Measuring the Efficacy of Pathology Career Recruitment Strategies in US Medical Students.

CONTEXT.­: Multiple articles and surveys in the literature suggest that medical students find a career in pathology undesirable and believe it is disproportionately focused primarily on the autopsy. OBJECTIVE.­: To measure the effect of applied interventions on medical student attitudes about the field of pathology. DESIGN.­: This prospective study involving medical students from first through fourth year was conducted as a pilot study in 2 medical schools in the United States. A 2-part anonymous survey regarding interest in pathology as a career and familiarity with the specialty using a 10-point scale was given to first- and second-year medical students before and after they listened to a 10-minute pathology career presentation. The same survey was given to third- and fourth-year medical students before and after a 4-week pathology elective. RESULTS.­: A total of 121 and 83 students responded to the survey before and after the intervention, respectively. Of the 121 students who responded to the survey before the intervention, 106 (87.6%) had not spent significant time in a pathology laboratory before the intervention. The majority of responses in interest in career, job responsibilities, and features of pathologists before and after the intervention demonstrated a statistically significant difference (P < .001). We compared survey scores of presentation versus 4-week rotation groups before and after the intervention. Students who experienced the presentation did not differ from students who experienced the rotation in the majority of questions related to interest in career, job responsibilities, and features of pathologists. CONCLUSIONS.­: Our study suggests that pathology exposure strategies can have a beneficial effect on student perceptions of the field and consideration of a career in pathology. Overall, the presentation intervention seemed to have the greatest effect on the first- and second-year students.

Extensive Fever of Unknown Origin (FUO) Workup to Unmask Pheochromocytoma.

Pheochromocytoma is a tumor arising from chromaffin cells of the medulla of adrenal gland and secretes excessive amounts of catecholamines: epinephrine and norepinephrine. It can also arise from sympathetic ganglia when it is referred to as catecholamine-secreting paragangliomas or extra-adrenal pheochromocytoma. Pheochromocytoma has been referred to as "the masquerader" for its numerous atypical presentations, which makes its diagnosis medically challenging. Here, we present a case of a 66-year-old female, presenting with high-grade fever for two weeks associated with generalized body aches. She had an extensive infectious, rheumatological and hematological workup. Ultimately, she was diagnosed with pheochromocytoma. After adrenalectomy, her fever and body ache resolved.

CD4 T Follicular Helper Cells Prevent Depletion of Follicular B Cells in Response to Cecal Ligation and Puncture.

Recent studies have demonstrated that induction of a diverse repertoire of memory T cells ("immune education") affects responses to murine cecal ligation and puncture (CLP), the most widely - used animal model of sepsis. Among the documented effects of immune education on CLP are changes in T cell, macrophage and neutrophil activity, more pronounced organ dysfunction and reduced survival. Little is known, however, about the effects of CLP on B cell responses, and how these responses might be altered by immune education. Importantly, effective B cell responses are modulated by IL21 produced by CD4+/CXCR5+/PD1+ T follicular helper (Tfh) cells. We examined the B cell population in control and immune educated mice 24 h and 60 days after CLP. Education alone increased Tfh cells. Twenty-four hours after CLP, Tfh cells were depleted. However, this reduction was less pronounced in immune educated mice than in controls and the percentage of CD4 T cells expressing a Tfh phenotype increased in the animals. CLP did not alter splenic architecture and decreased numbers of follicular, marginal, and germinal center B cells. CLP induced changes were not, however, noted following CLP in immune educated mice. At 60 days post - CLP, numbers of follicular, germinal center and marginal zone B cells were increased; this increase was more pronounced in immune educated mice. Finally, while CLP reduced the induction of antigen specific B cells in controls, this response was maintained following CLP in immune educated mice. Our data suggest that preexisting Tfh assists in rescuing the B cell response to CLP.

A Case Report on Metformin-Associated Lactic Acidosis.

