Search

Objective Liddle syndrome (LS) is a rare autosomal dominant condition secondary to a gain-of-function mutation affecting the epithelial sodium channels (ENaCs) in the distal nephron. It presents with early-onset hypertension, hypokalemia, and metabolic alkalosis in the face of hyporeninemia and hypoaldosteronism. We report a novel mutation affecting the ENaCs in a normotensive adolescent with LS. Methods We describe a pediatric case of LS with a novel mutation and review the condition's presentation and management. To date, 31 different mutations in the β- or γ-subunit of ENaCs have been reported as associated with LS. Results We describe a 16-year-old girl presenting with muscle cramps with a strong family history of hypertension and hypokalemia. Initial investigations revealed hypokalemia together with hypoaldosteronism and hyporeninemia. Subsequent genetic testing revealed a novel mutation in SCNN1B (deletion: c.1713delC), leading to the premature termination of the sodium channel epithelial 1 subunit-β protein and the LS phenotype. Treatment with triamterene (50 mg, twice daily) and potassium chloride (20 mEq, once daily) normalized the serum potassium and led to resolution of her muscle cramps. Conclusion It is essential to consider investigating the presence of rare genetic syndromes, like LS, when a patient presents with hypokalemia. Further studies are needed to understand the variable presentation of this condition.

The molecular scalpel of clustered regularly interspersed short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology may be sharp enough to begin cutting the genes implicated in inflammatory bowel disease (IBD) and consequently decrease the 6.3 billion dollar annual financial healthcare burden in the treatment of IBD. For the past few years CRISPR technology has drastically revolutionized DNA engineering and biomedical research field. We are beginning to see its application in gene manipulation of sickle cell disease, human immunodeficiency virus resistant embryologic twin gene modification and IBD genes such as Gatm (Glycine amidinotransferase, mitochondrial), nucleotide-binding oligomerization domain-containing protein 2, KRT12 and other genes implicated in adaptive immune convergence pathways have been subjected to gene editing, however there are very few publications. Furthermore, since Crohn's disease and ulcerative colitis have shared disease susceptibility and share genetic gene profile, it is paramount and is more advantageous to use CRISPR technology to maximize impact. Although, currently CRISPR does have its limitations due to limited number of specific Cas enzymes, off-target activity, protospacer adjacent motifs and crossfire between different target sites. However, these limitations have given researchers further insight on how to augment and manipulate enzymes to enable precise gene excision and limit crossfire between target sites.

Cardiovascular diseases (CVD) remain the leading cause of death in men and women. Biological sex plays a major role in cardiovascular physiology and pathological cardiovascular remodeling. Traditionally, pathological remodeling of cardiovascular system refers to the molecular, cellular, and morphological changes that result from insults, such as myocardial infarction or hypertension. Regular exercise training is known to induce physiological cardiovascular remodeling and beneficial functional adaptation of the cardiovascular apparatus. However, impact of exercise-induced cardiovascular remodeling and functional adaptation varies between males and females. This review aims to compare and contrast sex-specific manifestations of exercise-induced cardiovascular remodeling and functional adaptation. Specifically, we review (1) sex disparities in cardiovascular function, (2) influence of biological sex on exercise-induced cardiovascular remodeling and functional adaptation, and (3) sex-specific impacts of various types, intensities, and durations of exercise training on cardiovascular apparatus. The review highlights both animal and human studies in order to give an all-encompassing view of the exercise-induced sex differences in cardiovascular system and addresses the gaps in knowledge in the field.

A growing body of research suggests that alterations to the human microbiome are associated with disease states, including obesity and diabetes. During pregnancy, these disease states are associated with maternal microbial dysbiosis. This review discusses the current literature regarding the typical maternal and offspring microbiome as well as alterations to the microbiome in the context of obesity, type 2 diabetes mellitus, and gestational diabetes mellitus. Furthermore, this review outlines the proposed mechanisms linking associations between the maternal microbiome in the aforementioned disease states and offspring microbiome. Additionally, this review highlights associations between alterations in offspring microbiome and postnatal health outcomes.

