scholarly journals Developmental Programming of PCOS Traits: Insights from the Sheep

2019 ◽  
Vol 7 (7) ◽  
pp. 79 ◽  
Author(s):  
Rodolfo C. Cardoso ◽  
Vasantha Padmanabhan
Keyword(s):  
Prenatal Exposure ◽  
Polycystic Ovary ◽  
Female Offspring ◽  
Multiple Organ ◽  
Developmental Trajectory ◽  
Adult Disease ◽  
Complex Disorder ◽  
Metabolic Systems ◽  
Organ Systems ◽  
Progression Of Disease

Polycystic ovary syndrome (PCOS) is a complex disorder that results from a combination of multiple factors, including genetic, epigenetic, and environmental influences. Evidence from clinical and preclinical studies indicates that elevated intrauterine androgen levels increase the susceptibility of the female offspring to develop the PCOS phenotype. Additionally, early postnatal endocrine and metabolic imbalances may act as a “second-hit”, which, through activational effects, might unmask or amplify the modifications programmed prenatally, thus culminating in the development of adult disease. Animal models provide unparalleled resources to investigate the effects of prenatal exposure to androgen excess and to elucidate the etiology and progression of disease conditions associated with this occurrence, such as PCOS. In sheep, prenatal treatment with testosterone disrupts the developmental trajectory of the fetus, culminating in adult neuroendocrine, ovarian, and metabolic perturbations that closely resemble those seen in women with PCOS. Our longitudinal studies clearly demonstrate that prenatal exposure to testosterone excess affects both the reproductive and the metabolic systems, leading to a self-perpetuating cycle with defects in one system having an impact on the other. These observations in the sheep suggest that intervention strategies targeting multiple organ systems may be required to prevent the progression of developmentally programmed disorders.

scholarly journals Prenatal Steroids and Metabolic Dysfunction: Lessons from Sheep

2019 ◽  
Vol 7 (1) ◽  
pp. 337-360 ◽  
Author(s):  
Rodolfo C. Cardoso ◽  
Vasantha Padmanabhan
Keyword(s):  
Prenatal Exposure ◽  
Endocrine Disrupting Chemicals ◽  
Adverse Outcomes ◽  
Developmental Trajectory ◽  
Metabolic Dysfunction ◽  
Metabolic System ◽  
Sheep Model ◽  
Adult Disease ◽  
Organ Systems ◽  
Health And Disease

Prenatal exposure to excess steroids or steroid mimics can disrupt the normal developmental trajectory of organ systems, culminating in adult disease. The metabolic system is particularly susceptible to the deleterious effects of prenatal steroid excess. Studies in sheep demonstrate that prenatal exposure to excess native steroids or endocrine-disrupting chemicals with steroidogenic activity, such as bisphenol A, results in postnatal development of numerous cardiometabolic perturbations, including insulin resistance, increased adiposity, altered adipocyte size and distribution, and hypertension. The similarities in the phenotypic outcomes programmed by these different prenatal insults suggest that common mechanisms may be involved, and these may include hormonal imbalances (e.g., hyperandrogenism and hyperinsulinemia), oxidative stress, inflammation, lipotoxicity, and epigenetic alterations. Animal models, including the sheep, provide mechanistic insight into the metabolic repercussions associated with prenatal steroid exposure and represent valuable research tools in understanding human health and disease. Focusing on the sheep model, this review summarizes the cardiometabolic perturbations programmed by prenatal exposure to different native steroids and steroid mimics and discusses the potential mechanisms underlying the development of adverse outcomes.

scholarly journals Metformin and Glaucoma—Review of Anti-Fibrotic Processes and Bioenergetics

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2131
Author(s):  
Daire J. Hurley ◽  
Mustapha Irnaten ◽  
Colm O’Brien
Keyword(s):  
Multiple Stressors ◽  
Disease Incidence ◽  
Large Population ◽  
Multiple Organ ◽  
Retinal Ganglion ◽  
Organ Systems ◽  
Highly Sensitive ◽  
Slow Progression ◽  
Progression Of Disease

Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle modifiable risk factor, to slow progression of disease. However, there is a clear unmet clinical need to find a novel therapeutic approach that targets and halts the retinal ganglion cell (RGC) degeneration that occurs with fibrosis. RGCs are highly sensitive to metabolic fluctuations as a result of multiple stressors and thus their viability depends on healthy mitochondrial functioning. Metformin, known for its use in type 2 diabetes, has come to the forefront of medical research in multiple organ systems. Its use was recently associated with a 25% reduced risk of glaucoma in a large population study. Here, we discuss its application to glaucoma therapy, highlighting its effect on fibrotic signalling pathways, mitochondrial bioenergetics and NAD oxidation.

scholarly journals SARS-CoV-2 Viral Entry Proteins in Hyperandrogenemic Female Mice: Implications for Women with PCOS and COVID-19

2021 ◽  
Vol 22 (9) ◽  
pp. 4472
Author(s):  
Alexandra M. Huffman ◽  
Samar Rezq ◽  
Jelina Basnet ◽  
Licy L. Yanes Cardozo ◽  
Damian G. Romero
Keyword(s):  
Viral Entry ◽  
Fasting Glucose ◽  
Polycystic Ovary ◽  
Cathepsin L ◽  
Multiple Organ ◽  
Reproductive Age ◽  
Host Cells ◽  
Female Mice ◽  
Protein Levels ◽  
Organ Systems

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.

Microprobe analysis of inclusion bodies related to two benzofuran derivatives

1987 ◽  
Vol 45 ◽  
pp. 672-673
Author(s):  
T. L. Benning ◽  
P. Ingram ◽  
J. D. Shelburne
Keyword(s):  
Inclusion Bodies ◽  
Uranyl Acetate ◽  
Multiple Organ ◽  
High Dose ◽  
En Bloc ◽  
Tissue Samples ◽  
Transmission Electron ◽  
Organ Systems ◽  
Dense Inclusion ◽  
Melanin Complex

Two benzofuran derivatives, chlorpromazine and amiodarone, are known to produce inclusion bodies in human tissues. Prolonged high dose chlorpromazine therapy causes hyperpigmentation of the skin with electron-dense inclusion bodies present in dermal histiocytes and endothelial cells ultrastructurally. The nature of the deposits is not known although a drug-melanin complex has been hypothesized. Amiodarone may also cause cutaneous hyperpigmentation and lamellar lysosomal inclusion bodies have been demonstrated within the cells of multiple organ systems. These lamellar bodies are believed to be the product of an amiodarone-induced phospholipid storage disorder. We performed transmission electron microscopy (TEM) and energy dispersive x-ray microanalysis (EDXA) on tissue samples from patients treated with these drugs, attempting to detect the sulfur atom of chlorpromazine and the iodine atom of amiodarone within their respective inclusion bodies.A skin biopsy from a patient with hyperpigmentation due to prolonged chlorpromazine therapy was fixed in 4% glutaraldehyde and processed without osmium tetroxide or en bloc uranyl acetate for Epon embedding.

Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injuries ◽  
Functional Independence ◽  
Outcome Data ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Sixth Edition ◽  
Organ Systems ◽  
Cord Injury ◽  
Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

Renal Manifestations of Tuberous Sclerosis Complex

2020 ◽  
Vol 7 (3) ◽  
pp. 5-19
Author(s):  
Nikhil Nair ◽  
Ronith Chakraborty ◽  
Zubin Mahajan ◽  
Aditya Sharma ◽  
Sidarth Sethi ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Gene Disruption ◽  
Treatment Guidelines ◽  
Renal Cysts ◽  
Skin Lesions ◽  
Multiple Organ ◽  
Tsc2 Gene ◽  
Genetic Condition ◽  
Organ Systems

Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors and seizures. TSC can manifests in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.

scholarly journals Endothelial glycocalyx degradation is associated with early organ impairment in polytrauma patients

