Chronic Hypoxic State Research Articles

Chronic hypoxia prolongs postoperative mechanical ventilation and reduces the left atrial pressure threshold in children with tetralogy of Fallot.

Chronic hypoxia induces pulmonary microvascular endothelial dysfunction. The left atrial pressure (LAP) represents the hydrostatic pressure of pulmonary microcirculation. The conjunction of the LAP and any abnormal pulmonary microvascular endothelial barrier function will have an impact on pulmonary exudation, resulting in prolonged mechanical ventilation. This study aimed to investigate the tolerance threshold of the pulmonary microcirculation to LAP in children with tetralogy of Fallot (TOF) to avoid prolonged mechanical ventilation after surgery. This retrospective study included 297 Chinese patients who underwent TOF correction at Fuwai Hospital. Patients were categorized according to their preoperative oxygen saturation (SpO2) level. One-to-one propensity score matching (PSM) revealed a total of 126 participants in the SpO2 < 90% and SpO2 ≥ 90% groups. Between-group comparisons were conducted to verify the correlation between hypoxia and prolonged mechanical ventilation. A subgroup analysis was performed to reveal the significant role of postoperative LAP stewardship on prolonged mechanical ventilation. Failure to extubate within the first 48 h (23.81% vs. 9.52%, P = 0.031) and prolonged mechanical ventilation (26.98% vs. 11.11%, P = 0.023) were more commonly observed in children with preoperative SpO2 < 90%. The incidence of prolonged mechanical ventilation consistently increased with LAP in both the SpO2 < 90% and SpO2 ≥ 90% groups, although LAP was still within the normal range (6-12 mmHg). Children in chronic hypoxic conditions tolerated lower LAP well. The tolerance threshold for postoperative LAP in children diagnosed with TOF under chronic hypoxic conditions was identified as 7 mmHg. Children in a chronic hypoxic state may suffer from a high incidence of prolonged mechanical ventilation after surgical correction of TOF and may not tolerate higher postoperative LAP. To improve pulmonary prognosis, it is better to control and maintain the postoperative LAP at a lower state (≤7 mmHg) in children with chronic hypoxia.

Abstract 794: Pan-cancer proteogenomic analysis reveals functional mechanisms underlying DNA repair deficiencies

Abstract Emerging classifiers that leverage recent advances in the characterization of mutational signatures have identified a broader range of cancer patients with DNA repair deficiencies, many of whom do not harbor mutations or epigenetic silencing of canonical DNA repair genes. Investigating the various mechanisms underlying dysfunctional DNA damage response (DDR) and heterogeneity across patients will be crucial to understand disparate responses to therapy, including to PARP1 inhibitors and to immunotherapy. In this study, we integrate genomic, transcriptomic, proteomic, and post-translational modification (PTM) data across 11 cancer types to elucidate the diverse functional mechanisms of DNA repair deficiencies and their therapeutic implications through an in-depth proteogenomic analysis. We first characterized the landscape of mutational signatures in 1110 patients by applying SignatureAnalyzer, a tool that uses a Bayesian non-negative matrix factorization method to discover patterns of somatic mutations. Our analysis identified 144 homologous recombination-deficient (HRD) and 60 mismatch repair-deficient (MMRD) patients. Multi-omic (mRNA, protein, PTMs) signature based hierarchical clustering revealed two distinct clusters of HRD patients defined by either (i) acute or (ii) chronic hypoxic states. The acute hypoxia cluster exhibited typical HRD phenotypes, including a preference for non-homologous end joining (NHEJ) and enrichment in PARP1 activity, as well as phosphorylation patterns driven by DNA-PKcs, ATM, and ATR. In contrast, tumors under chronic hypoxia exhibited a halting of replication and silencing of DDR, suggesting that patients with these tumors may respond poorly to common HRD treatments that exploit alternative error-prone repair and PARP1 activation. Notably, these tumors were enriched in signatures representative of highly active kinases involved in cellular stress responses, potentially providing additional avenues for therapy. Additional analysis of both HRD and MMRD tumors revealed groups of highly immunogenic DNA repair-deficient tumors that may respond well to some types of immunotherapy given their increased mutagenesis. Moreover, differences in inflammation-related kinase activities offer further insight into the interaction between faulty DDR and the innate immune response (e.g., alterations in the cGAS-STING DNA sensing pathway). Overall, our multi-omic signature analysis provides insights into the mechanisms underlying DDR and its crosstalk with other cancer-related pathways that remain unexplained by evaluating genomic and transcriptomic data alone. Our characterization of the heterogeneity within the population of patients with DNA repair deficiency shows promise for improved prediction of treatment response, as well as identifying additional potential therapeutic targets. Citation Format: Yo Akiyama, Yifat Geffen, Shankara Anand, Tomer Yaron, Jared L. Johnson, Emily Huntsman, David Heiman, Chet Birger, Karl Clauser, Özgün Babur, Mendy Miller, Karsten Krug, D R Mani, Lewis C. Cantley, Steven A. Carr, PanCancer Oncogenic Drivers and Pathways Group, Clinical Proteomic Tumor Analysis Consortium (CPTAC), Francois Aguet, Li Ding, Gad Getz. Pan-cancer proteogenomic analysis reveals functional mechanisms underlying DNA repair deficiencies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 794.