Background: Perinatal Hypophosphatasia (HPP) is a rare and lethal disorder associated with a 50–100% mortality rate, usually due to respiratory complications. HPP occurs due to a loss-of-function mutation in the ALPL gene, responsible for the function of tissue-nonspecific alkaline phosphatase (TNSALP). Clinically, HPP presents as a severe lack of bone mineralization leading to a rickets-like presentation. Clinical Case: A 4-month-old female presented from an outside hospital for the ongoing care of perinatal HPP. Prenatal scans with long-bone fractures raised concern for Osteogenesis imperfecta. However, alkaline phosphatase (ALP) at birth was 250 ng/mL. Calcium, 25-OH vitamin D, and urine phosphoethanolamine were normal. A genetics panel for HPP confirmed two pathogenic autosomal recessive mutations on the ALPL gene. Treatment with asfotase alfa 3 mg/kg three times weekly was started on day two of life. The clinical course has been complicated by the need for mechanical ventilator support, seizure-event shortly after birth, recent EEG demonstrating epileptogenic potential in the bitemporal cortical regions now on treatment with Keppra, possible craniosynostosis with mild-to-moderate ventriculomegaly, and minimal grade 1 medullary nephrocalcinosis. Bone mineralization is monitored via skeletal surveys, and changes are measured using the Radiographic Global Impression of Change (RGI-C) and the Rickets Scoring Scale (RSS). After four months of asfotase alfa treatment, substantial progress in bone mineralization per RGI-C scoring has been noted, but RSS scoring still indicates severely low bone mineralization. ALP remains >3,000 U/L. Calcium, 25-OH vitamin D, and vitamin B6 are normal. Careful monitoring with weekly biochemical and urine profiles and monthly skeletal surveys, neuro assessments, and renal ultrasounds are ongoing. Conclusions: This clinical case demonstrates the improvement in bone mineralization with asfotase alfa, but the clinical course is slow and arduous. Despite the early initiation of asfotase alfa the patient’s bone mineralization remains severely low and is not in a safe range to proceed with G-tube, broviac, or tracheostomy placement. The current management goal is to maximize bone mineralization in preparation for the life-sustaining procedures mentioned above. With only a handful of surviving cases in the world, current long-term survival and outcomes for patients with perinatal HPP are unclear.

Introduction Type 1 diabetes impacts approximately 1.25 m Americans, many of them young children. As a child grows, there is a transition towards independence and they must learn to manage their diabetes independently. The objective of this study was to design, develop and conduct a prototype test to assess the satisfaction and feasibility of a mobile app for adolescents with type 1 diabetes and their parents to aid in this transition. Methods Ten parent/adolescent groups used MyT1DHero for four weeks. They were given a pre-test/post-test survey regarding family conflict with three tasks of diabetes management and the general tone of family communication. At post-test they were asked questions regarding their satisfaction and perception of ease of use of the app. They also participated in short interviews regarding the app. Additionally, we used server data to examine actual app usage. Results The parents’ perceptions of conflict around the results of the blood sugar tests increased ( t(9) = 2.71, p = .02) as did perceptions of conflict around logging the blood sugar results ( t(9) = 3.67, p = .005). The adolescents perceived increased conflict surrounding the results around logging the blood sugars results ( t(9) = 3.09, p = .01).There was no change in the tone of general family communication. During the prototype testing, we discovered that the app crashed repeatedly and several of the functions were not working properly. In the interview data, three main themes emerged, app-crashing issues, problems with notifications and positive feedback. Discussion Through this process, all of the reported issues were corrected and new features were planned for subsequent versions. A smartphone application has the potential to be a novel intervention for engaging adolescents and their parents in positive communication to support type 1 diabetes management.

