Incidence of Cardiovascular Instability in Patients With Guillain-Barré Syndrome: A Retrospective Study.

Introduction Guillain-Barré syndrome (GBS) is an autoimmune disease affecting radicles and peripheral nerves resulting in acute flaccid paralysis. Respiratory failure, autonomic dysfunction, and secondary complications such as pneumonia, and venous thromboembolism are the major causes of death and disability in GBS. Cardiovascular complications play a major role in the prognosis of GBS patients. The aim is to determine the incidence of cardiovascular instability in GBS patients and to see if there are any specific risk groups associated with the development of cardiovascular instability. Methodology This is a retrospective descriptive study conducted in a tertiary care center in South India. Data on 50 consecutive GBS patients were collected from hospital records including case sheets, death summaries, and discharge summaries. Patients with evidence of sepsis, blood loss, heavy alcohol consumption, and chronic liver disease were excluded from the study. Baseline demographic data, symptom onset to admission time, baseline Erasmus Guillain-Barré Syndrome Respiratory Insufficiency Score (EGRIS), and baseline liver function tests were documented. The presence of heart rate and blood pressure fluctuations was noted from the records. Frequency data were calculated from the categorical variables. Analysis of non-parametric variables by chi-square test was done using IBM SPSS Statistics for Windows, Version 25.0 (Released 2017; IBM Corp., Armonk, New York, United States). Results Cardiovascular instability was present in 15 (30%) patients in the study population. It was present in all patients (100%) who require mechanical ventilation. The incidence of cardiovascular instability was higher in patients who had lesser onset to admission times (41.9% vs 10.5%; p=0.019), EGRIS≥4 (40.6% vs 11.1%; p=0.029), and lower cranial nerve involvement (40% vs 6.7%; p=0.018). Conclusion Of patients with GBS, 30% developed cardiovascular instability during their disease course. Patients with lesser onset to admission times, EGRIS ≥4, and those with lower cranial nerve involvement had a greater incidence of cardiovascular instability.

Exophytic Subserosal Uterine Adenomyomatous Polyp Mimicking Malignancy: A Case Report.

The epidemiological profile of adenomyosis has drastically changed in recent years due to advancements in imaging techniques. Even though adenomyosis is not uncommon in women of childbearing age, we present an intriguing case of a 30-year-old woman with long-standing progressive dysmenorrhea and infertility who had a posterior wall exophytic adenomyomatous polyp with full-thickness pseudo-invasion out of the uterine serosa into the right ovarian endometriotic cyst, mimicking malignancy. After surgical excision, the patient spontaneously conceived and delivered a live-term baby, soon after which she experienced an early recurrence. Clinicians must be aware of the distinctive features of different subtypes of adenomyosis to plan treatment and avoid invasive surgery.

The comparison of Y chromosome microdeletion incidence in blood DNA and sperm cell DNA.

BACKGROUND: During gamete development and spermatogenesis, certain genes on the Y chromosome (Yq) in the Male-Specific Region (MSR) are responsible for human gametes formation. The long arm Yq is composed of both euchromatin and the genetically inactive heterochromatin regions. This region contains the Azoospermia factors AZFa, AZFb and AZFc. In the case of male infertility, microdeletions on the Yq chromosome appear to be structural chromosomal anomalies linked to sperm abnormality. METHODS: The present study aimed to look at the incidence, of Asthenospermia (AS), Teratospermia (TS), Oligospermia (OS) and Oligoasthenoteratospermia (OAT) patterns of Y chromosomal microdeletions in Indian infertile men with an (AZF a, b, c). This study was conducted with 75 infertile men as cases and 75 fertile men as a control for AZF locus microdeletion utilizing sequence-tagged sites. RESULTS: The AZFc region of germ cell DNA (50.6%) was the most deleted section in infertile men when compared to blood DNA (21.3%), followed by deletions in the AZFb region (21.3%) in germ cell DNA whereas blood DNA had no microdeletion in the AZFa region in both germ cell DNA and blood DNA. Infertile men displayed significant Yq microdeletion in both AZFb and also AZFc. Around 33% (25) of 75 infertile men had AZF (a, b, c) region microdeletion in blood DNA, compared to it germ cell DNA had a larger percentage of 72% (54) of Y chromosome microdeletions in the study samples. CONCLUSION: A high-frequency rate of microdeletions seen in germ cell DNA. PCR-based Y chromosome microdeletion screening using germ cell DNA along with Genomic DNA might help in screening for genetic abnormality in infertile men who endure assisted reproductive technology treatments. This study might be attributable to the interplay of lifestyle and genetic factors, both contributing to the risk of developing these germ-line deletions.

ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.

Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAFV600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.

ASN004, A 5T4-targeting scFv-Fc Antibody-Drug Conjugate with High Drug-to-Antibody Ratio, Induces Complete and Durable Tumor Regressions in Preclinical Models.