Periprostatic Adipose Tissue Displays a Chronic Hypoxic State that Limits Its Expandability

White adipose tissue accumulates at various sites throughout the body, some adipose tissue depots exist near organs whose function they influence in a paracrine manner. Prostate gland is surrounded by a poorly characterized adipose depot called periprostatic adipose tissue (PPAT), which plays emerging roles in prostate-related disorders. Unlike all other adipose depots, PPAT secretes proinflammatory cytokines even in lean individuals and does not increase in volume during obesity. These unique features remain unexplained because of the poor structural and functional characterization of this tissue. This study characterized the structural organization of PPAT in patients compared with abdominopelvic adipose tissue (APAT), an extraperitoneal adipose depot, the accumulation of which is correlated to body mass index. Confocal microscopy followed by three-dimensional reconstructions showed a sparse vascular network in PPAT when compared with that in APAT, suggesting that this tissue is hypoxic. Unbiased comparisons of PPAT and APAT transcriptomes found that most differentially expressed genes were related to the hypoxia response. High levels of the hypoxia-inducible factor 2α confirmed the presence of an adaptive response to hypoxia in PPAT. This chronic hypoxic state was associated with inflammation and fibrosis, which were not further up-regulated by obesity. This fibrosis and inflammation explain the failure of PPAT to expand in obesity and open new mechanistic avenues to explain its role in prostate-related disorders, including cancer.

Trelagliptin ameliorates oxygen-glucose deprivation/reperfusion (OGD/R)-induced mitochondrial dysfunction and metabolic disturbance of endothelial cells.

Acute myocardial infarction (AMI) is a severe cardiovascular disease with high mortality. It is reported to be closely related to the mitochondrial dysfunction and metabolic disturbance on endothelial cells under a chronic hypoxic state. Significant declined mitochondrial respiration, ATP production, and metabolic changes are the main characteristics of endothelial injury in the disease. Trelagliptin is a DPP-4 inhibitor applied for the treatment of type II diabetes and has been recently reported to exert various pharmacological properties. In this investigation, we examined whether Trelagliptin possessed a protective effect against mitochondrial dysfunction and metabolic disturbance in human aortic valvular endothelial cells (HAVECs) under oxygen-glucose deprivation/reperfusion (OGD/R) conditions. We found that both the cytotoxicity and mitochondrial oxidative stress in HAVECs induced by OGD/R stimulation were greatly alleviated by Trelagliptin. In addition, the declined mitochondrial respiration and ATP production decreased secretion of cystathionine and creatine, and the increased production of triglyceride and adiponectin in OGD/R-challenged HAVECs was dramatically reversed by Trelagliptin, accompanied by the upregulated expression level of PGC-1α and CPT-1. Lastly, the AMPK pathway was observed to be significantly activated in OGD/R-challenged HAVECs by Trelagliptin treatment. After co-administration of the inhibitor of the AMPK pathway, the effects of Trelagliptin on mitochondrial function and metabolic alterations were significantly abolished. Taken together, our data indicate that Trelagliptin ameliorated OGD/R-induced mitochondrial disturbance and metabolic changes by activating the AMPK pathway.

Hypoxia Inducible Factors as Central Players in the Pathogenesis and Pathophysiology of Cardiovascular Diseases.

Cardiovascular (CV) diseases are the major cause of death in industrialized countries. The main function of the CV system is to deliver nutrients and oxygen to all tissues. During most CV pathologies, oxygen and nutrient delivery is decreased or completely halted. Several mechanisms, including increased oxygen transport and delivery, as well as increased blood flow are triggered to compensate for the hypoxic state. If the compensatory mechanisms fail to sufficiently correct the hypoxia, irreversible damage can occur. Thus, hypoxia plays a central role in the pathogenesis and pathophysiology of CV diseases. Hypoxia inducible factors (HIFs) orchestrate the gene transcription for hundreds of proteins involved in erythropoiesis, glucose transport, angiogenesis, glycolytic metabolism, reactive oxygen species (ROS) handling, cell proliferation and survival, among others. The overall regulation of the expression of HIF-dependent genes depends on the severity, duration, and location of hypoxia. In the present review, common CV diseases were selected to illustrate that HIFs, and proteins derived directly or indirectly from their stabilization and activation, are related to the development and perpetuation of hypoxia in these pathologies. We further classify CV diseases into acute and chronic hypoxic states to better understand the temporal relevance of HIFs in the pathogenesis, disease progression and clinical outcomes of these diseases. We conclude that HIFs and their derived factors are fundamental in the genesis and progression of CV diseases. Understanding these mechanisms will lead to more effective treatment strategies leading to reduced morbidity and mortality.