This past century has seen the most advancement in medicine, leading to an almost thirty year increase in the average life expectancy. This increase in life expectancy has also increased cancer incidence in the global population. Cancer is a multifactorial disease, and thus its origin cannot be directly correlated with just one cause. To the best of our knowledge, this is the first study investigating how global meat consumption has influenced various cancers’ incidence rates across the world. Although the correlation between meat consumption and cancer risk has been investigated, a global temporal study investigating the national mortality rates of gastrointestinal cancers relating to meat production remains unexplored. We researched causes for the trends between meat production and GI cancer mortality in affluent nations of both the Eastern and the Western hemisphere including: the USA, Canada, Japan, France, and Singapore. Data was collected from the Food and Agricultural Organization of the United Nations and the World Health Organization Cancer Mortality Database. Meat consumption data was unavailable between the 1960s-2010, so meat production data was used instead. Interestingly, the pancreatic cancer mortality rate increased in each country except Canada. The spike is due to increased meat consumption, obesity, lack of screening modalities, poor prognosis, and late diagnosis of the disease. Canada’s 1% drop in mortality rate can be attributed to a decreased smoking rate amongst men (62% to 16% from 1965-2017) as well as an overall decline in meat consumption. The mortality rates of gastric and colorectal cancer (CRC) have decreased despite a meat production increase. Decreased H. pylori prevalence (Europe: 48.8% to 39.8%, North America: 42.4% to 26.6%, and Western Asia: 53.6% to 54.3%), better food preservation, and improvement in environmental conditions have lowered gastric cancer incidence. The CRC mortality rate in the USA, Canada, Japan, and France decreased mostly due to colonoscopy screening measures, better treatment, and decreased red meat consumption. In Singapore, increased obesity and a poor, high caloric diet accounts for an increased CRC mortality rate despite decreased meat production. This rate is exacerbated by lower screening rates due to decreased CRC risk awareness. Gastric and CRC mortality rates decreased despite increases in meat production, while pancreatic cancer incidence rates have increased. These trends are further investigated and necessary to understand in order to lower the mortality rates of GI cancers on a global scale.

Approximately 15-20% of breast cancer cases are diagnosed as Triple Negative Breast Cancer (TNBC), where there is a lack of expression of the Estrogen Receptor (ER), Progesterone Receptor (PR), and epidermal growth factor receptor 2 (HER2)..

Trauma is a leading cause of death worldwide and is particularly prevalent and troubling in the United States.

Objective: To examine the hospital-level variation in intensive care unit (ICU) utilization and quantify the relative contribution of patient and hospital characteristics versus individual hospital factors to the variation in ICU admission rates among pediatric hospitalizations with diabetic ketoacidosis (DKA). Methods: The Texas Inpatient Public Use Data File was used to identify hospitalizations of state residents aged 1 month to 19 years with a primary diagnosis of DKA between 2005 and 2014. Multilevel, mixed-effects logistic regression modeling was performed to examine the association of patient- and hospital-level factors with ICU admission. Risk and reliability adjustment was then performed to assess hospital-level variation in ICU utilization. Intraclass correlation coefficient was used to quantify variation in use of ICU attributable to individual hospitals. The association between adjusted rates of ICU admission and total hospital charges and length of stay was examined using linear regression. Results: Of the 23 585 DKA hospitalizations, 14 638 (62.1%) were admitted to ICU. On multilevel analysis, the odds of ICU admission progressively decreased with rising volume of DKA hospitalizations (adjusted odds ratio: 0.08 [highest vs lowest quartile]; 95% confidence interval [CI]: 0.03-0.24). The crude median (interquartile range [IQR]; range) of ICU admissions across hospitals was 82.6% (73%-90%; 11.1%-100%). The median (IQR) risk- and reliability-adjusted ICU admission rate was 81.0% (73.0%-86.9%), ranging from 11.2% to 94%. Following risk and reliability adjustment, the intraclass correlation coefficient was 0.005 (95% CI: 0.004-0.006). For each 10% increase in adjusted ICU admission rate, total hospital charges rose by 7% (95% CI: 3%-11%). There was no association between ICU admission rates and hospital length of stay. Conclusion: Although high variation in ICU utilization was noted across hospitals among pediatric DKA hospitalizations, the proportion of variation attributable to individual hospitals was negligible, once adjusted for patient mix and hospital characteristics.

