Durable fear memories require PSD-95.

Traumatic fear memories are highly durable but also dynamic, undergoing repeated reactivation and rehearsal over time. Although overly persistent fear memories underlie anxiety disorders, such as posttraumatic stress disorder, the key neural and molecular mechanisms underlying fear memory durability remain unclear. Postsynaptic density 95 (PSD-95) is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory. Using a loss-of-function mutant mouse lacking the guanylate kinase domain of PSD-95 (PSD-95(GK)), we analyzed the contribution of PSD-95 to fear memory formation and retrieval, and sought to identify the neural basis of PSD-95-mediated memory maintenance using ex vivo immediate-early gene mapping, in vivo neuronal recordings and viral-mediated knockdown (KD) approaches. We show that PSD-95 is dispensable for the formation and expression of recent fear memories, but essential for the formation of precise and flexible fear memories and for the maintenance of memories at remote time points. The failure of PSD-95(GK) mice to retrieve remote cued fear memory was associated with hypoactivation of the infralimbic (IL) cortex (but not the anterior cingulate cortex (ACC) or prelimbic cortex), reduced IL single-unit firing and bursting, and attenuated IL gamma and theta oscillations. Adeno-associated virus-mediated PSD-95 KD in the IL, but not the ACC, was sufficient to impair recent fear extinction and remote fear memory, and remodel IL dendritic spines. Collectively, these data identify PSD-95 in the IL as a critical mechanism supporting the durability of fear memories over time. These preclinical findings have implications for developing novel approaches to treating trauma-based anxiety disorders that target the weakening of overly persistent fear memories.

Depression and anxiety disorders in a sample of facial trauma: A study from Iran.

BACKGROUND: Various studies have shown that such patients are susceptible to psychological problems and poor quality of life. The aim of the present study was to evaluate and compare the prevalence of depression and anxiety disorders and quality of life in a group of facial trauma. MATERIAL AND METHODS: In the present cross-sectional study Hospital Anxiety and Depression Scale (HADS) and Oral Health Impact (OHIP-14) questionnaires were used. In this study, fifty subjects were selected from the patients with maxillofacial traumas based on the judgment of the physicians, referring to hospitals in Kerman and Rafsanjan during 2012-2013. In addition, 50 patients referring to the Dental School for tooth extraction, with no maxillofacial traumas, were included. SPSS 13.5 was used for statistical analysis with two-sample t-test, Mantel-Haenszel technique, Pearson's correlation coefficient and chi-squared test. RESULTS: Seven patients with maxillofacial traumas were depressed based on HADS depression scale, with 5 other borderline cases. However, patients referring for surgery or tooth extraction only 2 were depressed and 1 patient was a borderline case. The results showed that patients with maxillofacial traumas had higher rates of depression and anxiety, with significant differences between this group and the other group (P=0.01). The results of the present study showed a significant prelateship between depression severity and confounding factors. The mean of OHIP-14 parameters were 35.51 ±5.2 and 22.3±2.4 in facial trauma and dental surgery groups, respectively, with statistically significant differences (P=0.01). CONCLUSIONS: The results of the present study showed depression and anxiety disorders in patients with maxillofacial trauma. The results showed a higher rate of anxiety and anxiety in patients with maxillofacial traumas compared to the control group.

Competition for BLyS-mediated signaling through Bcmd/BR3 regulates peripheral B lymphocyte numbers.

Striking cell losses occur during late B lymphocyte maturation, reflecting BcR-mediated selection coupled with requisites for viability promoting signals. How selection and survival cues are integrated remains unclear, but a key role for B lymphocyte stimulator (BLyS(TM); trademark of Human Genome Sciences, Inc.) is suggested by its marked effects on B cell numbers and autoantibody formation as well as the B lineage-specific expression of BLyS receptors. Our analyses of the B cell-deficient A/WySnJ mouse have established Bcmd as a gene controlling follicular B cell life span, and recent reports show Bcmd encodes a novel BLyS receptor. Here we show that A/WySnJ B cells are unresponsive to BLyS, affording interrogation of how Bcmd influences B cell homeostasis. Mixed marrow chimeras indicate A/WySnJ peripheral B cells compete poorly for peripheral survival. Moreover, in vivo BrdU labeling shows that (A/WySnJ x BALB/c)F(1) B cells have an intermediate but uniform life span, indicating viability requires continuous signaling via this pathway. Together, these findings establish the BLyS/Bcmd pathway as a dominant mediator of B cell survival, suggesting competition for BLyS/Bcmd signals regulates follicular B cell numbers.

