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Surveillance of the renal allograft recipient is essential when monitoring renal function to detect the early onset of rejection and alter therapeutic treatments to treat acute rejection or other causes and improve long-term graft function. If renal function begins to deteriorate, a renal biopsy is often indicated to assess the Banff grade of potential rejection or other causes, especially in the setting of polyoma BK viral load elevation. Although BK infection in the allograft is asymptomatic, reactivation of the virus is known to be associated with the acceleration of pathologic change and a poor outcome in the allograft. BK reactivation in a transplant kidney is not uncommon, and determining inflammation related to the virus versus acute rejection is paramount for appropriate immunosuppressive therapy management. We identified a concomitant polyoma BK virus and West Nile Virus (WNV) infection in two renal transplant patients which, to our knowledge, has not previously been reported. However, other concomitant infections have been reported in renal allografts including BK virus and cytomegalovirus (CMV), CMV and hepatitis C (HCV), and HCV and human immunodeficiency virus (HIV). As WNV has become endemic in many regions of the United States, and since the transmission of the virus via transplanted organs is associated with significant morbidity and mortality, it may be prudent to consider serologic screening for WNV in living donors prior to organ procurement. Regardless, the observation we made and report here should underscore the potential for concomitant viral infections that may be masked when a renal allograft has a significant inflammatory response to BK virus. [ABSTRACT FROM AUTHOR]

Qualitative platelet disorders remain rare and varied. We describe here 2 additional patients with giant platelets, thrombocytopenia, deficiency in alpha granules and the presence of membranous inclusions within the cytoplasm. Collectively known as Medich syndrome, we further elucidated structural and clinical features of this rare syndrome. Platelets obtained from 2 patients with macrothrombocytopenia were evaluated by electron microscopy. Structural findings were correlated with clinical characteristics. The defining morphologic feature found in the platelets of these patients is the presence of long, tubular inclusions consisting of several layers of membrane wrapped around a core of cytoplasm. These inclusions may deform the discoid shape of the platelet. In addition, abnormal giant alpha granules are present. Clinically all patients in the current report and review of the literature had mucosal bleeding and were often misdiagnosed as having immune related thrombocytopenia. To date five cases of Medich giant platelet syndrome have been reported. The cases are unified by the ultrastructural findings of abnormal alpha granules and unusual cytoplasmic scrolls. All patients experienced mucosal bleeding, however many clinical, biologic and genetic characteristics of this rare disorder remain to be determined. [ABSTRACT FROM AUTHOR]

Cessation of one-week oral administration of the benzodiazepine flurazepam (FZP) to rats results in withdrawal anxiety after 1 day of withdrawal. FZP withdrawal is correlated with synaptic incorporation of homomeric GluA1-containing α-amino-3- hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) in the proximal stratum radiatum of CA1 neurons. After 2 days of withdrawal, Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates GluA1 subunits at Ser831, increasing channel conductance. Secondary to AMPAR potentiation, GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), known binding partners of CaMKII, are selectively removed from the postsynaptic density (PSD). While activation of synaptic CaMKII is known to involve translocation to the PSD, CaMKII bound to NMDARs may be removed from the PSD. To distinguish these possibilities, the current studies used postembedding immunogold electron microscopy to investigate alterations in CaMKII signaling at CA1 stratum radiatum synapses after 2 days of FZP withdrawal. These studies revealed decreased total, but not autophosphorylated (Thr286) CaMKIIα expression in CA1 PSDs. The removal of CaMKII-GluN2B complexes from the PSD during drug withdrawal may serve as a homeostatic mechanism to limit AMPAR-mediated CA1 neuron hyperexcitability and benzodiazepine withdrawal anxiety. [ABSTRACT FROM AUTHOR]

An organotypic slice preparation of the adult mouse parotid salivary gland amenable to a variety of optical assessments of fluid and protein secretion dynamics is described. The semi-intact preparation rendered without the use of enzymatic treatment permitted live-cell imaging and mul- tiphoton analysis of cellular and supracellular signals. Toward this end we demonstrated that the parotid slice is a significant addition to the repertoire of tools available to investigators to probe exocrine struc- ture and function since there is currently no cell culture system that fully recapitulates parotid acinar cell biology. Importantly, we show that a subpopulation of the acinar cells of parotid slices can be maintained in short-term culture and retain their morphology and function for up to 2 days. This in vitro model system is a significant step forward compared with enzymatically dispersed acini that rapidly lose their morphological and functional characteristics over several hours, and it was shown to be long enough for the expression and trafficking of exogenous protein following adenoviral infection. This system is compatible with a variety of genetic and physiological approaches used to study secretory function. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that postural orthostatic tachycardia syndrome (POTS) may be an autoimmune disorder. We have reported in a previous manuscript that 89% of POTS patients (n = 55) had elevations in G-protein-coupled adrenergic A1 receptor autoantibodies and 53% had elevations in muscarinic acetylcholine M4 receptor autoantibodies, as assessed by ELISA. Patients with autoimmune disorders have been reported with a variety of elevated cytokines and cytokines (such as rheumatoid arthritis); thus, we evaluated a limited number of cytokines/chemokines in POTS patients with elevated adrenergic and muscarinic receptor autoantibodies. We utilized the plasma of 34 patients from a previous study; all of the patients (100%) had autoantibodies against the A1 adrenergic receptor and 55.9% (19/34) had autoantibodies against the M4 muscarinic acetylcholine receptor. In particular, the plasma cytokine/chemokine levels were measured as biomarkers of inflammation by Quantibody® technology (Raybiotech, Peachtree Corners, GA, USA). We also evaluated the platelet dense granule numbers, as these patients frequently complain of symptoms related to platelet dysfunction. Patients were predominantly young females who displayed a multitude of co-morbidities but generally reported viral-like symptoms preceding episodes of syncope. Eighty five percent (29/34) had platelet storage pool deficiency. Patients had elevations in five of ten cytokine/chemokines biomarkers (IL1β, IL21, TNFα, INFγ, and CD30), whereas two biomarkers had decreased levels (CD40L and RANTES). Our observations demonstrate that POTS patients known to have autoantibodies against the G-protein-coupled adrenergic A1 receptor have abnormal plasma concentrations of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

One thousand and eighty patients, having prolonged bleeding times, frequent epistaxis, menorrhagia or easy bruising or other bleeding manifestations, and excluding those with von Willebrand's disease, were evaluated for platelet dense granule deficiency. The mean diameter of platelet dense granules was determined for all patients using image analysis. Four hundred and ninety-nine had "classic" dense (delta) granule storage pool deficiency (δ-SPD). Five hundred and eighty-one individuals (53.8%) were found to have a normal mean number of dense granules, but for some of these patients, the dense granules were smaller than for the controls. Of the patients having a normal number of dense granules, 165 (28.4%) were found to have significantly smaller granules than the platelets obtained from the control subjects. Their average granule diameter was 123.35 ± 0.86 nm, that is more than three standard deviations below the mean of the control data. Total δ-granule storage pool volumes (TDGV)/platelet were calculated using these measurements. Individuals with δ-SPD had half the number of granules (2.25 ± 0.04 DG/PL) and storage pool volume (3.88 ± 1.06 × 106 nm3) when compared to our control data (4.64 ± 0.11 DG/PL; 10.79 × 106 nm3 ± 0.42). Individuals having a bleeding history but a normal average of small dense granules had a calculated storage pool volume statistically different than controls and essentially the same storage pool volume as patients with δ-SPD. We have identified a sub-classification of δ-SPD that we have defined as micro-granular storage pool deficiency (δ-MGSPD). [ABSTRACT FROM AUTHOR]