In both human and animals, in utero exposure to bisphenol A (BPA), an endocrine disrupting chemical used in the production of plastics and epoxy resins, has been shown to affect offspring reproductive and metabolic health during adult life. We hypothesized that the effect of prenatal exposure to environmentally relevant doses of BPA will be evident during fetal organogenesis and fetal / postnatal growth trajectory. Pregnant ewes were administered BPA subcutaneously from days 30–90 days of gestation (term 147 days). Fetal organ weight, anthropometric measures, maternal / fetal hormones and postnatal growth trajectory were measured in both sexes. Gestational BPA administration resulted in higher accumulation in male than female fetuses only at fetal day 65, with minimal impact on fetal / maternal steroid milieu in both sexes at both time points. BPA-treated male fetuses were heavier than BPA-treated female fetuses at fetal day 90 whereas this sex difference was not evident in the control group. At the organ level, liver weight was reduced in prenatal BPA-treated female fetuses, while heart and thyroid gland weights were increased in BPA-treated male fetuses relative to their sex-matched control groups. Prenatal BPA treatment also altered postnatal growth trajectory in a sex-specific manner. Males grew slower during the early postnatal period, caught up later. Females, in contrast, demonstrated the opposite growth trend. Prenatal BPA-induced changes in fetal organ differentiation and early life growth strongly implicate translational relevance of in utero contributions to reproductive and metabolic defects previously reported in adult female offspring.

Epidemiologic studies and studies in rodents point to potential risks from developmental exposure to BPA on cardiometabolic diseases. Furthermore, it is becoming increasingly evident that the manifestation and severity of adverse outcomes is the result of interaction between developmental insults and the prevailing environment. Consistent with this premise, recent studies in sheep found prenatal BPA treatment prevented the adverse effects of postnatal obesity in inducing hypertension. The gene networks underlying these complex interactions are not known. mRNA-seq of myocardium was performed on four groups of four female sheep to assess the effects of prenatal BPA exposure, postnatal overfeeding and their interaction on gene transcription, pathway perturbations and functional effects. The effects of prenatal exposure to BPA, postnatal overfeeding, and prenatal BPA with postnatal overfeeding all resulted in transcriptional changes (85-141 significant differentially expressed genes). Although the effects of prenatal BPA and postnatal overfeeding did not involve dysregulation of many of the same genes, they affected a remarkably similar set of biological pathways. Furthermore, an additive or synergistic effect was not found in the combined treatment group, but rather prenatal BPA treatment led to a partial reversal of the effects of overfeeding alone. Many genes previously known to be affected by BPA and involved in obesity, hypertension, or heart disease were altered following these treatments, and AP-1, EGR1, and EGFR were key hubs affected by BPA and/or overfeeding. Environ. Mol. Mutagen. 58:4-18, 2017. © 2016 Wiley Periodicals, Inc.

Objectives To examine the temporal patterns of hospitalizations with diabetic ketoacidosis (DKA) in the pediatric population and their associated fiscal impact. Methods The Texas Inpatient Public Use Data File was used to identify hospitalizations of state residents aged 1month-19 years with a primary diagnosis of DKA during 2005–2014. Temporal changes of population-adjusted hospitalization rates and hospitalization volumes were examined for the whole cohort and on stratified analyses of sociodemographic attributes. Changes in the aggregate and per-hospitalization charges were assessed overall and on stratified analyses. Results There were 24,072 DKA hospitalizations during the study period. The population-adjusted hospitalization rate for the whole cohort increased from 31.3 to 35.9 per 100,000 between 2005–2006 and 2013–2014. Hospitalization volume increased by 30.2% over the same period, driven mainly by males, ethnic minorities, those with Medicaid insurance and uninsured patients. The aggregate hospital charges increased from approximately $69 million to $130 million between 2005–2006 and 2013–2014, with 66% of the rise being due to increased per-hospitalization charges. Conclusions There was progressive rise in pediatric DKA hospitalizations over the last decade, with concurrent near-doubling of the associated fiscal footprint. Marked disparities were noted in the increasing hospitalization burden of DKA, born predominantly by racial and ethnic minorities, as well as by the underinsured and the uninsured. Further studies are needed to identify scalable preventive measures to achieve an equitable reduction of pediatric DKA events.