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Feng Qi ◽  
Hao Zhou ◽  
Peng Gu ◽  
Zhi-He Tang ◽  
Bao-Feng Zhu ◽  
...  
Keyword(s):  
Injury Severity ◽  
Early Stage ◽  
Endothelial Glycocalyx ◽  
Control Group ◽  
Metabolic System ◽  
Metabolic Systems ◽  
Organ Systems ◽  
Severity Scores ◽  
Polytrauma Patients ◽  
Trauma Group

Abstract Background Endothelial glycocalyx (EG) abnormal degradation were widely found in critical illness. However, data of EG degradation in multiple traumas is limited. We performed a study to assess the EG degradation and the correlation between the degradation and organ functions in polytrauma patients. Methods A prospective observational study was conducted to enroll health participants (control group) and polytrauma patients (trauma group) at a University affiliated hospital between Feb 2020 and Oct 2020. Syndecan1 (SDC1) and heparin sulfate (HS) were detected in serum sample of both groups. In trauma group, injury severity scores (ISS) and sequential organ failure assessments (SOFA) were calculated. Occurrences of acute kidney injury (AKI), trauma-induced coagulopathy (TIC) within 48 h and 28-day all-cause mortality in trauma group were recorded. Serum SDC1 and HS levels were compared between two groups. Correlations between SDC1/HS and the indicators of organ systems in the trauma group were analyzed. ROC analyses were performed to assess the predictive value of SDC1 and HS for AKI, TIC within 48 h, and 28-day mortality in trauma group. Results There were 45 polytrauma patients and 15 healthy participants were collected, totally. SDC1 and HS were significantly higher in trauma group than in control group (69.39 [54.18–130.80] vs. 24.15 [13.89–32.36], 38.92 [30.47–67.96] vs. 15.55 [11.89–23.24], P <  0.001, respectively). Trauma group was divided into high degradation group and low degradation group according to SDC1 median. High degradation group had more severe ISS, SOFA scores, worse organ functions (respiratory, kidney, coagulation and metabolic system), and higher incidence of hypothermia, acidosis and shock. The area under the receiver operator characteristic curves (AUC) of SDC1 to predict AKI, TIC occurrence within 48 h and 28-day mortality were 0.838 (95%CI: 0.720–0.957), 0.700 (95%CI: 0.514–0.885) and 0.764 (95%CI: 0.543–0.984), respectively. Conclusions EG degradation was elevated significantly in polytrauma patients, and the degradation was correlated with impaired respiratory, kidney, coagulation and metabolic systems in early stage. Serum SDC1 is a valuable predictive indicator of early onset of AKI, TIC, and 28-day mortality in polytrauma patients.

scholarly journals Attenuation of COVID-19-induced cytokine storm in a young male patient with severe respiratory and neurological symptoms

2021 ◽  
Author(s):  
Christian Muschitz ◽  
Anita Trummert ◽  
Theresa Berent ◽  
Norbert Laimer ◽  
Lukas Knoblich ◽  
...  
Keyword(s):  
Decision Making ◽  
Male Patient ◽  
Young Male ◽  
Standard Of Care ◽  
Multiple Organ ◽  
Cytokine Storm ◽  
Invasive Ventilation ◽  
Organ Systems ◽  
The Central Nervous System

SummarySevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), produces protean manifestations and causes indiscriminate havoc in multiple organ systems. This rapid and vast production of proinflammatory cytokines contributes to a condition termed cytokine storm. A 35-year-old, otherwise healthy, employed, male patient was tested positive for COVID-19. He was admitted to the hospital on disease day 10 due to retarded verbal reactions and progressive delirium. On account of these conditions and the need for noninvasive/invasive ventilation, a combination treatment with baricitinib and remdesivir in conjunction with standard of care was initiated. The cytokine storm was rapidly blocked, leading to a vast pulmonary recovery with retarded recovery of the central nervous system. We conclude that the rapid blockade of the COVID-19-induced cytokine storm should be considered of avail as a principle of careful decision-making for effective recovery.

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