Metformin is the first-line therapy for patients with type 2 diabetes, and its most common adverse effects are gastrointestinal. Lactic acidosis associated with metformin use is rare. Here, we report the case of a 77-year-old man with a medical history of diabetes (treated with metformin), hypertension, chronic alcohol abuse, and prostate and bladder cancer, who presented with abdominal pain, nausea, vomiting, and diarrhea for five days. He was admitted with severe metabolic acidosis due to metformin toxicity (metformin-associated lactic acidosis) with metformin level 23 mcg/mL (therapeutic range approximately 1-2 mcg/mL) in the setting of acute kidney failure due to acute pancreatitis and sepsis secondary to aspiration pneumonia. He was intubated, required pressor support, and received daily hemodialysis. Despite aggressive management, his hospital course became complicated with acute respiratory distress syndrome, myocardial infarction, acute hepatic failure, and ischemic and metabolic encephalopathy. In the end, the family decided to withdraw care and the patient was terminally extubated.

A Case of Severe Psychosis Due to Cushing's Syndrome Secondary to Primary Bilateral Macronodular Adrenal Hyperplasia.

Hypercortisolism is a multisystem disorder that results from inappropriate and excessive glucocorticoid secretion and loss of normal feedback mechanisms of the hypothalamic-pituitary axis. It is broadly divided into adrenocorticotropic hormone (ACTH) dependent and ACTH-independent categories. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent hypercortisolism, accounting for less than 2% of cases. It usually presents as hypertension, metabolic abnormalities, thromboembolic, cardiovascular, or endocrine disorders but rarely as a neuropsychiatric illness. Therefore, a delay in the diagnosis and management of cognitive illnesses substantially increases morbidity in these patients. Herein, we report a case of severe psychosis due to Cushing's syndrome with PBMAH.  A 49-year-old male with a past medical history of diabetes and hypertension presented with acute onset of confusion. The patient's uncontrolled hypertension, hypokalemia, metabolic alkalosis, and resistant psychosis to various psychotropic medications raised the suspicion of an underlying metabolic disorder. Further workup revealed an inappropriate suppression of morning (AM) cortisol after administration of dexamethasone and elevated values of serum AM cortisol and 24-hour urinary cortisol, in addition to low ACTH. Computed tomography (CT) of the abdomen and pelvis with intravenous (IV) contrast was performed to evaluate the adrenal gland which showed multiple nonspecific adrenal nodules bilaterally measuring between 3.5 cm - 4.5 cm. The patient was hence diagnosed with hypercortisolism secondary to PBMAH. The patient was treated with ketoconazole after he refused surgery as a treatment option and was noted to have significant improvement in his psychosis within a week, along with improvement of his hypertension, electrolyte abnormalities, and a significant decrease in the 24-hour urine cortisol level. Neuropsychiatric illness is a rare manifestation and an unusual initial presenting symptom of Cushing's syndrome secondary to primary bilateral macronodular adrenal hyperplasia. A delay in diagnosis often subjects these patients to unnecessary psychotropic medications and prolonged psychiatric hospitalizations. Hence, clinicians must be cognizant of this rare entity when making a diagnostic evaluation to prevent subsequent morbidity and mortality.