Portomesenteric venous thrombosis in a postmenopausal female with testosterone implant: a case report

BackgroundAcute portal vein thrombosis is a rare medical event usually seen in liver disease, but it can also occur due to any inherited or acquired procoagulable state that triggers venous occlusion. Hormonal therapies have been associated with an increased risk of prothrombotic states. This case report documents a portomesenteric venous thrombosis in a postmenopausal woman with testosterone implant for the treatment of hypoactive sexual desire and discusses the importance of identifying hypercoagulable risk factors before initiating hormone replacement therapy. We want to improve the awareness of an unusual medical complication associated with hormone replacement therapy and shed light on how testosterone implants could facilitate a thrombotic event related to other risk factors such as obesity and chronic hypoxic states, as well as the importance of differential diagnosis in the evaluation of postmenopausal women on testosterone replacement therapy presenting with acute abdominal pain.Case presentationA 55-year-old obese postmenopausal Hispanic female with medical history of chronic obstructive pulmonary disease presents with intractable abdominal pain, is found to have elevated hemoglobin and hematocrit, and an abdominopelvic computed tomography scan revealing portal and superior mesenteric vein thrombosis. Further evaluation excluded inherited and acquired thrombophilia but revealed elevated testosterone levels. The patient was treated with anticoagulation, which resulted in recanalization of the portal and superior mesenteric veins.ConclusionSupraphysiologic levels of testosterone caused by testosterone implants as a treatment of hypoactive sexual desire in postmenopausal women can contribute to thrombotic events in the presence of additional prothrombotic risk factors. Therefore, testosterone therapy should include a thorough risk assessment for prothrombotic states, be tailored to patients’ physiologic testosterone levels, and have close follow-up with testosterone level monitoring.

The relationship between the findings of vestibular evoked myogenic potentials and severity of obstructive sleep apnea syndrome.

Our study aimed to evaluate the effects of chronic hypoxic state in Obstructive Sleep Apnea Syndrome (OSAS) on brainstem pathways using Vestibular Evoked Myogenic Potential (VEMP) test and to investigate the presence of new markers likely to be correlated with the severity of the disease. The study was planned as prospective and double blind. A total of 60 patients (120 ears) diagnosed with mild, moderate and severe OSAS were included in the study and the patients are grouped as 20 patients in each group. Twenty volunteer healthy individuals (40 ears) shown to be without OSAS were included in the study. VEMP measurements were made in 60 study group patients (120 ears) and in 20 healthy controls (40 ears). The groups were compared in terms of variables such as the acquisition rate of oVEMP and cVEMP waves, interval between the waves, latency and amplitude of the waves. p < 0.05 values were considered as significant. The results of cVEMP test showed that the rate of wave acquisition in the moderate and severe OSAS groups was significantly lower than the control group and mild OSAS groups (p = 0.008). There was no difference between the control group and the mild OSAS group in terms of the rate of obtaining the wave (p > 0.05). In the moderate and severe OSAS groups, P1N1 amplitude and N1P2 amplitude values were found to be significantly lower than the mild OSAS group (p = 0.007 and p = 0.017, respectively). In the oVEMP test, there was no significant difference between the mild OSAS group and the control group in terms of the wave yield (p > 0.05); however, it was found that the rate of wave acquisition in the moderate and severe OSAS groups was significantly lower than the mild OSAS group (p = 0.041). There was inverse correlation between the N1P2 interval and P1N1 amplitude value and AHI in simple regression analysis and multiple regression analysis (p = 0.012 and p = 0.021; p = 0.009 and p = 0.040, respectively). The negative effects of chronic intermittent hypoxia related with OSAS on the brainstem and vestibular system can be demonstrated by VEMP tests. Especially, the inability to obtain the wave is the most important finding showing this situation. Also, we think that N1P2 interval and P1N1 amplitude markers can be used to detect the subclinical negative effect of chronic hypoxia on vestibular nuclei in the brainstem.

