Evaluation of Unexplained Peripheral Lymphadenopathy and Suspected Malignancy Using a Distinct Quick Diagnostic Delivery Model: Prospective Study of 372 Patients

Although rapid diagnostic testing is essential in suspicious peripheral lymphadenopathy, delays in accessing them can be considerable. We investigated the usefulness of an internist-led outpatient quick diagnosis unit (QDU) in assessing patients with unexplained peripheral lymphadenopathy, focusing on the characteristics, diagnostic, and treatment waiting times of those with malignancy. Patients aged ≥18 years, consecutively referred from 12 primary health care centers (PHCs) or the emergency department (ED) for unexplained peripheral lymphadenopathy, were prospectively evaluated during 7 years. Diagnostic investigations were done using a predefined study protocol. Three experienced cytopathologists performed a fine-needle aspiration cytology (FNAC) systematic approach of clinically suspicious lymphadenopathy with cytomorphology and immunophenotyping analyses. We evaluated 372 patients with a mean age (SD) of 45.3 (13.8) years; 56% were women. Malignancy was diagnosed in 120 (32%) patients, including 81 lymphomas and 39 metastatic tumors. Metastatic lymphadenopathy was diagnosed by FNAC in all 39 patients and the primary tumor site was identified in 82% of them when cytomorphology and immunocytochemistry were combined. A correct diagnosis of lymphoma was reached by FNAC in 73% of patients. When accepting “suspicious of” as correct diagnosis, the FNAC diagnosis rate of lymphoma increased to 94%. Among patients with malignancy, FNAC yielded 1.3% of false negatives and no false positives. All patients with an FNAC report of correct or suspicious lymphoma underwent a surgical biopsy, as it is a mandatory requirement of the hematology department. Mean times from first QDU visit to FNAC diagnosis of malignancy were 5.4 days in metastatic lymphadenopathy and 7.5 days in lymphoma. Mean times from receiving the initial referral report to first treatment were 29.2 days in metastatic lymphadenopathy and 40 days in lymphoma. In conclusion, a distinct internal medicine QDU allows an expeditious, agile, and prearranged system to diagnose malignant peripheral lymphadenopathy. Because of the close collaboration with the cytopathology unit and the FNAC methodical approach, diagnostic and treatment waiting times of patients with malignancy fulfilled national and international time frame standards. This particular diagnostic delivery unit could help overcome the difficulties facing PHC, ED, and other physicians when trying to provide rapid access to investigations to patients with troublesome lymphadenopathy.     

Seroprevalence study of Hantavirus infection in the community based population

The genus Hantavirus, family Bunyaviridae, comprise at least 20 distinct viruses. Ten of these have been linked to specific human diseases. Hemorrhagic fever with renal syndrome has been recognized since the 1950s. Hantavirus pulmonary syndrome was recognized in the United States in 1993. Epizootiologic studies of Norway rats in the Baltimore area have shown that rodent infections with hantaviruses are common and geographically widespread with prevalence reaching 44% in tested rat populations. These viruses are antigenically related to the Seoul virus. Hantavirus infections in humans occur through transmission from a rodent reservoir, primarily by inhalation of virus laden rodent excreta. There is no evidence to support person-to-person transmission of any known Hantavirus. To establish the prevalence of Hantavirus infections in humans in the Baltimore area we collected sera from 1,212 persons attending a community based health care system. These were tested for antibodies against three reference Hantavirus strains: Hantaan (HTN), Seoul (SEO), and Convict Creek (HN017). HN017 was chosen to represent the SinNombre (SN-like) strains of Hantavirus. Sera from nine patients were positive to Hantavirus specific antibodies, HTN, and SEO by Enzyme Linked Imuno Sorbent Assay (ELISA). No sera were positive for HN017 antigen. All sera that were positive for HTN and SEO were tested by western blot for HTN. All nine sera were confirmed positive by western blot. This suggests that unrecognized infections with Hantaan or Seoul-like viruses occur in the Baltimore area in humans, although the prevalence rate in humans is low (0.74%). Epidemiologic monitoring may be warranted to establish the health implications of these infections.     