Reducing Central Line-Associated Bloodstream Infections in Three ICUs at a Tertiary Care Hospital in the United Arab Emirates.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is associated with significant morbidity and mortality. A quality improvement project was conducted to decrease CLABSI rates by 50% across all ICUs in a tertiary care hospital (Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates). METHODS: A multifaceted interventional program was implemented in a drive to reduce CLABSI rates. Stage 1 of the intervention entailed implementation of a central line insertion bundle, an insertion checklist, dedicated central line trolleys, education of all staff involved in insertion and maintenance of central lines, and empowerment of nurses. Stage 2 entailed implementation of a maintenance bundle and a CLABSI prevention policy and inclusion of central line assessment in the daily goals. Stage 3 was implemented in the form of CLABSI champions, spot checks on maintenance techniques, and review of every CLABSI. Stage 4 entailed the implementation of a Comprehensive Unit-based Safety Program (CUSP). Stage 5 consisted of a "back to basics" campaign, which included refocusing on basic evidence-based care bundles, introduction of bundle-compliance verification, and educational sessions and awareness programs. RESULTS: Overall CLABSI rates significantly decreased (p < .0001) from a mean of 2.99 (standard deviation [SD], 1.69) in the preimplementation period (January 2008-June 2011) to 1.47 (SD, 1.01) in the postimplementation period (July 2011-August 2014) across all ICUs. Overall, there were significantly more months with CLABSI-free days in the post-implementation than in the preimplementation period. CONCLUSION: The combination of evidence-based interventions, standardization of procedures, teamwork, and front-line staff involvement in the decision-making process contributed to decreases in CLABSI rates across three ICUs.

Procedures and drugs in pediatric dermatology: iatrogenic risks and situations of concern.

Over the past several decades, improved technologies used in the care of hospitalized and outpatient pediatric populations have resulted in a decreased but still significant number of iatrogenic injuries. Children at the highest risk for cutaneous injury include those with the most immature skin barriers, such as neonates younger than 32 weeks of gestational age. Additional risk factors include low birth weight, increased length of hospital stay, and indwelling instrumentation. Also at risk are older children with compromised skin barriers owing to infectious disease (staphylococcal scalded skin syndrome), inflammatory disease (atopic dermatitis), drug eruptions, and inherited or acquired blistering disorders. This review highlights the presentation, course, and management of iatrogenic skin injury events in children.

Forensics in dermatology: part I.

Examination of the skin and adnexae is a critical part of the forensic examination. Little information on forensic sciences has been published in the dermatologic literature. Correct forensic terminology and documentation of dermatologic findings is of critical importance in forensic investigations. The skin may reveal clues to the identity of an individual and the time and method of death or injury. Normal postmortem changes in the skin are described along with pseudopathology and damage from postmortem animal activity. The forensic classification of types of injuries is introduced in this first of a two-part paper on forensics in dermatology.

Forensics in dermatology: part II.

The evaluation of skin findings is critical in identifying many types of injury, whether self- inflicted or accidentally or intentionally inflicted. Specific causes of injury include homicide, abuse, neglect, assault, self-inflicted injury, suicide, torture, poisoning, and bioterrorism. Forensic findings in hair and nails are also discussed. This overview of dermatologic findings in forensic pathology highlights the significance of the cutaneous manifestations of injury.

Tris (dibenzylideneacetone) dipalladium, a N-myristoyltransferase-1 inhibitor, is effective against melanoma growth in vitro and in vivo.

PURPOSE: Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been shown to contribute to melanoma tumorigenesis, including constitutive activation of mitogen-activated protein kinase, Akt, and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, Tris (dibenzylideneacetone) dipalladium (Tris DBA), showed significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA. EXPERIMENTAL DESIGN: Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. To find the mechanism of action of Tris DBA, we did Western blot and gene array analyses. The ability of Tris DBA to block tumor growth in vivo was assessed. RESULTS: Tris DBA has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of mitogen-activated protein kinase, Akt, Stat-3, and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase-1, which is required for optimal activity of membrane-based signaling molecules. Tris DBA showed potent antitumor activity in vivo against melanoma. CONCLUSION: Tris DBA is thus a novel inhibitor of N-myristoyltransferase-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.

The antidepressant sertraline downregulates Akt and has activity against melanoma cells.