Genesis of Antibiotic Resistance (AR) XLIX: Mechanism(s) of Sepsis‐induced Increase in Mortality Cobblestone Antibiotic Resistance Pandemic (ARP)

NCT01663701: is a clinical trial with the principle hypothesis that early fluid resuscitation will significantly decrease in‐hospital mortality in patients with severe sepsis and hypotension. Based on the observations from NCT01663701, 209 adults with sepsis and hypotension presenting to an emergency department in Zambia, a 6‐hour sepsis protocol emphasizing administration of intravenous fluids, vasopressors, and blood transfusion significantly increased in‐hospital mortality compared with usual care (48.1% vs 33.0%, respectively)(Verbatim). Here, we present a rationale for the plausible reason for such an outcome of 48.1% mortality in sepsis protocol group as opposed to expected decrease in the mortality rate with a “time zero” of admittance to emergency room (ER) and 28 days. Based on the intake criteria of admission to ER, observations and limitations of this investigation, it is hypothesized that “Colonization Pressure” (CP) of “Persisters (Prs)” is the most ostensible factor for the sepsis and septic shock induced increase in mortality rate from “time zero” of admittance to ER. “Persisters”(Prs) are antibiotic‐sensitive bacterial populations have a small fraction (~10−6) of slow or non‐growing, antibiotic‐tolerant cells”. Stochastic switch of specific toxin‐antitoxin (TA) expression and alarmone (p) ppGpp has been implicated in evolution of AR. Additional contributing factors could be a. Lack of “Antibiogram” for P. aeruginosa, S. aureus, C. difficile (C. diff), b. failure to implementation of “Antibiotic Stewardship Program”; c. lack of information on the “CP” data on a daily basis. It is suggested that sustained “low tissue perfusion index (PI)”; “Oxygen Saturation of arterial hemoglobin (SpO2)” would hypothetically generate a chronic hypoxic state enabling the emergence of anaerobic gram negative bacilli (GNB)” acquiring antibiotic resistance via multidrug‐resistant (MDR); extensively drug‐resistant (XDR), Gain of function (GOF) mutations and Pandrug‐resistant (PDR) escalating the horizontal gene transfer. Chronic tissue hypoxia would likely to increase the “CP” of GNB due to the sub‐therapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and suboptimal infection control in the setting of outbreaks such as NCT01663701. Lack of information on utilization antifungals via antifungal stewardship is critical to reduce the morbidity &amp; mortality by limiting emergence of MDR in the Intensive Care Units (ICU). Candida bloodstream infections (BSI) / Candidemia and candidiasis in (C.albicans, C.glabrata, C.auris with MDR and XDR attributes with higher “CP” indices transmitted via horizontal transmission (~30%) posing serious challenges in caring for chronically ill (HIV patients) in the long term care facilities, ICU, and also across the globe. Taken together, the observed 48% mortality in NCT01663701 is a consequence of solidification of factors beyond the realm of current clinical practices caring for chronically ill infectious diseases patients (ex. HIV) across the globe leading to ARP.Support or Funding InformationSupported by professional development funds from SWTJC and CME activities of Subburaj Kannan MDThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Multifocal pheochromocytoma-paraganglioma in a 29-year-old woman with cyanotic congenital heart disease

BackgroundMultifocal pheochromocytoma/paraganglioma presenting at an early age is commonly associated with a hereditary syndrome. Case ReportA 29-year-old woman was referred for evaluation of multifocal pheochromocytoma/paraganglioma. Interestingly, her family history did not include pheochromocytoma/paraganglioma, and comprehensive genetic testing for the well-documented pheochromocytoma/paraganglioma susceptibility genes was negative. Of note, this patient had a history of a complex cardiac defect resulting in cyanotic congenital heart disease and had never undergone operative repair. Thus she lived in a chronic hypoxic state with a baseline oxygen saturation of about 80%. Laboratory evaluation found marked increases in plasma norepinephrine and normetanephrines with normal epinephrine and metanephrines. Imaging revealed 4 aortocaval masses and a right adrenal mass. After appropriate preoperative preparation she underwent successful resection of each of the neoplasms, with pathologic testing revealing multifocal pheochromocytoma/paraganglioma. DiscussionThis case highlights a growing recognition of the potential development of pheochromocytoma/paraganglioma in patients with cyanotic congenital heart disease. The underlying pathophysiology and phenotypic similarities between pheochromocytoma/paraganglioma in patients with cyanotic congenital heart disease and those with mutations that lead to cellular pseudohypoxia are reviewed.

White matter degeneration in vascular and other ageing-related dementias.

