Inflammatory vaginitis in four B-cell suppressed women with Multiple Sclerosis.

B-cell depleting therapies are effective in multiple sclerosis (MS) and are widely used (Hauser et al., 2017). Inflammatory vaginitis (IV), characterized by unexplained vaginal symptoms including mucopurulent discharge, pain, irritation, and dyspareunia, has been reported in one MS patient on ocrelizumab (Filikci and Jensen, 2022), and to be present in 3.5 % of women on rituximab for autoimmune diseases (Yockey et al., 2021). We report here four cases of IV in B cell depleted women with MS. B-cell reconstitution was temporally associated with improvement of IV symptoms. Further investigation and vigilance for this potential treatment emergent adverse event affecting sexual and reproductive health of women with MS is needed.

Hypertensive disorders of pregnancy and long-term cardiovascular health: FIGO Best Practice Advice.

Hypertensive disorders of pregnancy (HDP) are the most common causes of maternal and perinatal morbidity and mortality. They are responsible for 16% of maternal deaths in high-income countries and approximately 25% in low- and middle-income countries. The impact of HDP can be lifelong as they are a recognized risk factor for future cardiovascular disease. During pregnancy, the cardiovascular system undergoes significant adaptive changes that ensure adequate uteroplacental blood flow and exchange of oxygen and nutrients to nurture and accommodate the developing fetus. Failure to achieve normal cardiovascular adaptation is associated with the development of HDP. Hemodynamic alterations in women with a history of HDP can persist for years and predispose to long-term cardiovascular morbidity and mortality. Therefore, pregnancy and the postpartum period are an opportunity to identify women with underlying, often unrecognized, cardiovascular risk factors. It is important to develop strategies with lifestyle and therapeutic interventions to reduce the risk of future cardiovascular disease in those who have a history of HDP.

The challenges of obesity for fertility: A FIGO literature review.

Obesity has been linked to infertility through several mechanisms, including at a molecular level. Those living with obesity face additional barriers to accessing fertility treatments and achieving a successful pregnancy, which can contribute to their economic and psychosocial stressors. There is scope to further improve care for people living with obesity and infertility with empathy, via a multidisciplinary approach.

Management of obesity across women's life course: FIGO Best Practice Advice.

Obesity is a chronic, progressive, relapsing, and treatable multifactorial, neurobehavioral disease. According to the World Health Organization, obesity affects 15% of women and has long-term effects on women's health. The focus of care in patients with obesity should be on optimizing health outcomes rather than on weight loss. Appropriate and common language, considering cultural sensitivity and trauma-informed care, is needed to discuss obesity. Pregnancy is a time of significant physiological change. Pre-, ante-, and postpartum clinical encounters provide opportunities for health optimization for parents with obesity in terms of, but not limited to, fertility and breastfeeding. Pre-existing conditions may also be identified and managed. Beyond pregnancy, women with obesity are at an increased risk for gastrointestinal and liver diseases, impaired kidney function, obstructive sleep apnea, and venous thromboembolism. Gynecological and reproductive health of women living with obesity cannot be dismissed, with accommodations needed for preventive health screenings and consideration of increased risk for gynecologic malignancies. Mental wellness, specifically depression, should be screened and managed appropriately. Obesity is a complex condition and is increasing in prevalence with failure of public health interventions to achieve significant decrease. Future research efforts should focus on interprofessional care and discovering effective interventions for health optimization.

Using FIGO Nutrition Checklist counselling in pregnancy: A review to support healthcare professionals.

The period before and during pregnancy is increasingly recognized as an important stage for addressing malnutrition. This can help to reduce the risk of noncommunicable diseases in mothers and passage of risk to their infants. The FIGO Nutrition Checklist is a tool designed to address these issues. The checklist contains questions on specific dietary requirements, body mass index, diet quality, and micronutrients. Through answering these questions, awareness is generated, potential risks are identified, and information is collected that can inform health-promoting conversations between women and their healthcare professionals. The tool can be used across a range of health settings, regions, and life stages. The aim of this review is to summarize nutritional recommendations related to the FIGO Nutrition Checklist to support healthcare providers using it in practice. Included is a selection of global dietary recommendations for each of the components of the checklist and practical insights from countries that have used it. Implementation of the FIGO Nutrition Checklist will help identify potential nutritional deficiencies in women so that they can be addressed by healthcare providers. This has potential longstanding benefits for mothers and their children, across generations.

Pregnancy as an opportunity to prevent type 2 diabetes mellitus: FIGO Best Practice Advice.