Melanoma is a common malignancy which is poorly responsive to chemotherapy and radiation. One of the major reasons melanoma responds poorly to these modalities is constitutive expression of Akt, which protects against apoptosis. The antidepressant sertraline was found to be a potent cytotoxic agent against A375 human melanoma. To determine the mechanism by which sertraline kills melanoma cells, Western blot analysis of signaling molecules, including phosphorylated Akt, caspase 9 and phospho-p70 S6 kinase was performed. Finally, the effects of sertraline on A375 xenografts in mice were assessed. Sertaline potently inhibited the phosphorylation of Akt, and caused cell death through induction of endoplasmic reticulum in vitro. Sertraline monotherapy demonstrated activity against A375 xenografts in vivo. Akt is a major cause of resistance of melanoma to current therapy. Antidepressants are commonly used to prevent interferon-induced depression. Use of antidepressants that decrease Akt may improve the efficacy of interferon and other therapies against melanoma. Further studies are needed to elucidate whether sertraline acts as an Akt inhibitor in melanoma.

Shb gene knockdown increases the susceptibility of SVR endothelial tumor cells to apoptotic stimuli in vitro and in vivo.

The Shb adapter protein is an Src homology 2-domain containing signaling intermediate operating downstream of several tyrosine kinase receptors, including vascular endothelial growth factor receptor-2. Shb is multifunctional and apoptosis is one response that Shb regulates. Inhibition of angiogenesis can be used in cancer therapy, and one way to achieve this is by inducing endothelial cell apoptosis. The angiosarcoma cell line SVR is of endothelial origin and can be used as a tool for studying in vivo inhibition of angiogenesis, and we thus employed an Shb-knockdown strategy using an inducible lentiviral system to reduce Shb levels in SVR cells and to study their responses. Shb knockdown increases the susceptibility of SVR cells to the apoptotic agents, cisplatin and staurosporine. Simultaneously, Shb knockdown causes reduced focal adhesion kinase (FAK) activation, monitored as phosphorylation of the regulatory residues tyrosines 576/577. No detectable effects on Akt or extracellular signal-regulated kinase activity were noted. The altered FAK activity coincided with an elongated cell phenotype that was particularly noticeable in the presence of staurosporine. In order to relate the effects of Shb knockdown to in vivo tumorigenicity, cells were exposed to the angiogenesis inhibitor honokiol, and again the cells with reduced Shb content exhibited increased apoptosis. Tumor growth in vivo was strongly reduced in the Shb-knockdown cells upon honokiol treatment. It is concluded that Shb regulates apoptosis and cell shape in tumor endothelial cells via FAK, and that Shb is a potential target for inhibition of angiogenesis.

Presence of p16 hypermethylation and Epstein-Barr virus infection in transplant-associated hematolymphoid neoplasm of the skin.

BACKGROUND: Epstein-Barr virus (EBV) is associated with the malignant transformation of B, T, and NK lymphocytes in humans, especially in immunosuppressed individuals. OBJECTIVE: We describe an unusual case confined to the skin in a 39-year-old African American female following a renal transplant. METHODS: Morphologically and immunophenotypically, the tumor was best classified as a plasmablastic lymphoma; however, the neoplastic population revealed rearrangements of both immunoglobulin heavy chain (IgG) and T cell receptor gamma (TCR-gamma). In situ hybridization demonstrated the presence of Epstein-Barr early RNA species (EBER) in the lymphoma cells, consistent with EBV infection. RESULTS: We have previously demonstrated that EBV-induced reactive oxygen is associated with hypermethylation of the tumor suppressor gene p16 in Burkitt lymphoma, and that p16 hypermethylation is nearly always associated with EBV infection in Burkitt lymphoma. LIMITATIONS: Further studies are needed to determine whether p16 is widely suppressed in immunosuppression-induced lymphoma. CONCLUSION: In this study, we demonstrated high levels of hypermethylation of the tumor suppressor gene p16, thus supporting the role of EBV as a carcinogen in post-transplant lymphoproliferative disease.

Quantifying the effect of antiplatelet therapy: a comparison of the platelet function analyzer (PFA-100) and modified thromboelastography (mTEG) with light transmission platelet aggregometry.