Advances in neuroimaging have enabled greater understanding of the progression of cerebral degenerative processes associated with ageing-related dementias. Leukoaraiosis or rarefied white matter (WM) originally described on computed tomography is one of the most prominent changes which occurs in older age. White matter hyperintensities (WMH) evident on magnetic resonance imaging have become commonplace to describe WM changes in relation to cognitive dysfunction, types of stroke injury, cerebral small vessel disease and neurodegenerative disorders including Alzheimer's disease. Substrates of WM degeneration collectively include myelin loss, axonal abnormalities, arteriolosclerosis and parenchymal changes resulting from lacunar infarcts, microinfarcts, microbleeds and perivascular spacing. WM cells incorporating astrocytes, oligodendrocytes, pericytes and microglia are recognized as key cellular components of the gliovascular unit. They respond to ongoing pathological processes in different ways leading to disruption of the gliovascular unit. The most robust alterations involve oligodendrocyte loss and astrocytic clasmatodendrosis with displacement of the water channel protein, aquaporin 4. These modifications likely precede arteriolosclerosis and capillary degeneration and involve tissue oedema, breach of the blood-brain barrier and induction of a chronic hypoxic state in the deep WM. Several pathophysiological mechanisms are proposed to explain how WM changes commencing with haemodynamic changes within the vascular system impact on cognitive dysfunction. Animal models simulating cerebral hypoperfusion in man have paved the way for several translational opportunities. Various compounds with variable efficacies have been tested to reduce oxidative stress, inflammation and blood-brain barrier damage in the WM. Our review demonstrates that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment. This article is part of the Special Issue "Vascular Dementia".

The histological and histomorphometric changes in the mandible after radiotherapy: An animal model

PurposeApproximately 5% of irradiated head and neck cancer patients develop osteoradionecrosis of the mandible. The current non-surgical treatment options for osteoradionecrosis have limited effects and are based on a small number of studies. Therefore, we aimed to enhance the understanding of the pathophysiology of osteoradionecrosis by investigating changes induced by external irradiation in mini-pigs. MethodsSixteen Göttingen mini-pigs were divided into four groups for the application in two fractions with total equivalent radiation dosages of 25, 50, 70 Gray, and one group served as control. Thirteen weeks after irradiation, the left lateral teeth the mandible were removed and implants were placed. The pigs were sacrificed twenty-six weeks after irradiation, and the bone samples were stained with Masson's trichrome. ResultsThe amount of fibrosis, resorption lacunae, necrosis, and the woven/lamellar bone ratios were increased after higher radiation dosages. The diameter of the lumen of the inferior alveolar artery was reduced depending on the irradiation dosages. The rate of bone remodeling decreased after irradiation. ConclusionBoth surgery and increasing irradiation dosages cause architectural bone changes and damage the vascularization. This might result in a chronic hypoxic state of the mandibular bone. In general, the bone formation rate was markedly decreased after radiotherapy.

Hypoxia in Obesity and Diabetes: Potential Therapeutic Effects of Hyperoxia and Nitrate.

The prevalence of obesity and diabetes is increasing worldwide. Obesity and diabetes are associated with oxidative stress, inflammation, endothelial dysfunction, insulin resistance, and glucose intolerance. Obesity, a chronic hypoxic state that is associated with decreased nitric oxide (NO) bioavailability, is one of the main causes of type 2 diabetes. The hypoxia-inducible factor-1α (HIF-1α) is involved in the regulation of several genes of the metabolic pathways including proinflammatory adipokines, endothelial NO synthase (eNOS), and insulin signaling components. It seems that adipose tissue hypoxia and NO-dependent vascular and cellular dysfunctions are responsible for other consequences linked to obesity-related disorders. Although hyperoxia could reverse hypoxic-related disorders, it increases the production of reactive oxygen species (ROS) and decreases the production of NO. Nitrate can restore NO depletion and has antioxidant properties, and recent data support the beneficial effects of nitrate therapy in obesity and diabetes. Although it seems reasonable to combine hyperoxia and nitrate treatments for managing obesity/diabetes, the combined effects have not been investigated yet. This review discusses some aspects of tissue oxygenation and the potential effects of hyperoxia and nitrate interventions on obesity/diabetes management. It can be proposed that concomitant use of hyperoxia and nitrate is justified for managing obesity and diabetes.