Triple negative breast cancer exhibit increased IL-6 expression compared with matched healthy breast tissue and a strong link between inflammation and cancer progression and metastasis has been reported. We investigated whether doxorubicin-hyaluronan-super-paramagnetic iron oxide nanoparticles (DOX-HA-SPION) would show greater therapeutic efficacy in human triple negative breast cancer cells (TNBC) MDA-MB-231, as was recently shown in drug-sensitive and multi-drug-resistant ovarian cancer cells. Therefore, we measured cellular DOX uptake via confocal microscopy; observed morphologic changes: mitochondrial and nuclear changes with electron microscopy, and quantitated apoptosis using FACS analysis after Annexin V and PI staining in MDA-MB-231 cells treated with either DOX alone or DOX-HA-SPION. We also measured both proinflammatory and anti-inflammatory cytokines; IL-6, IL-10 respectively and also measured nitrate levels in the conditioned medium by ELISA. Inaddition, NF-κB activity was measured by luciferase assay. Confocal microscopy demonstrated greater cytoplasmic uptake of DOX-HA-SPION than free DOX. We also demonstrated reduction of Vimentin with DOX-HA-SPION which is significantly less than both control and DOX. DOX-HA-SPION enhanced apoptosis and significantly down regulated both pro-inflammatory mediators IL-6 and NF-κB in comparison to DOX alone. The secretion levels of anti-inflammatory mediators IL-10 and nitrate was not decreased in the DOX or DOX-HA-SPION treatment groups. Our data suggest that DOX-HA-SPION nanomedicine-based drug delivery could have promising potential in treating metastasized and chemoresistant breast cancer by enhancing the drug efficacy and minimizing off-target effects.

Nuclear factor kappa B (NF-κB) has an established role in the regulation of innate immunity and inflammation. NF-κB is also involved in critical mechanisms connecting inflammation and cancer development. Recent investigations suggest that the NF-κB signaling cascade may be the central mediator of gastrointestinal malignancies including esophageal, gastric and colorectal cancers. This review will explore NF-κB’s function in inflammation-associated gastrointestinal malignancies, highlighting its oncogenic contribution to each step of carcinogenesis. NF-κB’s role in the inflammation-to-carcinoma sequence in gastrointestinal malignancies warrants stronger emphasis upon targeting this pathway in achieving greater therapeutic efficacy.

Mercury (Hg) poisoning is considered a rare disease by the National Institutes of Health and the diagnosis can present great challenges to clinicians. Children who are exposed to Hg can present with a wide variety of symptoms, including acrodynia, tremor, excessive salivation, and psychiatric symptoms, including insomnia. However, endocrinologic manifestations from Hg exposure are less well known. This is a case report of a 12-year-old boy who presented with body rash, irritability, insomnia, and profuse sweating after returning from a summer camp. The child was initially managed in the outpatient setting, and the investigation was mainly targeted toward infectious etiology, including Rocky Mountain spotted fever and Lyme disease. He was eventually admitted to the hospital with altered mental status and was noted to have hyponatremia with serum sodium of 121 mEq/L. Thyroid studies also revealed elevated free thyroxine levels in the presence of normal triiodothyronine and thyrotropin. The patient developed hypertension and tachycardia, and was found to have elevated 24-hour vanillylmandelic acid and metanephrines. Finally, heavy metal measurements revealed a blood Hg level that was greater than the reference values of 0 to 9 ng/mL. Chelation treatment with 2,3-dimercaptopropane-1-sulfonate was subsequently initiated and over a period of 8 months his symptoms resolved and his thyroid function test returned to normal. This case highlights some of the challenges commonly encountered in identifying Hg exposure. More importantly, it illustrates that exposure to Hg should be considered in children who present with the symptoms and abnormal endocrinologic test results described in this report.

Colorectal cancer is the second leading cause of mortality in men and women in the United States. While there is a definite advantage regarding the use of colonoscopies in screening, there is still a lack of widespread acceptance of colonoscopy use in the general public. This is evident by the fact that up to 75% of patients diagnosed with colorectal cancer present with locally advanced disease. In order to make colonoscopy and in turn colorectal cancer screening a patient friendly and a comfortable test some changes in tool are necessary. The conventional colonoscope has not changed much since its development. There are several new advances in colorectal screening practices. One of the most promising new advances is the advent of robotic endoscopic techniques.

