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Seminars in Respiratory and Critical... Jun 2022Acute Respiratory Distress Syndrome (ARDS) accounts for 10% of ICU admissions and affects 3 million patients each year. Despite decades of research, it is still...
Acute Respiratory Distress Syndrome (ARDS) accounts for 10% of ICU admissions and affects 3 million patients each year. Despite decades of research, it is still associated with one of the highest mortality rates in the critically ill. Advances in supportive care, innovations in technologies and insights from recent clinical trials have contributed to improved outcomes and a renewed interest in the scope and use of Extracorporeal life support (ECLS) as a treatment for severe ARDS, including high flow veno-venous Extracorporeal Membrane Oxygenation (VV-ECMO) and low flow Extracorporeal Carbon Dioxide Removal (ECCO2R). The rationale being that extracorporeal gas exchange allows the use of lung protective ventilator settings, thereby minimizing ventilator-induced lung injury (VILI). Ventilation strategies are adapted to the patient's condition during the different stages of ECMO support. Several areas in the management of mechanical ventilation in patients on ECMO, such as the best ventilator mode, extubation-decannulation sequence and tracheostomy timing, are tailored to the patients' recovery. Reduction in sedation allowing mobilization, nutrition and early rehabilitation are subsequent therapeutic goals after lung rest has been achieved.
Topics: Extracorporeal Membrane Oxygenation; Humans; Lung; Respiration, Artificial; Respiratory Distress Syndrome
PubMed: 35760300
DOI: 10.1055/s-0042-1749450 -
Cell Jul 2011FMRP loss of function causes Fragile X syndrome (FXS) and autistic features. FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a...
FMRP loss of function causes Fragile X syndrome (FXS) and autistic features. FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a key role in regulating neuronal translation, but there has been little consensus regarding either its RNA targets or mechanism of action. Here, we use high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) to identify FMRP interactions with mouse brain polyribosomal mRNAs. FMRP interacts with the coding region of transcripts encoding pre- and postsynaptic proteins and transcripts implicated in autism spectrum disorders (ASD). We developed a brain polyribosome-programmed translation system, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs. Our results suggest that loss of a translational brake on the synthesis of a subset of synaptic proteins contributes to FXS. In addition, they provide insight into the molecular basis of the cognitive and allied defects in FXS and ASD and suggest multiple targets for clinical intervention.
Topics: Animals; Autistic Disorder; Brain; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Mice; Mice, Knockout; Polyribosomes; Protein Biosynthesis; RNA-Binding Proteins; Ribosomes; Sequence Analysis, RNA; Synapses
PubMed: 21784246
DOI: 10.1016/j.cell.2011.06.013 -
The Journal of Clinical Endocrinology... Aug 2021Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility.
OBJECTIVE
This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS.
METHODS
This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed.
RESULTS
Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/day were -0.80 (0.13) and -0.39 (0.12) nmol/L vs -0.05 (0.10) nmol/L with placebo (P < .001 and P < .05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for fezolinetant 180 and 60 mg/d were -10.17 (1.28) and -8.21 (1.18) vs -3.16 (1.04) IU/L with placebo (P < .001 and P = .002); corresponding changes in follicle-stimulating hormone (FSH) were -1.46 (0.32) and -0.92 (0.30) vs -0.57 (0.26) IU/L (P = .03 and P = .38), underpinning a dose-dependent decrease in the LH-to-FSH ratio vs placebo (P < .001). Circulating levels of progesterone and estradiol did not change significantly vs placebo (P > .10). Fezolinetant was well tolerated.
CONCLUSION
Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.
Topics: Adolescent; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follicle Stimulating Hormone; Gonadotropins; Heterocyclic Compounds, 2-Ring; Humans; Hyperandrogenism; Luteinizing Hormone; Middle Aged; Ovarian Function Tests; Polycystic Ovary Syndrome; Receptors, Neurokinin-3; Testosterone; Thiadiazoles; Treatment Outcome; Young Adult
PubMed: 34000049
DOI: 10.1210/clinem/dgab320 -
Current Neurology and Neuroscience... Mar 2022Until the last 5 years, there was very little in the literature about the phenomenon now known as visual snow syndrome. This review will examine the current thinking on... (Review)
Review
PURPOSE OF REVIEW
Until the last 5 years, there was very little in the literature about the phenomenon now known as visual snow syndrome. This review will examine the current thinking on the pathology of visual snow and how that thinking has evolved.