B cell production and turnover in CBA/Ca, CBA/N and CBA/N-bcl-2 transgenic mice: xid-mediated failure among pre B cells is unaltered by bcl-2 overexpression.

The CBA/N strain carries xid, a murine btk missense mutation that reduces peripheral B cell numbers. Using in vivo BrdU labeling and cytofluorimetry, we have compared the magnitude, production rates, and turnover rates of each B lineage subset in the marrow and periphery of CBA/Ca and CBA/N mice. Our results show the pro-B compartment is largely unaffected by xid. In contrast, the pre-B cell pool is markedly reduced, reflecting a diminished production rate and unaltered turnover time. Despite diminished pre-B cell formation, the size of the immature B cell pool is relatively normal in CBA/N mice, due to increased proportional survival of pre-B cells. In addition, we have assessed the marrow and peripheral B cell subsets of CBA/N mice transgenic for bcl-2. These results indicate that while the bcl-2 transgene promotes lengthened survival in most B cell subsets, the pro/pre-B cell losses mediated by xid are not abrogated by bcl-2 overexpression. Taken together, these findings suggest that the initial [not readable: see text] from the pro- to pre-B cell pools, and that anomalies in subsequent compartments likely reflects the action of homeostatic mechanisms compensating for compromised pre-B cell production.

B cell maturation and selection at the marrow-periphery interface.

More than 95% of newly formed B cells die in the short interval spanning sIgM acquisition in the bone marrow and entry into the long-lived pool, suggesting that selective events dictating B cell longevity occur at this stage. These likely include both ligand-induced deletion as well as discrete events that mediate recruitment to the long-lived recirculating pool. We are probing these events through the examination of normal B cell differentiation during this critical period: the characterization of a natural mutation that blocks late maturation, an irradiation/autoreconstitution model of marrow-derived B cell differentiation, and the identification of life span regulatory genes whose expression changes within this window.

Synthesis, characterisation and crystal structures of Schiff bases from the reaction of 4,6-O-ethylidene-beta-D-glucopyranosylamine with substituted salicylaldehydes.

Multiple chemical modifications were carried out on D-glucose to result in the corresponding Schiff bases. Such modifications performed on D-glucose not only helped in increasing the solubility of the products in nonaqueous solvents, but also restricted the anomerisation of the saccharide moiety in solution. NMR study of the products revealed the presence of the beta-anomeric form of the saccharide moiety in Me(2)SO solution. All the compounds were characterised by analytical and spectral methods. The literature is devoid of any crystal structures of saccharide-Schiff base combinations of the type reported in this paper. The crystal structures of these molecules exhibited a tridentate, ONO binding core. These studies further revealed that the compounds in the solid state were in the beta-D-pyranose form with the (4)C(1) chair conformation. The compounds exhibited interesting lattice structures assisted through weak interactions of the type O-H...O and C-H...O. The lattice structure of one of these compounds exhibited channels filled with chloroform molecules.

Synthesis, characterization and the first crystal structure of the Zn(II) complex of 4,6-O-ethylidine-N-(2-hydroxybenzylidene)-beta-D-glucopyranosylamine.

4,6-O-Ethylidine-N-(2-hydroxybenzylidene)-beta-D-glucopyranosylamine (H(3)L(1)) and N-(5-bromo-2-hydroxybenzylidene-4,6-O-ethylidine-beta-D-glucopyranosylamine (H(3)L(2)) molecules possessing a single bond C-1 single bond N double bond C(H) single bond moiety for metal-ion binding were synthesized by condensing the 4,6-O-ethylidene-beta-D-glucopyranosylamine with salicylaldehyde or 5-bromosalicylaldehyde. Complexes of these ligands with Zn(II) were isolated and characterized using elemental analysis, FTIR, UV-Vis absorption, NMR spectroscopic and FAB mass spectrometric techniques. The structure of the Zn(II) complex derived from H(3)L(1) was established for the first time by a single-crystal X-ray diffraction study. The anomeric nature of the saccharide moiety was established based on (1)H NMR studies and was confirmed by the crystal structure. Further, the structure and binding aspects of the ligand, and the coordination features of this in its Zn(II) complex were derived from the corresponding crystal structure.