BACKGROUND: Antiplatelet therapy with aspirin and clopidogrel is known to confer protection against ischemic events. Increasing numbers of patients are presenting for surgery while taking these drugs. This may lead to an increase in perioperative blood loss, particularly in those who have a heightened response to the drugs. Identifying these patients preoperatively would allow us to plan appropriate management. METHODS: The antiplatelet effect of aspirin and/or clopidogrel was measured using two point-of-care monitors: the platelet function analyzer (PFA-100; Dade, Miami, FL) and the modified thromboelastograph (mTEG; Haemoscope Corp., Niles, IL). This was compared with optical light transmission aggregometry. RESULTS: All people taking aspirin displayed a definitive aspirin effect on aggregometry (n = 20). Ninety percent of these were identified by modified thromboelastography (n = 18). Seventy percent were identified by the platelet function analyzer (n = 14). Fifty percent of people taking clopidogrel displayed a definitive response to the drug on aggregometry. Seventy percent of these were identified on modified thromboelastography (n = 7). None were identified by the platelet function analyzer. There was good agreement between the results of the aggregometry and modified thromboelastography in clopidogrel patients (kappa = 0.81). CONCLUSION: The search for a point-of-care monitor of platelet function has been the focus of much research. This study has shown that the modified thromboelastograph can be used for monitoring the effect of clopidogrel as well as aspirin. It potentially has a wide scope to be used for the monitoring of effectiveness of therapy as well as a possible predictor of perioperative bleeding.

Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests.

OBJECTIVES: The Thromboelastogram (TEG; Haemoscope Corporation, Niles, IL) and the ROTEM thromboelastometry analyzer (Pentapharm GmbH, Munich, Germany) are coagulation monitors that measure the viscoelastic changes accompanying whole-blood coagulation generation and lysis. It is not clear whether TEG and ROTEM transfusion algorithms suggest similar blood component intervention. This study aims to report the extent to which administration of platelets, fresh frozen plasma, and cryoprecipitate would be indicated using protocol-dictated interventions by the Rotem, TEG, and conventional coagulation screens during orthotopic liver transplantation (OLT). DESIGN: Prospective observational study. SETTING: University hospital. PARTICIPANTS: Twenty patients undergoing orthotopic liver transplantation. INTERVENTIONS: Coagulation was managed with native TEG protocols. Additional samples for kaolin TEG, kaolin heparinase TEG, Rotem in-TEM, Rotem hep-TEM, Rotem fib-TEM, full blood count, prothrombin time, and Clauss fibrinogen assays were taken at 5 fixed operative stages. MEASUREMENTS AND MAIN RESULTS: Results were reviewed and protocol-indicated interventions recorded. There was moderate agreement between Clauss fibrinogen and Rotem fib-TEM assays about fulfilling fibrinogen transfusion criteria (kappa = 0.42, p < or = 0.05). Agreement between TEG and Rotem to transfuse platelets was fair (Rotem in-TEM/native heparinase TEG, kappa = 0.33, Rotem in-TEM/kaolin heparinase TEG, kappa = 0.28). There was moderate agreement between Rotem in-TEM and prothrombin time (kappa = 0.42), and poor agreement between other tests about the point to administer fresh frozen plasma. CONCLUSIONS: Transfusion practice is likely to differ according to the method of coagulation monitoring used. A prospective case-matched study using the viscoelastic tests used in this study would be beneficial in determining the optimal therapy. Rotem fib-TEM monitoring may improve hemostasis management.

Time-dependent effects of free fatty acids on glucose effectiveness in type 2 diabetes.

Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-(3)H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t=0-240 min), and hyperglycemia (10 mmol/l, t=240-360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA(1c) 10.9 +/- 0.4%, age 50 +/- 3 years, BMI 30 +/- 2 kg/m(2)) on at least two occasions with saline (NA- group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 +/- 6% suppression of EGP with hyperglycemia vs. NA- = 8 +/- 7%; P<0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 +/- 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.