Angiogenesis in villous chorangiosis observed by ultrastructural studies

Chorangiosis is microscopically designated as more than ten terminal capillaries within the villous stroma of the placenta and is mostly related to chronic fetal hypoxia. However, the histogenetic relationship between increased number of terminal villous capillaries and chronic hypoxia has not yet been clarified. Of 665 placentas histologically examined at Saitama Medical University from 2003 to 2010, chorangiosis was found in 58 cases (8.7 %), which were mostly more than 35 gestational weeks. In addition, low birth weight (less than 2,500 g) infants (74.1 %) and those who suffered from cardiac anomalies, chromosome anomalies, and single umbilical artery comprised 32.7 % of cases. Placental lesions were associated with chorangiosis involved in infarct (46.6 %), intervillous thrombosis (20.7 %), and marginal hemorrhages (22.4 %). Scanning electron microscopic studies showed narrowing of vessel ostium and disorders of endothelium in the umbilical cord vessel complicated by chorangiosis. Furthermore, in transmission electron microscopic observation, not only the chorionic villi had multiple enlarged vessels within the villous stroma, but we also found that new capillaries were formed by angiogenesis with endothelial cells derived from fibroblasts under the chronic hypoxic state.

Characteristic Changes in Brain Electrical Activity Due to Chronic Hypoxia in Patients with Obstructive Sleep Apnea Syndrome (OSAS): A Combined EEG Study Using LORETA and Omega Complexity

EEG background activity of patients with obstructive sleep apnea syndrome (OSAS, N = 25) was compared to that of normal controls (N = 14) to reflect alterations of brain electrical activity caused by chronic intermittent hypoxia in OSAS. Global and regional (left vs. right, anterior vs. posterior) measures of spatial complexity (Omega) were used to characterize the degree of spatial synchrony of EEG. Low resolution electromagnetic tomography (LORETA) was used to localize generators of EEG activity in separate frequency bands. Comparing patients to controls, lower Omega complexity was found globally and in the right hemisphere. Using LORETA, an increased medium frequency activity was seen bilaterally in the precuneus, paracentral and posterior cingulate cortex. These findings indicate that alterations caused by chronic hypoxia in brain electrical activity in regions associated with influencing emotional regulation, long-term memory and the default mode network. Global synchronization (lower Omega complexity) may indicate a significantly reduced number of relatively independent, parallel neural processes due to chronic global hypoxic state in apneic patients as well as over the right hemisphere.

The other end of spectrum in hypertension: ‘Idiopathic nodular glomerulosclerosis’

Dear Editor, Nodular glomerulosclerosis is observed in diabetes mellitus, dysproteinemias, lobular membranoproliferative glomerulonephritis, glomerular deposition disease, and chronic hypoxic states. Idiopathic nodular glomerulosclerosis (ING), which is a rare clinical entity, is diagnosed in the absence of these conditions. We report a case of ING in an elderly hypertensive lady. An 82-year-old woman was evaluated for chronic kidney disease. Her medical history included hypertension, permanent atrial fibrillation, and osteoarthritis. There was no personal or family history of diabetes mellitus, hepatitis, autoimmune, or connective tissue disease. She did not use any over-the-counter medications, herbal remedies, cigarettes, alcohol, or recreational drugs. On examination, her vitals revealed blood pressure of 140/93 mmHg, with an irregular heart rate of 74–86 beats/min. The rest of the physical examination was unremarkable. Laboratory parameters were significant for mild normocytic anemia with a hemoglobin level of 10.2 mg/dl, BUN of 65 mg/dl, and creatinine level of 1.7 mg/dl. Fasting blood glucose, 2-h glucose tolerance test, autoantibody screening, complements, hepatitis serology, and cryoglobulins were normal. Urinalysis was normal with random protein 18 mg/dl and creatinine 59.2 mg/dl. Serum protein electrophoresis confirmed by immunofixation revealed monoclonal IgM lambda quantitated at 0.11 g/dl; free kappa/lambda ratio was 1.17 (normal 0.26–1.65). Renal ultrasound demonstrated slightly asymmetric kidneys. Renal artery magnetic resonance angiography was normal. Light microscopy of left kidney biopsy showed 6 end-stage sclerotic glomeruli and 14 viable glomeruli. Nodular mesangial expansion, thickened peripheral capillary basement membranes, tubular atrophy, interstitial fibrosis, arteriolar intimal sclerosis, and patchy lymphoplasmacytic infiltrates were observed (Fig. 1). Congo red stain was negative. Immunofluorescence was positive for focal granular mesangial IgM deposits. Electron microscopy showed thickened glomerular basement membranes and expanded mesangial matrix, frequently forming mesangial matrix nodules. There were no electron dense deposits, and foot processes were fused in a patchy pattern. These findings were suggestive of diffuse and nodular glomerulosclerosis with moderate to severe arteriosclerosis. In the absence of other etiologies, it is possible that hypertension was responsible for nodular glomerulosclerosis in this patient. It is speculated that individuals with long standing hypertension have an increased or reset sensitivity to non-diabetic glycemic levels resulting in an exaggerated glomerulovascular response [1]. R. Kasmani (&) T. Thiyagarajan R. NarwalChadha K. Okoli F. Irani Department of Internal Medicine, St. Vincent Mercy Medical Center, Toledo, 2213, Cherry Street, Toledo, OH 43608, USA e-mail: rahilkasmani@hotmail.com

Overview of Cardiac Status in Thalassemia Intermedia: The Lebanese Experience.