RECENT FINDINGS
While migraine is a common comorbidity to visual snow syndrome, evidence points to these conditions being distinct clinical entities, with some overlapping pathophysiological processes. There is increasing structural and functional evidence that visual snow syndrome is due to a widespread cortical dysfunction. Cortical hyperexcitability coupled with changes in thalamocortical pathways and higher-level salience network controls have all shown differences in patients with visual snow syndrome compared to controls. Further work is needed to clarify the exact mechanisms of visual snow syndrome. Until that time, treatment options will remain limited. Clinicians having a clearer understanding of the basis for visual snow syndrome can appropriately discuss the diagnosis with their patients and steer them towards appropriate management options.
Topics: Comorbidity; Humans; Migraine Disorders; Vision Disorders
PubMed: 35235167
DOI: 10.1007/s11910-022-01182-x -
Indian Journal of Ophthalmology Jul 2022Fraser syndrome is a rare congenital disorder comprising cryptophthalmos, syndactyly, and many times, urogenital anomalies. Herein, the authors aimed to study and report... (Review)
Review
PURPOSE
Fraser syndrome is a rare congenital disorder comprising cryptophthalmos, syndactyly, and many times, urogenital anomalies. Herein, the authors aimed to study and report the clinical features and orbital anomalies in cases diagnosed with Fraser syndrome.
METHODS
The authors retrospectively evaluated the records of patients with Fraser syndrome who had presented to a tertiary eye care hospital in northern India in the last 2 years (from January 2019 to December 2020). The clinical features were studied, entered in MS Excel, and the data was evaluated.
RESULTS
Data of 15 patients with Fraser syndrome were found. Majority of the patients were males and presented in the pediatric age group. Bilateral involvement was more common, and the most common variant of cryptophthalmos was abortive. Complete and medial madarosis of the eyebrows was the most common periocular finding. Complete cryptophthalmos was associated with cystic globes, whereas abortive forms had superior symblepharon. Common systemic features included syndactyly, bifid nose, and urogenital anomaly.
CONCLUSION
Fraser syndrome is an extremely rare developmental disorder; it encompasses a wide range of ocular, periocular, and orbital anomalies, along with multiple pre-existing systemic anomalies. The treating ophthalmologist should always be careful in examining these patients.
Topics: Abnormalities, Multiple; Child; Eyelids; Female; Fraser Syndrome; Humans; Male; Microphthalmos; Rare Diseases; Retrospective Studies; Syndactyly
PubMed: 35791156
DOI: 10.4103/ijo.IJO_2627_21 -
Medicina (Kaunas, Lithuania) Dec 2020Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) gained worldwide attention at the end of 2019 when it was identified to cause severe respiratory distress... (Review)
Review
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) gained worldwide attention at the end of 2019 when it was identified to cause severe respiratory distress syndrome. While it primarily affects the respiratory system, we now have evidence that it affects multiple organ systems in the human body. Cardiac manifestations may include myocarditis, life threatening arrhythmias, acute coronary syndrome, systolic heart failure, and cardiogenic shock. Myocarditis is increasingly recognized as a complication of Coronavirus-19 (COVID-19) and may result from direct viral injury or from exaggerated host immune response. The diagnosis is established similar to other etiologies, and is based on detailed history, clinical exam, laboratory findings and non-invasive imaging studies. When available, cardiac MRI is the preferred imaging modality. Endomyocardial biopsy may be performed if the diagnosis remains uncertain. Current management is mainly supportive with the potential addition of interventions recommended for severe COVID-19 disease, such as remdesivir, steroids, and convalescent plasma. In the setting of cardiogenic shock and refractory, life-threatening arrhythmias that persist despite medical therapy, advanced mechanical circulatory support devices should be considered. Ultimately, early recognition and aggressive intervention are key factors in reducing morbidity and mortality. Our management strategy is expected to evolve further as we learn more about COVID-19 disease and the associated cardiac complications.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; Humans; Immunization, Passive; Myocarditis; SARS-CoV-2; Steroids; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 33317101