Gestational diabetes (GDM) impacts approximately 17 million pregnancies worldwide. Women with a history of GDM have an 8-10-fold higher risk of developing type 2 diabetes and a 2-fold higher risk of developing cardiovascular disease (CVD) compared with women without prior GDM. Although it is possible to prevent and/or delay progression of GDM to type 2 diabetes, this is not widely undertaken. Considering the increasing global rates of type 2 diabetes and CVD in women, it is essential to utilize pregnancy as an opportunity to identify women at risk and initiate preventive intervention. This article reviews existing clinical guidelines for postpartum identification and management of women with previous GDM and identifies key recommendations for the prevention and/or delayed progression to type 2 diabetes for global clinical practice.

Cardiovascular Health After Preeclampsia: Patient and Provider Perspective.

Background: Preeclampsia predicts future cardiovascular disease (CVD) yet few programs exist for post-preeclampsia care. Methods: The Health after Preeclampsia Patient and Provider Engagement Network workshop was convened at the Radcliffe Institute for Advanced Study in June 2018. The workshop sought to identify: 1) patient perspectives on barriers and facilitators to CVD risk reduction; 2) clinical programs specialized in post-preeclampsia care; 3) recommendations by national organizations for risk reduction; and 4) next steps. Stakeholders included the Preeclampsia Foundation, patients, clinicians who had initiated CVD risk reduction programs for women with prior preeclampsia, researchers, and national task force members. Results: Participants agreed there is insufficient awareness and action to prevent CVD after preeclampsia. Patients suggested a clinician checklist to ensure communication of CVD risks, enhanced training for clinicians on the link between preeclampsia and CVD, and a post-delivery appointment with a clinician knowledgeable about this link. Clinical programs primarily served patients in the first postpartum year, bridging obstetrical and primary care. They recommended CVD risk modification with periodic blood pressure, weight, lipid and diabetes screening. Barriers included the paucity of programs designed for this population and gaps in insurance coverage after delivery. The American Heart Association, the American College of Obstetricians and Gynecologists, and the Preeclampsia Foundation have developed guidelines and materials for patients and providers to guide management of women with prior preeclampsia. Conclusions: Integrated efforts of patients, caregivers, researchers, and national organizations are needed to improve CVD prevention after preeclampsia. This meeting's recommendations can serve as a resource and catalyst for this effort.

Hypertension Across a Woman's Life Cycle.

Hypertension accounts for 1 in 5 deaths among American women, posing a greater burden for women than men, and is among their most important risk factors for death and development of cardiovascular and other diseases. Hypertension affects women in all phases of life, with specific characteristics relating to risk factors and management for primary prevention of hypertension in teenage and young adult women; hypertension in pregnancy; hypertension during use of oral contraceptives and assisted reproductive technologies, lactation, menopause, or hormone replacement; hypertension in elderly women; and issues of race and ethnicity. All are detailed in this review, as is information relative to women in clinical trials of hypertension and medication issues. The overarching message is that effective treatment and control of hypertension improves cardiovascular outcomes. But many knowledge gaps persist, including the contribution of hypertensive disorders of pregnancy to cardiovascular disease risk, the role of hormone replacement, blood pressure targets for elderly women, and so on.

Preeclampsia: an obstetrician's perspective.

Preeclampsia is a pregnancy-specific syndrome that usually develops after 20 weeks gestation. The exact pathogenic mechanisms remain uncertain and are likely multifactorial. Preeclampsia is a heterogeneous condition with potentially maternal and fetal consequences. As part of the spectrum of hypertensive disorders of pregnancy, preeclampsia may progress rapidly and is a leading cause of maternal and perinatal morbidity and mortality worldwide. In the United States, the incidence of preeclampsia has increased. Clinical manifestations are highly variable and may occur antepartum, intrapartum, or postpartum. Hypertension and proteinuria are the traditional hallmarks for the diagnosis of preeclampsia. These signs may occur with or without multisystem dysfunction and fetal involvement. Risk factors have been identified for the development of preeclampsia; however, ideal methods for prevention, screening, and treatment remain elusive. Preeclampsia resolves after delivery of the fetus, but patients may still have hypertension postpartum. Women and fetuses affected by preeclampsia are at higher risk of developing long-term health issues. There appear to be risk factors common to hypertensive disorders of pregnancy and cardiovascular disease seen later in adulthood. Physicians providing healthcare to women are urged to recognize potential risk factors that arise from patient obstetric histories so that optimal long-term health surveillance is provided.

Identification and characterization of a potent, selective nonpeptide agonist of the CC chemokine receptor CCR8.