Introduction: Thalassemia intermedia (TI) is a heterogeneous genetic disease affecting the β-globin chain of the hemoglobin molecule resulting in a unique and wide clinical spectrum. The majority of TI patients are mildly anemic requiring merely occasional blood transfusions. Their mild anemia might be tolerable at a young age but over years it is proven to cause multiple system damage due to the chronic hypoxic and compensatory states. One of the systems affected, and the number one cause of mortality in this group, is the cardiovascular system. In this study we tried to assess echocardiographically the global left heart condition in TI patients and its relation to haematologic measurable variables (NT-proBNP, Ferritin, Hb, and HbF) as well as liver iron concentration (LIC).Subjects and Methods: A total of 74 patients were enrolled in our observational, case-series study having already met the conventional clinical and genetic criteria for diagnosing TI. LIC was measured by R2* MRI for all of the 74 patients who were then referred to an outpatient clinic for cardiac evaluation and echocardiographic testing between December 2006 and June 2007. Blood samples were also collected for measuring NT-proBNP levels in a random subgroup of 19 patients.Results: Of the 74 TI patients, 33 were male and 41 were female with a mean age of 26.54 (range 8–63) years and body surface area (BSA) of 1.54 (range 0.82–2.14) m2. Their mean hemoglobin was 8.43 (range 4.90–13.10) g/dl having a mean serum ferritin of 1023 (range 15–4140) ng/mL, a mean LIC of 9.00 (range 0.5–32.1) mg/g, and a mean NT-proBNP of 113.50 (range 16.42–371). The majority 59 (79.7%) had undergone splenectomy with only 11 (14.86%) maintained on iron chelation. Pulmonary hypertension (PHT) defined as peak systolic tricuspid gradient >30 mm Hg was present in 15 (38.5%) of our TI patients group excluding 35 patients with undetected tricuspid regurgitation. LV dilatation was significantly above the normal range in 48 (68.57%) patients. Left ventricular mass index (LVMI) was increased in 34(49.27%) patients; and all of them showed eccentric hypertrophy. The left ventricular ejection fraction (LVEF) was within normal range for most of the patients; only 3 had LVEF <55%. There was a negative correlation between LVEF and LIC with borderline significance (r = −0.22; p=0.061) but not between LVEF and ferritin (r = 0.06; p=0.61). NT-proBNP was above upper limit of normal in 7(36.8%) patients of the subgroup. It was significantly and negatively correlated with hemoglobin (r = −0.49; p = 0.032) but not with age, LIC, mean serum ferritin, left ventricular end-diastolic diameter, LVMI, LVEF, or Doppler indices.Conclusion: Although TI patients primarily develop PHT leading to right heart failure, our study has shown that many do exhibit sub-clinical left heart dysfunction (characterized by LV dilation and/or eccentric hypertrophy) as well. Knowing that iron overload correlates better with LIC than with ferritin in TI and after showing that LIC is negatively (but weakly) correlated with LVEF, iron overload might be a contributing factor to LV dysfunction similar to that encountered in TM. Finally; NT-proBNP is found to be negatively related only to hemoglobin level which adds to the poor prognosis of the profoundly anemic TI patients.

Discharge evoked by N2 inhalation is increased in catecholaminergic and non‐catecholaminergic neurons in caudal NTS following chronic exposures to hypoxia

To determine if the responses of neurons within caudal portions of the nucleus of the solitary tract (cNTS) to chemoreceptor activation are altered following chronic hypoxia, action potential (AP) discharge evoked by N2 inhalation (2–15 sec) was recorded in cNTS neurons in Inactin anesthetized rats exposed to room air (NORM) or 10% FIO2 (CH) for 7 days. Juxtacellular labeling with Neurobiotin followed by immunohistochemistry for tyrosine hydroxylase immunoreactivity (TH-IR) was used to identify catecholaminergic neurons. In NORM rats, the number of APs evoked by 10sec N2 inhalation was not different comparing 8 TH-IR cNTS neurons (6±2 APs) and 14 cNTS neurons that were not TH-IR (7±2 APs). Above threshold, the slope of the curve relating discharge to the duration of N2 inhalation was 1.7±.2 APs/sec of N2 inhalation. In CH rats, the number of APs evoked by 10sec N2 inhalation was not different comparing 5 TH-IR cNTS neurons (12±4 APs) and 12 cNTS neurons that were not TH-IR (10±3 APs). Above threshold, the slope of the curve relating discharge to the duration of N2 inhalation was 3.1±.4 APs/sec of N2 inhalation, significantly greater than that in NORM rats (p<.05). The results indicate that discharge evoked by chemoreceptor activation is increased in cNTS neurons in rats exposed to hypoxia for 7 days. Enhanced discharge of cNTS neurons following chronic exposures to hypoxia could form a basis for enhanced chemoreflex function in chronic hypoxic states (e.g., travel to altitude, heart failure).