Bidirectional rescue of extreme genetic predispositions to anxiety: impact of CRH receptor 1 as epigenetic plasticity gene in the amygdala.

The continuum of physiological anxiety up to psychopathology is not merely dependent on genes, but is orchestrated by the interplay of genetic predisposition, gene x environment and epigenetic interactions. Accordingly, inborn anxiety is considered a polygenic, multifactorial trait, likely to be shaped by environmentally driven plasticity at the genomic level. We here took advantage of the extreme genetic predisposition of the selectively bred high (HAB) and low anxiety (LAB) mouse model exhibiting high vs low anxiety-related behavior and tested whether and how beneficial (enriched environment) vs detrimental (chronic mild stress) environmental manipulations are capable of rescuing phenotypes from both ends of the anxiety continuum. We provide evidence that (i) even inborn and seemingly rigid behavioral and neuroendocrine phenotypes can bidirectionally be rescued by appropriate environmental stimuli, (ii) corticotropin-releasing hormone receptor 1 (Crhr1), critically involved in trait anxiety, shows bidirectional alterations in its expression in the basolateral amygdala (BLA) upon environmental stimulation, (iii) these alterations are linked to an increased methylation status of its promoter and, finally, (iv) binding of the transcription factor Yin Yang 1 (YY1) to the Crhr1 promoter contributes to its gene expression in a methylation-sensitive manner. Thus, Crhr1 in the BLA is critically involved as plasticity gene in the bidirectional epigenetic rescue of extremes in trait anxiety.

Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior.

Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety.

Pulmonary cryptococcosis and tuberculoma mimicking primary and metastatic lung cancer in 18F-FDG PET/CT.

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been widely incorporated in cancer management. Although, it has increased sensitivity, 18F-FDG is not tissue specific thus posing diagnostic dilemma in certain situations. False positivity in pulmonary nodules have been seen in various inflammatory, infective as well as post operative conditions while false negativity is common with adenomas, low grade lymphomas, bronchoalveolar carcinomas and carcinoid tumors. We present two cases of granulomatous diseases as pulmonary cryptococcosis and tuberculosis showing false positivity in a resected colorectal cancer patient and highlight the importance of recognition of this entity in an endemic region for granulomatous infections.

Tunneled central venous catheters: Experience from a single center.

In the past vascular surgeons were called in to place tunneled central venous catheter (TVC) for hemodialysis patients. Advent of percutaneous technique has resulted in an increasing number of interventional nephrologists inserting it. A single centre three year audit of 100 TVCs with a cumulative follow up of 492 patient months is presented here. From 2007 to 2010, 100 TVCs were placed by nephrologists in a percutaneous fashion in the operative room or the interventional nephrology suite. Those who completed minimum of three months on the catheter were included in analysis. There were 69 males and 31 females with a mean age of 52.3±13.6 years.(range: 25-76). Chronic glomerulonephritis was the commonest cause of CKD (45%) followed by diabetes (39%).Right internal jugular vein was the preferred site (94%). TVC was utilized as the primary access to initiate dialysis in 25% of patients in whom a live donor was available for renal transplant. The blood flow was 250-270 ml/min. The Kaplan-Meier analysis showed that 3 months and 6 months catheter survival rates were 80% and 55%, respectively. The main complications were exit site blood ooze, catheter block and kink. Catheter related bacteremia rate was low at 0.4/1000 patient days. Primary cause of drop out was patient death unrelated to the TVCs. Those under the age of 40 years showed better survival, but there was no bearing of gender, catheter site, and etiology of CKD on survival. Tunneled central venous catheters could find a niche as the primary access of choice for pretransplant live donor renal transplants in view of its immediate usage, high blood flows, low infection rates and adequate patency rates for 3-6 months.

ANCA negative pauci-immune glomerulonephritis with systemic involvement.