Protein–Protein Interactions: A Simple Strategy to Identify Binding Sites and Peptide Antagonists

Secondary structure motifs and small protein domains can act as building blocks that are isolated and investigated to gain insights into protein global structure but can also modulate interactions with external partners. Most progress has been made in this field using synthetic peptides. Fragmentation of folded proteins by proteolytic enzymes that act preferentially on exposed and less structured sites can help to isolate shorter polypeptides with preserved secondary and tertiary structures that mimic the original protein architecture. Such molecules can be used as probes for structural studies and as tools for in vitro assays to select active fragments useful as agonists or antagonists of the original protein or as scaffolds for the design of more potent and selective ligands. This simple but effective proteolytic methodology has been successfully applied to determine antagonists of protein–protein interactions, allowing the identification of inhibitors with high efficacy and specificity. Here, we present several studies including the complex between phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes and phospholipase 1, believed to play a relevant role in the insulin resistance mechanism in phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes‐overexpressing tissues, the self‐association of BCL10 caspase recruitment domain that mediates a protein oligomerization process responsible for NF‐κB activation and the self‐association of growth arrest and DNA damage‐inducible factor 45β, a major player of the endogenous NF‐κB‐mediated resistance to apoptosis.     

Efficacy of extended thrombo-prophylaxis in major abdominal surgery: what does the evidence show? A meta-analysis

Venous thromboembolism (VTE) is a frequent complication following major abdominal surgery. The use of low-molecular-weight heparins (LMWH) to prevent thrombotic events in these patients is a common and well documented practice. However, there is some controversy surrounding the duration of the prophylaxis, as it has been suggested that the risk persists for several weeks after surgery. The objective of this meta-analysis is to systematically review the clinical studies that compared safety and efficacy of extended use of LMWH (for three to four weeks after surgery) versus conventional in-hospital prophylaxis. An electronic data base search was performed. Only randomized, controlled studies were eligible. Data on the incidence of deep vein thrombosis (DVT), VTE and bleeding were extracted. Only three studies fulfilled the inclusion criteria. The indication for surgery was neoplastic disease in 70.6% (780/1104) of patients. The administration of extended LMWH prophylaxis significantly reduced the incidence of VTE, 5.93% (23/388) versus 13.6% (55/405), RR 0.44 (CI 95% 0.28 - 0.7); DVT 5.93% (23/388) versus 12.9% (52/402), RR 0.46 (CI 95% 0.29 - 0.74); proximal DVT 1% (4/388) versus 4.72% (19/402), RR 0.24 (CI 95% 0.09 - 0.67). We found no significant difference in major or minor bleeding between the two groups: 3.85% (21/545) in the extended thrombo-prophylaxis (ETP) group versus 3.48% (19/559) in the conventional prophylaxis group; RR 1.12 (CI 95% 0.61 - 2.06). There was no heterogeneity between the studies. We conclude that ETP with LMWH should be considered as a safe and useful strategy to prevent VTE in high-risk major abdominal surgery.     

Activation of KCNN3/SK3/KCa2.3 channels attenuates enhanced calcium influx and inflammatory cytokine production in activated microglia

In neurons, small‐conductance calcium‐activated potassium (KCNN/SK/K_Ca2) channels maintain calcium homeostasis after N‐methyl‐D ‐aspartate (NMDA) receptor activation, thereby preventing excitotoxic neuronal death. So far, little is known about the function of KCNN/SK/K_Ca2 channels in non‐neuronal cells, such as microglial cells. In this study, we addressed the question whether KCNN/SK/K_Ca2 channels activation affected inflammatory responses of primary mouse microglial cells upon lipopolysaccharide (LPS) stimulation. We found that N‐cyclohexyl‐N‐[2‐(3,5‐dimethyl‐pyrazol‐1‐yl)‐6‐methyl‐4‐pyrimidinamine (CyPPA), a positive pharmacological activator of KCNN/SK/K_Ca2 channels, significantly reduced LPS‐stimulated activation of microglia in a concentration‐dependent manner. The general KCNN/SK/K_Ca2 channel blocker apamin reverted these effects of CyPPA on microglial proliferation. Since calcium plays a central role in microglial activation, we further addressed whether KCNN/SK/K_Ca2 channel activation affected the changes of intracellular calcium levels, [Ca²⁺]_i,, in microglial cells. Our data show that LPS‐induced elevation of [Ca²⁺]_i was attenuated following activation of KCNN2/3/K_Ca2.2/K_Ca2.3 channels by CyPPA. Furthermore, CyPPA reduced downstream events including tumor necrosis factor alpha and interleukin 6 cytokine production and nitric oxide release in activated microglia. Further, we applied specific peptide inhibitors of the KCNN/SK/K_Ca2 channel subtypes to identify which particular channel subtype mediated the observed anti‐inflammatory effects. Only inhibitory peptides targeting KCNN3/SK3/K_Ca2.3 channels, but not KCNN2/SK2/K_Ca2.2 channel inhibition, reversed the CyPPA‐effects on LPS‐induced microglial proliferation. These findings revealed that KCNN3/SK3/K_Ca2.3 channels can modulate the LPS‐induced inflammatory responses in microglial cells. Thus, KCNN3/SK3/K_Ca2.3 channels may serve as a therapeutic target for reducing microglial activity and related inflammatory responses in the central nervous system. © 2012 Wiley Periodicals, Inc.     