The 5T4 oncofetal antigen (trophoblast glycoprotein) is expressed in a wide range of malignant tumors but shows very limited expression in normal adult tissues. ASN004 is a 5T4-targeted antibody-drug conjugate (ADC) that incorporates a novel single-chain Fv-Fc antibody and Dolaflexin drug-linker technology, with an Auristatin F hydroxypropylamide payload drug-to-antibody ratio of approximately 10-12. The pharmacology, toxicology, and pharmacokinetic properties of ASN004 and its components were investigated in vitro and in vivo ASN004 showed high affinity for the 5T4 antigen and was selectively bound to and internalized into 5T4-expressing tumor cells, and potent cytotoxicity was demonstrated for a diverse panel of solid tumor cell lines. ASN004 induced complete and durable tumor regression in multiple tumor xenograft models, derived from human lung, breast, cervical, and gastric tumor cell lines having a wide range of 5T4 expression levels. A single dose of ASN004, as low as 1 mg/kg i.v., achieved complete tumor regression leading to tumor-free survivors in the A431 cervical cancer model. In head-to-head studies, superior activity of ASN004 was demonstrated against trastuzumab-DM1, in a low-5T4/high-HER2 expressing gastric tumor model, and 10-fold greater potency was found for ASN004 against the 5T4-targeted ADC PF-06263507 in a lung tumor model. In marmoset monkeys, ASN004 was well tolerated at doses up to 1.5 mg/kg Q3W i.v., and showed dose-dependent exposure, linear pharmacokinetics, and markedly low exposure of free payload drug. Taken together, these findings identify ASN004 as a promising new ADC therapeutic for clinical evaluation in a broad range of solid tumor types.

Association of estrogen, progesterone and follicle stimulating hormone receptor polymorphisms with in vitro fertilization outcomes.

Despite the advances in in vitro fertilization (IVF), the implantation success rate for infertile women remains approximately only 15%. In this study, we sought to determine whether implantation failure after repeated IVF treatments is influenced by the presence of common variants in estrogen α, progesterone and follicle stimulating hormone receptor genes. The study population included three groups of women: group 1 were 50 women who had the transfer of ≥3 high-quality embryos during the IVF procedure without ever having had a clinical pregnancy; group 2 were 50 women who achieved a clinical pregnancy after ≤3 high-quality embryos transfers and group 3 were 50 control subjects who achieved a clinical pregnancy without any fertility therapy that resulted in a one live-born infant. Genotype analysis was performed using polymerase chain reaction and Sanger sequencing for rs6165, rs6166, rs2234693, rs9340799. While progesterone receptor single nucleotide polymorphism (SNP)  was genotyped based on the amplicon size, the repeats for the ESR1 TA-repeat polymorphism were calculated based on the fragment length. A higher frequency of the heterozygote AG genotype was observed in the infertile groups when compared to controls. Significantly, an allele combination of T of rs2234693, A of rs9340799; S of ESR1 (TA), A of rs6166, G of rs6165 and del of PROGINS had a higher frequency in women who had a successful IVF outcome compared to women who had an unsuccessful IVF outcome, indicating a possible protective combined genotype that could reduce a negative outcome during IVF. This study has demonstrated that combining several candidate genes is needed to assess which may play a role in fertility. ABBREVIATIONS: CI: confidence interval; COH: controlled ovarian hyperstimulation; DNA: deoxyribonucleic acid; ESR: estrogen receptors; FSH: follicle stimulating hormones; FSHR: FSH receptor; IVF: in vitro fertilization; PGR: progesterone receptors; SNP: single nucleotide polymorphism.

Multicenter Study of Contraceptive Vaginal Ring (NuvaRing(®)) in Normal Daily Practice in Indian Women.

OBJECTIVE: This was the first Indian multicenter study at six specialty hospitals, to assess the real-life usage of the vaginal ring in daily clinical practice. METHODS: This open-label, prospective, single-arm, nonrandomized, interventional study enrolled 252 women aged >18 years, seeking contraception with no contraindications to the use of combined hormonal contraceptive. Women were provided the ring with a monthly follow-up schedule for three cycles. Cycle control, acceptability, tolerability, and safety assessments were recorded at each visit. RESULTS: Regular menstrual bleeding was reported by 76.2 % (192/252) at baseline. In study completers, regular bleeding was seen in 94.1 % (192/204), 97.5 % (199/204), and 98 % (200/204) in the 1st, the 2nd, and the 3rd cycles, respectively. Most (94.2 % [195/207]) women were very satisfied or satisfied with the ring, and 93.2 % (193/207) would recommend it to others. No pregnancies or serious adverse events were reported. CONCLUSION: The study demonstrated that NuvaRing(®) is a highly effective contraceptive method with an excellent cycle control. It is well tolerated and accepted by Indian women.