Characteristics of histopathological and ultrastructural features of placental villi in pregnant Nepalese women

The placenta is an important functional unit for gas transfer between mother and fetus. The placental membrane, consisting of trophoblast layer interposed between maternal and fetal blood, plays an active role for intensity of respiration, but no morphological evidence has been documented. Until now, it has been reported that fetal growth retardation and increased fetal mortality rate usually could be seen at high altitude. In an attempt to find the cause of high perinatal mortality rate in Nepal, this study was undertaken to examine pathologically about 1000 Himalayan placentas obtained in Nepal and Tibet since 1977, and the results were compared with those of 5500 Japanese placentas at Saitama Medical School since 1990. In this study, characteristics of ultrastructural features of the Nepalese placental villi investigated in recent years are reported. (1) The gross characteristics of placental pathology in the Himalayan group were represented by marked subchorionic fibrin deposits and increased chorionic cysts in contrast to low incidence of intervillous thrombosis compared with those of the Japanese group. (2) As characteristics of histological findings of the placental villi between Himalayan and Japanese groups, the incidence of chorangiosis and chorangioma in the Himalayan group was significantly higher than that in the Japanese group. (3) Accompanying an increase of vasculosyncytial membrane (VSM) in the villi, thickness and separation of basement membrane of the syncytium in addition to increased apoptosis of syncytial cell nuclei were recognized. (4) As characteristic ultrastructural features of chorionic villi of Nepalese placentas, an increase of mitochondria and cystic formation of rough endoplasmic reticulum (rER), in addition to appearance of lamellar bodies similar to alveolar epithelial type II cell in organellae of the syncytium, were observed. These ultrastructural changes of the placental villous capillaries may be ascribed to hypervascularization caused by the chronic hypoxic state. It is, therefore, presumed that trophoblast cells may play an important role for gas transfer mechanism under such a hypoxic state at high altitude.

‘Hair-on-end’ skull changes resembling thalassemia caused by marrow expansion in uncorrected complex cyanotic heart disease

"Hair-on-end" skull changes resembling thalassemia were rarely described in the 1950s and 1960s in children with cyanotic congenital heart diseases; these changes were described almost entirely in patients with tetralogy of Fallot or D-transposition of the great arteries. As these lesions have become correctable, the osseous changes, never common, seem now only to exist in a small number of patients with uncorrectable complex cyanotic congenital heart disease who survive in a chronic hypoxic state. We present two cases: a case of marked marrow expansion in the skull of a 5-year-old boy with uncorrectable cyanotic heart disease studied by CT, and a second case of an 8-year-old with tetralogy of Fallot and pulmonary atresia studied by plain skull radiographs. The true incidence of these findings is unknown.

The expression of a novel stress protein ‘150-kDa oxygen regulated protein’ in sudden infant death

The oxygen regulated protein 150-kDa (ORP-150) is only induced in hypoxic conditions. We performed an immunohistochemical and morphometrical study on the expression of ORP-150 in the brains of sudden infant death (SID) victims. The cerebral cortexes of 18 infants were used for this study. Each tissue section was incubated with anti-ORP-150 polyclonal antibodies and the number of ORP-150 positive cells was counted. In the cluster analysis, the 18 cases were classified into three groups (A–C groups). Group A was composed of six sudden infant death syndrome (SIDS) cases and its mean value of ORP-150 positive cells was 66.75±3.44, Group B (six severe respiratory infectious disease such as pneumonia and bronchitis including sepsis): 39.50±2.52 and Group C (five SIDS and one severe respiratory infectious disease): 16.00±2.92, respectively. These results might reflect chronic hypoxic condition before death, because ORP-150 is only induced when a hypoxic condition exist, but not acute hypoxia. And chronic hypoxic state is likely to be antecedent to SIDS. Therefore, immunohistochemical analysis of OPR-150 in the brain of SID cases may be very useful to differentiate between SIDS and acute asphyxia.