DOI: 10.3390/medicina56120678 -
Journal of Medical Genetics Sep 2002Fraser syndrome is characterised by cryptophthalmos, cutaneous syndactyly, malformations of the larynx and genitourinary tract, craniofacial dysmorphism, orofacial... (Review)
Review
Fraser syndrome is characterised by cryptophthalmos, cutaneous syndactyly, malformations of the larynx and genitourinary tract, craniofacial dysmorphism, orofacial clefting, mental retardation, and musculoskeletal anomalies. The inheritance is autosomal recessive. No diagnostic cytogenetic abnormalities have been documented in affected patients, and no molecular genetic studies have been reported. We have reviewed 117 cases diagnosed as Fraser syndrome or cryptophthalmos published since the comprehensive review of Thomas et al in 1986 in order to validate the published diagnostic criteria and to delineate the phenotype associated with this syndrome. Our series showed more females (57/117) than males and consanguinity was present in 29/119 (24.8%). Eighty-eight patients satisfied the diagnostic criteria for Fraser syndrome (75%). Cryptophthalmos was present in 103/117 (88%), syndactyly in 72/117 (61.5%), and ambiguous genitalia in 20/117 (17.1%). Ear malformations were recorded in 69/117 (59%), and renal agenesis in 53/117 (45.3%). Use of the published diagnostic criteria excluded several patients with cryptophthalmos and one or more physical feature(s) consistent with Fraser syndrome. The frequency of additional anomalies in our series was also higher than previously reported (for example, imperforate anus or anal stenosis were found in 34/117 (29%) compared with 2/124 (2%) in the series of Thomas et al (1986) and choanal stenosis or atresia was present in 7/117 (6%) compared to 0/124. These findings emphasise the clinical variability associated with Fraser syndrome and support genetic heterogeneity of the syndrome. We also noted patterns of anomalies (for example, bicornuate uterus with imperforate anus or anal stenosis and renal malformations) that are found in other syndromes and associations without cryptophthalmos, suggesting that common modifier genes may explain some of the phenotypic variation in Fraser syndrome.
Topics: Abnormalities, Multiple; Diagnosis, Differential; Eye Abnormalities; Eyelids; Female; Humans; Male; Phenotype; Pregnancy; Pregnancy Complications; Sex Factors; Syndactyly; Syndrome
PubMed: 12205104
DOI: 10.1136/jmg.39.9.623 -
Archives of Pathology & Laboratory... Jan 2007Placental mesenchymal dysplasia is characterized by placentomegaly and may be mistaken for molar pregnancy both clinically and macroscopically because of the presence of... (Review)
Review
CONTEXT
Placental mesenchymal dysplasia is characterized by placentomegaly and may be mistaken for molar pregnancy both clinically and macroscopically because of the presence of "grapelike vesicles." It may be associated with a completely normal fetus, a fetus with growth restriction, or a fetus with features of Beckwith-Wiedemann syndrome.
OBJECTIVE
To review the etiology, molecular pathology, gross and microscopic features, clinical presentation, complications, and differential diagnosis of placental mesenchymal dysplasia.
DATA SOURCES
The PubMed and the Medline databases were systematically searched for articles between 1970 and 2006. The following keywords were used: placental mesenchymal dysplasia, mesenchymal hyperplasia, molar pregnancy, pseudomolar pregnancy, Beckwith-Wiedemann syndrome, and placentomegaly. Relevant references from review articles were also searched.
CONCLUSIONS
Placental mesenchymal dysplasia should be considered in the differential diagnosis when the ultrasonographic findings show a cystic placenta. Close attention should be paid to fetal morphology for early recognition of fetal complications and to prevent unnecessary termination of pregnancy in cases associated with a normal fetus.