This paper reviews recent, though limited, articles on the topic of robotic single-site cholecystectomy (RSSC), a relatively new approach that is rapidly advancing in both research and clinical application. Laparoscopy has typically been the standard method of performing a cholecystectomy, but recent medical advances have led to usage of the da Vinci® Surgical System robot technology to assist in performing the procedure. Several studies have compared outcomes of the RSSC to single-port laparoscopic cholecystectomies and to the traditional multiport laparoscopic cholecystectomies. Single port advocates think it as a tool with better cosmetic results and questionable less post-operative pain; however, single port also limits the maneuverability of the instrument arms, making some tasks more difficult, bigger single incision, more chances of post operative hernia. Overall, the RSSC is considered as safe with no worse outcomes regarding pain, hospital stay length, operative time, and patient satisfaction when compared to other cholecystectomy methods. Future direction includes expanding use of the miniature instruments and further advanced tools to overcome manipulation and visualization limitations. Thus far, though, there may be enough evidence with these smaller studies to support lack of harm with more use of resources.

Background: Proteasome inhibitors limit tumor growth by lowering the capacity of cancer cells to degrade pro-apoptotic signals. Given the success of proteasome inhibitors as a treatment for multiple myeloma, this class of drugs has been investigated as a possible treatment for other malignancies with poor prognoses, such as metastatic triple negative breast cancer (TNBC). Doxorubicin (DOX), is the current standard of treatment for TNBC but it has a very toxic side effect profile. Furthermore, it has been shown that the pro-inflammatory markers IL-6/NF-kB plays a critical role in angiogenesis, anti-apoptosis, metastasis and hematogenous spread of tumor cells, and is elevated at baseline in TNBC and increases further with DOX treatment. Recent studies with SGPI on myeloma patients have reported that only 2-5% patients exhibited side effects as compared to the 25% heart failure seen with DOX, a more tolerable side-effect profile. However, in a recent clinical trial, Bortezomib (BOR), a first-generation proteasome inhibitor, showed limited activity in metastatic breast cancer when used as single agent. SGPI differs from BOR in its structure and its activity on the proteasome complex. Therefore, we studied the effect of SGPI on proliferation and inflammation in the triple negative breast cancer cell line MDA-MB-231. Method: MDA-MB-231 cells were treated with known D50 concentrations of DOX, SGPI, and BOR alone and in combination for 24 hours. Cells were then incubated in complete medium for another 24 hours. The viability of each group was analyzed by quantitating cell proliferation (MTT assay). The inflammatory markers IL-6 and NF-kB were measured by ELISA and lentiviral signal assay. Results: DOX (2 uM) decreased TNBC proliferation by 40% while SGPI (10nM) and the combined regimen decreased it by over 70%. BOR (5 nM) was less efficacious than DOX or SGPI. Treatment/Proliferation MEDIA (DMEM 10%FBS)*DOX (2uM)*SGPI (10nM)*DOX + SGPI (2uM, 10nM)*BOR (5nM)DOX + BOR (2uM, 5nM)*Proliferation (%)100+/-1.4559.9 +/-1.6528.7+/-0.38**28.0+/-0.57 **75.0 +/-5.856.2 (±0.97)NF-kB (LMU)12882+/-176 **22821+/-24003675+/-241 **4115+/-140 **12586+/-2771 **17989 (±1074)IL-6 (pg/ml)1117+/-23.1**2831(±23.3)517+/-17.0 **212+/-14.6 **1256+/-36.7**1211 (±1074) ***n = 4/** & 0.01 Compared to DOX Although the combination showed no appreciable synergism, the large proliferation difference between the treatments suggests that SGPI has a greater anti-tumor activity than DOX at a D50 concentration. The DOX/BOR combination also showed no synergism. SGPI halved baseline IL-6 levels and reduced DOX-stimulated levels 6-fold. Similar results were seen with NF-kB. BOR also lowered inflammation but to a lesser extent. Conclusion: SGPI is more efficacious than either DOX or BOR in inhibiting TNBC proliferation in vitro, perhaps as a result of a reduced IL-6/NF-kB pathway pro-inflammatory response, which represents a potential improvement in the toxicity profile of existing chemotherapy. These preliminary results indicate that SGPI might reduce angiogenesis and metastasis. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-09.