Magnetic resonance signal intensity measurements in the diagnosis of fetal central nervous system anomalies.

OBJECTIVES: To evaluate the possible role of Magnetic Resonance (MR) signal intensity measurements in diagnosing Central Nervous System (CNS) anomalies antenatally. METHODS: MR images of 110 fetal brains between 18 and 38 weeks were studied. Nine were excluded due to destroyed brain. 50 had CNS anomalies. 51 had normal CNS and were used as controls. Regions of interest (ROI) cursors were placed in Vitreous, cerebellar vermis, thalamus, frontal white matter, corona radiata, periventricular region and grey matter. The lateral ventricle diameters were also obtained. Signal intensity ratio (SIR) was calculated by the signal intensity of each of the above regions to that of the vitreous. SIR in controls were compared with fetuses having: (1) Hydrocephalus. (2) Arnold Chiari type-2 Malformation (ACM-2) (3) Non-progressive ventriculomegaly (4) Miscellaneous CNS anomalies. The correlation of the normalcy or abnormalcy of the brain was based on Clinical/Physical examination in 51, Ultrasound in 20, MRI in 2 and autopsy in 28. RESULTS: In hydrocephalus and ACM-2, the SIR of vermis and periventricular region were higher than controls whereas in non-progressive ventriculomegaly and miscellaneous CNS anomalies there was no significant difference. CONCLUSION: Signal intensity measurements are useful to differentiate physiological and non-progressive ventriculomegaly from hydrocephalus and ACM-2.

Ultrasound versus MRI in the diagnosis of fetal head and trunk anomalies.

OBJECTIVE: To compare antenatal sonography and magnetic resonance (MR) imaging (MRI) in the diagnosis of fetal head and trunk anomalies. METHODS: Forty pregnant women with fetal anomalies on ultrasound (US) examination underwent MRI. The MR examination was done by a radiologist who was provided with the US data. The MR images were then read by one of the two radiologists who were blinded to the US data. They were however told that the region of interest was (1) head-neck or (2) trunk or (3) both. Antenatal US and MRI findings were compared with postnatal diagnosis. Postnatal evaluation included plain radiograph, US, computed tomography, MRI, surgery, physical evaluation and autopsy. RESULTS: Sixty anomalies were detected in the 40 women studied. This included 36 central nervous system (CNS), 7 thoracic, 7 gastrointestinal, 8 genitourinary and 2 face-neck anomalies. In the evaluation of CNS and thoracic anomalies, more number of confident diagnoses could be obtained by MRI when compared with that by US. In the detection of gastrointestinal and genitourinary anomalies, there was no significant difference between the two modalities. CONCLUSION: More number of confident diagnoses could be obtained by MRI when compared with that by US, in the evaluation of fetal CNS and thoracic anomalies. MRI can be used in complex fetal anomalies as a supplementary tool following US.

Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitors.

A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC(50)<10nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carried out with a CDK1 homology model, and provide a rationale for the observed activities.

Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity.

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC50 of 50 nmol/L and inhibited cell growth with a GI50 of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G2-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI50 value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent.

Discovery of substituted N-phenyl nicotinamides as potent inducers of apoptosis using a cell- and caspase-based high throughput screening assay.

By applying a novel cell- and caspase-based HTS assay, a series of N-phenyl nicotinamides has been identified as a new class of potent inducers of apoptosis. Through SAR studies, a 20-fold increase in potency was achieved from a screening hit N-(4-methoxy-2-nitrophenyl)pyridine-3-carboxamide (1) to lead compound 6-methyl-N-(4-ethoxy-2-nitrophenyl)pyridine-3-carboxamide (10), with an EC(50) of 0.082 microM in the caspase activation assay in T47D breast cancer cells. The N-phenyl nicotinamides also were found to be active in the growth inhibition assay where compound 10 had a GI(50) value of 0.21 microM in T47D cells. More importantly, compound 10 was found to be equipotent in MES-SA cells and paclitaxel-resistant, p-glycoprotein overexpressed MES-SA/DX5 cells. Compounds 1 and 6-chloro-N-(4-ethoxy-2-nitrophenyl)pyridine-3-carboxamide (8), a more potent analogue, were found to arrest T47D cells in G(2)/M phase of the cell cycle followed by induction of apoptosis as measured by flow cytometry. Compound 8, which was more potent than 1 in the caspase activation assay, also was found to be more potent in G(2)/M arrest and apoptosis assay. These data confirm that the cell-based caspase activation assay is useful for screening for inducers of apoptosis, as well as for SAR studies and lead optimization. Upon further characterization, N-phenyl nicotinamides were found to be inhibitors of microtubule polymerization in vitro. The identification of N-phenyl nicotinamides as a novel series of inducers of apoptosis demonstrates that our cell- and caspase-based HTS assay is useful for the discovery and optimization of potentially novel anticancer agents.