Topics: Beckwith-Wiedemann Syndrome; Diagnosis, Differential; Female; Fetal Growth Retardation; Humans; Hydatidiform Mole; Mesoderm; Placenta; Placenta Diseases; Placentation; Pregnancy; Ultrasonography
PubMed: 17227114
DOI: 10.5858/2007-131-131-PMD -
Evolution, Medicine, and Public Health 2021We provide the first analysis and synthesis of the evolutionary and mechanistic bases for risk of endometriosis in humans, structured around Niko Tinbergen's four... (Review)
Review
We provide the first analysis and synthesis of the evolutionary and mechanistic bases for risk of endometriosis in humans, structured around Niko Tinbergen's four questions about phenotypes: phylogenetic history, development, mechanism and adaptive significance. Endometriosis, which is characterized by the proliferation of endometrial tissue outside of the uterus, has its phylogenetic roots in the evolution of three causally linked traits: (1) highly invasive placentation, (2) spontaneous rather than implantation-driven endometrial decidualization and (3) frequent extensive estrogen-driven endometrial proliferation and inflammation, followed by heavy menstrual bleeding. Endometriosis is potentiated by these traits and appears to be driven, proximately, by relatively low levels of prenatal and postnatal testosterone. Testosterone affects the developing hypothalamic-pituitary-ovarian (HPO) axis, and at low levels, it can result in an altered trajectory of reproductive and physiological phenotypes that in extreme cases can mediate the symptoms of endometriosis. Polycystic ovary syndrome, by contrast, is known from previous work to be caused primarily by high prenatal and postnatal testosterone, and it demonstrates a set of phenotypes opposite to those found in endometriosis. The hypothesis that endometriosis risk is driven by low prenatal testosterone, and involves extreme expression of some reproductive phenotypes, is supported by a suite of evidence from genetics, development, endocrinology, morphology and life history. The hypothesis also provides insights into why these two diametric, fitness-reducing disorders are maintained at such high frequencies in human populations. Finally, the hypotheses described and evaluated here lead to numerous testable predictions and have direct implications for the treatment and study of endometriosis. Endometriosis is caused by endometrial tissue outside of the uterus. We explain why and how humans are vulnerable to this disease, and new perspectives on understanding and treating it. Endometriosis shows evidence of being caused in part by relatively low testosterone during fetal development, that 'programs' female reproductive development. By contrast, polycystic ovary syndrome is associated with relatively high testosterone in prenatal development. These two disorders can thus be seen as 'opposite' to one another in their major causes and correlates. Important new insights regarding diagnosis, study and treatment of endometriosis follow from these considerations.
PubMed: 33854783
DOI: 10.1093/emph/eoab008 -
Current Medicinal Chemistry 2023Metformin has been used as an oral anti-hyperglycaemic drug since the late 1950s; however, following the release in 1998 of the findings of the 20-year United Kingdom... (Review)
Review
Metformin has been used as an oral anti-hyperglycaemic drug since the late 1950s; however, following the release in 1998 of the findings of the 20-year United Kingdom Prospective Diabetes Study (UKPDS), metformin use rapidly increased and today is the first-choice anti-hyperglycaemic drug for patients with type 2 diabetes (T2D). Metformin is in daily use by an estimated 150 million people worldwide. Historically, the benefits of metformin as an anti-diabetic and cardiovascular-protective drug have been linked to effects in the liver, where it acts to inhibit gluconeogenesis and lipogenesis, as well as reduce insulin resistance and enhance peripheral glucose utilization. However, direct protective effects on the endothelium and effects in the gut prior to metformin absorption are now recognized as important. In the gut, metformin modulates the glucagon-like peptide- 1 (GLP-1) - gut-brain axis and impacts the intestinal microbiota. As the apparent number of putative tissue and cellular targets for metformin has increased, so has the interest in re-purposing metformin to treat other diseases that include polycystic ovary syndrome (PCOS), cancer, neurodegenerative diseases, and COVID-19. Metformin is also being investigated as an anti-ageing drug. Of particular interest is whether metformin provides the same level of vascular protection in individuals other than those with T2D, including obese individuals with metabolic syndrome, or in the setting of vascular thromboinflammation caused by SARS-CoV-2. In this review, we critically evaluate the literature to highlight clinical settings in which metformin might be therapeutically repurposed for the prevention and treatment of vascular disease.
Topics: Drug Repositioning; Vascular Diseases; Metformin; Humans; Animals; Endothelial Cells; Exercise; Aging; COVID-19
PubMed: 35909294
DOI: 10.2174/0929867329666220729154615