Androgen excess (hyperandrogenism) is a common endocrine disorder affecting women of reproductive age. The potential causes of androgen excess in women include polycystic ovary syndrome, congenital adrenal hyperplasia (CAH), adrenal tumors, and racial disparity among many others. During pregnancy, luteoma, placental aromatase deficiency, and fetal CAH are additional causes of gestational hyperandrogenism. The present report reviews the various phenotypes of hyperandrogenism during pregnancy and its origin, pathophysiology, and the effect of hyperandrogenism on the fetal developmental trajectory and offspring consequences.

Trauma-related injury in fast developing countries are linked to 90% of international mortality rates, which can be greatly reduced by improvements in often non-existent or non-centralized emergency medical systems (EMS)-particularly in the pre-hospital care phase. Traditional trauma training protocols-such as Advanced Trauma Life Support (ATLS), International Trauma Life Support (ITLS), and Basic Life Support (BLS)-have failed to produce an effective pre-hospital ground force of medical first responders. To overcome these barriers, we propose a new four-tiered set of trauma training protocols: Massive Open Online Course (MOOC) Trauma Training, Acute Trauma Training (ATT), Broad Trauma Training (BTT), and Cardiac and Trauma Training (CTT). These standards are specifically differentiated to accommodate the educational and socioeconomic diversity found in fast developing settings, where each free course is taught in native, lay language while ensuring the education standards are maintained by fully incorporating high-fidelity simulation, video-recorded debriefing, and retraining. The innovative pedagogy of this trauma education program utilizes MOOC for global scalability and a "train-the-trainer" approach for exponential growth-both components help fast developing countries reach a critical mass of first responders needed for the base of an evolving EMS.

Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30–90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells –c3 (NFATc3) and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess.

Colorectal cancer accounts for a significant proportion of cancer deaths worldwide. The need to develop more chemotherapeutic agents to combat this disease is critical. Cyclin dependent kinases (CDKs), along with its binding partner cyclins, serve to control the growth of cells through the cell cycle. A new class of drugs, termed CDK inhibitors, has been studied in preclinical and now clinical trials. These inhibitors are believed to act as an anti-cancer drug by blocking CDKs to block the uncontrolled cellular proliferation that is hallmark of cancers like colorectal cancer. CDK article provides overview of the emerging drug class of CDK inhibitors and provides a list of ones that are currently in clinical trials.

The rising interest in the utilization of nanoparticles for diagnosis and treatment in all cancers including gastrointestinal cancer has increased research interest, and funding in the area of medical nanotechnology. Interesting outcomes of research studies on different applications are published every day, and it include approaches such as molecular targeting, photodynamic therapy, and magnetic localization. The discoveries being made by research teams and the hypothesized applications are thus far very promising. There are limitations that must be researched and overcome, but the increasing evidence for the use of nanoparticles in cancer treatment cannot be ignored. In this review, several recent techniques are discussed on the development of more effective and targeted cellular/molecular techniques in the diagnosis and treatment of gastrointestinal cancer.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, with a prevalence of 5-8%. Type 2 diabetes and cardiovascular disease (CVD) are its long-term complications. Targeted therapies addressing both these complications together are lacking. Glucagon like peptide-1 (GLP-1) agonists that are used to treat type 2 diabetes mellitus have beneficial effects on the cardiovascular system. Hence we hypothesized that a GLP-1 agonist would improve both cardiovascular and metabolic outcomes in PCOS. To test this hypothesis, we used an established rat model of PCOS. Prepubertal female Sprague Dawley rats were sham-implanted or implanted s.c. with dihydrotestosterone (DHT) pellets (90 day release; 83 μg/day). At 12 wks of age, sham implanted rats received saline injections and the DHT treated animals were administered either saline or liraglutide (0.2 mg/kg s.c twice daily) for 4 weeks. Subgroups of rats were implanted with telemeters between 12-13 weeks of age to monitor blood pressure. DHT implanted rats had irregular estrus cycles and were significantly heavier than the control females at 12 weeks (mean± SEM 251.9±3.4 vs 216.8±3.4 respectively; p