In this study, we report the first example of a nonpeptide chemokine receptor agonist, 2-{2-[4-(3-phenoxybenzyl)piperazin-1-yl]ethoxy}ethanol (ZK 756326), for the CC chemokine receptor CCR8. ZK 756326 inhibited the binding of the CCR8 ligand I-309 (CCL1), with an IC(50) value of 1.8 muM. Furthermore, ZK 756326 was a full agonist of CCR8, dose-responsively eliciting an increase in intracellular calcium and cross-desensitizing the response of the receptor to CCL1. In addition, ZK 756326 stimulated extracellular acidification in cells expressing human CCR8. The ability of ZK 756326 to induce a response was receptor-specific and mediated through Galpha(i), because it could be blocked by treatment with pertussis toxin. The CCR8 agonist activated cells expressing murine CCR8, eliciting their chemotaxis and inducing phosphorylation of extracellular signal-regulated kinase ERK1/2. Like CCL1, ZK 756326 inhibited human immunodeficiency virus (HIV) fusion of cells expressing CD4 and CCR8. Finally, unlike mCCL1, ZK 756326 bound to and activated a form of mCCR8 that was mutated to eliminate O-linked sulfation at tyrosines 14 and 15. Therefore, ZK 756326 is most probably not binding in the same manner as CCL1 but can activate the switch mechanism involved in transducing signaling events. In summary, we have identified a nonpeptide agonist of CCR8. This compound may be useful in evaluating the physiological role of CCR8 in HIV infection, as well as in the general study of CCR8 biology without the constraints inherent to the use of protein agonists such as its natural ligand.

High levels of protein expression using different mammalian CMV promoters in several cell lines.

With the recent completion of the human genome sequencing project, scientists are faced with the daunting challenge of deciphering the function of these newly found genes quickly and efficiently. Equally as important is to produce milligram quantities of the therapeutically relevant gene products as quickly as possible. Mammalian expression systems provide many advantages to aid in this task. Mammalian cell lines have the capacity for proper post-translational modifications including proper protein folding and glycosylation. In response to the needs described above, we investigated the protein expression levels driven by the human CMV in the presence or absence of intron A, the mouse and rat CMV promoters with intron A, and the MPSV promoter in plasmid expression vectors. We evaluated the different promoters using an in-house plasmid vector backbone. The protein expression levels of four genes of interest driven by these promoters were evaluated in HEK293EBNA and CHO-K1 cells. Stable and transient transfected cells were utilized. In general, the full-length human CMV, in the presence of intron A, gave the highest levels of protein expression in transient transfections in both cell lines. However, the MPSV promoter resulted in the highest levels of stable protein expression in CHO-K1 cells. Using the CMV driven constitutive promoters in the presence of intron A, we have been able to generate >10 microg/ml of recombinant protein using transient transfections.

Transient transfection of CHO-K1-S using serum-free medium in suspension: a rapid mammalian protein expression system.

With the recent completion of the human genome sequencing project, scientists now face the daunting challenge of deciphering the function of these newly found genes quickly and efficiently. For biotechnology, it is equally important to identify the therapeutically relevant genes as quickly as possible. Mammalian expression systems provide many advantages to aid in this task. Mammalian cell lines have the capacity for proper post-translational modifications, including proper protein folding and glycosylation. In response to these needs, a CHO-K1 cell line that grows in suspension and in serum-free media was initially established and designated CHO-K1-S. An antibody gene of interest was chosen as the target for optimization rather than a reporter gene system. A comparison of various lipid transfection reagents was made using recombinant protein expression as the endpoint readout. Various other parameters including lipid:DNA ratios, cell density, and transfections in shaker versus spinner flasks were tested using the CHO-K1-S cell line. As a result, a rapid and reliable transient transfection protocol was developed. Using this procedure, we have produced milligram/per liter quantities of bioactive recombinant proteins from several genes of interest.

Structure function differences in nonpeptide CCR1 antagonists for human and mouse CCR1.

A useful strategy for identifying ligand binding domains of G protein-coupled receptors has been the exploitation of species differences in antagonist potencies. We have used this approach for the CCR1 chemokine receptor with a novel series of antagonists, the 4-hydroxypiperidines, which were discovered by high throughput screening of human CCR1 and subsequently optimized. The structure-activity relationships for a number of different 4-hydroxypiperidine antagonists for human and mouse CCR1 were examined by receptor binding and functional assays. These compounds exhibit major differences in their rank order of potency for the human and mouse chemokine receptor CCR1. For example, the initial lead template, BX 510, which was a highly potent functional antagonist for human CCR1 (K(i) = 21 nM) was >400-fold less active on mouse CCR1 (K(i) = 9150 nM). However, increasing the length of the linker between the piperidine and dibenzothiepine groups by one methylene group generated a compound, BX 511, which was equipotent for both human and mouse CCR1. These and other analogs of the lead template BX 510, which have major differences in potency for human and mouse CCR1, are described, and a model for their interaction with human CCR1 is presented.