Relevance and therapeutic potential of CypA targeting to block apoptosis inducing factor-mediated neuronal cell death

<正>Programmed cell death(PCD)signaling pathways are important contributors to acute neurological insults such as hypoxic-ischemic brain damage,traumatic brain injury,stroke etc.The pathogenesis of all these diseases is closely linked with aberration of apoptotic cell death pathways.Mitochondria play a crucial role during PCD,acting as both     

Leukemia after liver transplant.

INTRODUCTION: Acute leukemia is rare after solid organ transplantation. METHODS: Review of data on 3 patients with acute leukemia identified among 1365 who underwent liver transplantation at our center, and a review of the literature. RESULTS: In patient 1, AML-M4 developed 19 months after transplant for cryptogenic cirrhosis. In patient 2, B cell acute lymphoid leukemia was diagnosed 10 months after liver transplant for fulminant hepatitis. Both patients had normal cytogenetics, and achieved complete remission with chemotherapy. In patient 3, acute monocytic leukemia-M3 with t(15;17) arose 18 months after transplant for hepatitis C cirrhosis. This patient received treatment with retinoic acid and chemotherapy, but developed a disseminated intravascular coagulation and died before completing therapy. No patient presented with chromosomal abnormalities commonly seen in secondary leukemia. The latency period to diagnosis after transplant was 10-19 months. CONCLUSIONS: Acute leukemia, although rare after liver transplantation, should be considered in the differential diagnosis of hematological complications.     

Effective tactile noise facilitates visual perception

The fulcrum principle establishes that a subthreshold excitatory signal (entering in one sense) that is synchronous with a facilitation signal (entering in a different sense) can be increased (up to a resonant-like level) and then decreased by the energy and frequency content of the facilitating signal. As a result, the sensation of the signal changes according to the excitatory signal strength. In this context, the sensitivity transitions represent the change from subthreshold activity to a firing activity in multisensory neurons. Initially the energy of their activity (supplied by the weak signals) is not enough to be detected but when the facilitating signal enters the brain, it generates a general activation among multisensory neurons, modifying their original activity. In our opinion, the result is an integrated activation that promotes sensitivity transitions and the signals are then perceived. In other words, the activity created by the interaction of the excitatory signal (e.g., visual) and the facilitating signal (tactile noise) at some specific energy, produces the capability for a central detection of an otherwise weak signal. In this work we investigate the effect of an effective tactile noise on visual perception. Specifically we show that tactile noise is capable of decreasing luminance modulated thresholds.     

Dermatomyositis presenting with severe subcutaneous edema: Five additional cases and review of the literature

Objectives

Dermatomyositis (DM) constitutes a subset of idiopathic inflammatory myopathies clinically characterized by proximal muscle weakness and skin involvement. Some of the dermatologic manifestations are highly prevalent and characteristic, but others such as generalized or limb edema are truly rare. The aim of the present study was to describe five cases of edematous DM diagnosed at our institution and to perform a review of the literature, as well as identify clinical, laboratory, or pathological data associated with this manifestation.

Methods

We performed a retrospective clinical, laboratory, and pathological evaluation of five cases of this edematous presentation out of 86 DM cases diagnosed at our hospital from 2004 to 2013. Moreover, we undertook a medical literature search using inflammatory myopathy, dermatomyositis, and edema as key words, limited to articles published in MEDLINE, EMBASE, and LILACS database in English and Spanish from 1987 to 2013.

Results

A total of 19 patients were identified, five diagnosed at our hospital and 14 cases from the literature. Overall, the median time from disease onset to diagnosis was 2 months, and most of the patients (16/84 patients, 21%) required more aggressive therapy, including immunosuppressive agents and intravenous immunoglobulin (12/63 patients, 15%). Microinfarction was present 2.3 times more frequently in DM patients with edema compared with those without edema.

Conclusions

The presence of edema in DM is uncommon but seems to be a sign of severe disease, requiring early and aggressive treatment. Microischemia-producing microinfarction may play an important pathophysiological role and determine the degree of disease severity.