A major factor contributing to global trauma mortality and morbidity is the lack of effective prehospital trauma services in developing settings. We developed a 2-d training course for nondoctor first responders featuring high-fidelity simulation and video-assisted debriefing, self-directed learning videos, and native language instruction.A pilot session was conducted in Jodhpur, Rajasthan. Eighteen local instructors were recruited to train 48 layperson first responders in 10 essential subjects. Didactic sessions of 15-20 min consisting of self-directed learning videos were followed by 30-40 min skill sessions featuring high-fidelity simulation, and concluded with 15-20 min video-debriefing periods. Changes in competence were evaluated using pretraining and posttraining surveys.Results demonstrated that statistically significant competence increases in all areas of trauma management assessed: airway (t[46] = 7.30, P0.000), hemorrhage (t[46] = 9.96, P0.000), fractures (t[46] = 9.22, P0.000), cervical spine injury (t[46] = 12.12, P = 0.000), chest injury (t[46] = 7.84, P0.000), IV line placement (t[46] = 4.36, P0.000), extrication (t[46] = 2.81, P0.005), scene assessment (t[46] = 7.06, P0.000), triage (t[46] = 5.92, P0.000), and communication (t[46] = 5.56, P0.000). Highest increases in competence were observed in cervical spine injury and hemorrhage management, with lowest increases in IV line placement and extrication.Results suggest this approach may be effective in imparting prehospital trauma management concepts to layperson first responders. This study highlights an innovative educational avenue through which trauma management capacity can be enhanced in developing settings.

Worldwide, breast cancer remains as one of the most common cancer diagnosis and cause of cancer related death among women. Fortunately, nanomedicine has brought forth new potential and hope in breast cancer research. The extremely small size of nanoparticles makes it advantageous and potentially superior to use in tumor detection and imaging. One of the more extensively studied particles is quantum dots, semiconductor crystals which are capable of enhanced labeling and imaging of cancer cells. In addition, due to serious toxicity of chemotherapeutic agents, nano-formulations of breast cancer chemotherapy are under investigation and development. This may provide easier administering route and reduced frequency of drugs. With the use of nanoparticles, drug delivery can be carried out in a minimally invasive fashion and treatment regimens can be made much more targeted and specific for each patient. In this review article, we provide an overview on the role nanomedicine has played in breast cancer and mention some of the latest diagnostic and treatment modalities researched to date.

Over the past decade, research has shown that aberrant expression of microRNA (miRNA) is involved in colorectal cancer development and progression. MicroRNAs are small sequences of non-coding RNA that regulate expression of genes involved in important cellular functions, such as cell differentiation, multiplication, and apoptosis. A specific miRNA may display the effects of a tumor suppressor or oncogene. Altered miRNA expression is found in colorectal cancer (CRC) and patterns of miRNA expression correlate with CRC detection and outcome. Studies also have examined the use of circulating serum miRNA and fecal miRNA expression as non-invasive markers for early detection. Here, we review recent evidence demonstrating the potential role of miRNA in CRC and the implications of its use in the diagnosis, prognosis, and management of CRC.

The benign cystic mesothelioma of the peritoneum is a rare lesion and is known for local recurrence. This is first case report of a rapidly developing massive abdominal tumor with histological finding of benign cystic mesothelioma (BCM). We describe a BCM arising in the retroperitoneal tis[sue on the right side, lifting ascending colon and cecum to the left side of abdomen. Patient was an active 58-year-old man who noticed a rapid abdominal swelling within a two month time period with a weight gain of 40 pounds. Patient had no risk factors including occupational (asbestos, cadmium), family history, social (alcohol, smoking) or history of trauma. We will discuss the clinical, radiologic, intra-operative, immunohistochemical, pathologic findings, and imaging six months after surgery. Patient has no recurrence and no weight gain on follow up visits and imaging.