin basic protein were resistant to excitotoxic injury produced by kainate, whereas earlier stages in the oligodendrocyte lineage were vulnerable to this insult. To test the hypothesis that the sensitivity of immature oligodendrocytes and the resistance of mature oligodendrocytes to kainate toxicity were due to differences in membrane responsiveness to kainate, we used whole-cell patch-clamp recording. Oligodendrocyte precursors in cultures vulnerable to kainate toxicity responded to 500 microM kainate with large inward currents, whereas mature myelin basic protein-expressing oligodendrocytes in cultures resistant to kainate toxicity showed no clear response to application of this agonist. We assayed expression of glutamate receptor subunits (GluR) -2, -4, -6, -7, and KA2 using immunoblot analysis and found that expression of all of these glutamate receptors was significantly down-regulated in mature oligodendrocytes. These results suggest a striking developmental regulation of glutamate receptors in oligodendrocytes and suggest that the vulnerability of oligodendrocytes to non- N-methyl-D-aspartate receptor-mediated excitotoxicity might be much greater in developing oligodendrocytes than after the completion of myelination.