Systemic vasculitides (SV) are a group of diseases with multi system involvement and varied clinical presentation. Anti-neutrophil cytoplasmic antibody (ANCA) testing has high sensitivity and specificity for SV. We describe the clinical course of four patients who had pauci-immune glomerulonephritis with systemic involvement without serological ANCA positivity; they were followed up for a cumulative 55 patient months. The mean Birmingham vasculitis score score was 23. All four had systemic symptoms with arthralgias and fever (100%). Neurological manifestations were seen in two patients (66%). Accelerated hypertension was seen in one. One patient had pulmonary renal syndrome. Renal manifestation was characterized by nephrotic range of proteinuria with glomerular hematuria in all (100%) and severe renal failure requiring dialysis in three (66%). At admission the mean blood urea was 146 +/- 19 mg% and mean serum creatinine was 5.6 +/- 1.9 mg%. Renal biopsy revealed focal proliferative glomerulonephritis with crescents only in 20-30% of glomeruli. There was significant chronic interstitial involvement in two patients (66%). Therapy with pulse steroids, cyclophosphamide, and mycophenolate mofetil (MMF) was effective in three patients while one died with lung hemorrhage. In conclusion, majority of patients with ANCA negative pauci-immune glomerulonephritis have multi-system involvement at admission. Renal biopsy is characterized by focal proliferative lesions with crescents and significant chronic interstitial fibrosis. Immunosuppressive drugs in the form of corticosteroids, MMF and cyclophosphamide bring about marked renal recovery in most patients.

Correlation of plain radiographic indices of the hip with quantitative bone mineral density.

UNLABELLED: Radiographic parameters of the hip can be useful as an indication of bone mineral density at the femoral neck. Measurements available from routine hip radiographs were correlated with DXA values. Although radiographs are not a test for osteoporosis, measurements of cortical thickness provide information useful for referral for osteoporosis assessment. INTRODUCTION: Plain hip radiographs are widely used for evaluation of hip pathology in osteoarthritis. A purpose of this study was to determine whether there are relationships between radiographic parameters of bone structure and bone mineral density T-scores, as assessed by dual energy x-ray absorptiometry (DXA). METHODS: Pre-operative radiographs of 32 postmenopausal, osteoarthritic women undergoing hip arthroplasty were evaluated. Radiographic parameters including the Singh index, Dorr classification, canal-to-calcar ratio, and cortical thickness indices (CTI) were measured and compared with T-score, serum 25 hydroxyvitamin D levels, body mass index (BMI), and body weight. RESULTS: The T-score at the femoral neck for type C bone was significantly lower than that of type A (p = 0.041). The CTIs were correlated positively with T-scores for anteroposterior radiographs (r = 0.5814, p = 0.0005), and for lateral radiographs (r = 0.571, p = 0.0006). A threshold for lateral CTI set at a value of < or =0.40 results in sensitivity of 0.85 and specificity of 0.79 to segregate the osteoporotic and non-osteoporotic patients. CONCLUSION: Femurs with small radiographic cortical thickness indices had lower T-scores. Finding a radiographic hip cortical thickness index (LAT) with a value of < or =0.40 should be an alert for referral for osteoporosis evaluation and bone mineral density testing.

Cutaneous B-cell lymphoma: pathological spectrum and clinical outcome in 51 consecutive patients.

The clinical behavior and optimal treatment of patients presenting with skin infiltration by B-cell lymphoma have not been established. To clarify this we assessed the clinical and laboratory features of 51 patients presenting with cutaneous infiltration by B-cell lymphoma. Follow-up data was available for 46 patients with a median age of 68 years (range 16-89 years) and a median follow-up of 32.5 months (range 5-123 months). Thirty-three of 51 (65%) patients had diffuse large B-cell lymphoma (DLBCL), and 15/51 (29%) had marginal zone lymphoma (MZL). The remaining 3 patients had follicular lymphoma, CLL, and post-transplant lymphoproliferative disease. Of the 33 patients with DLBCL, follow-up was available in 29; 24/29 (83%) had primary cutaneous disease, which was unifocal in 17/24 (71%). Following treatment, 8/24 (33%) of the primary cases relapsed. Of the 8 who relapsed, 7 had received local forms of treatment only. Follow-up data was available in 14/15 patients with MZL. 11/14 (79%) had primary cutaneous disease, which was unifocal in 8 (73%). Following treatment, 4 of these cases relapsed (36%); all had received local therapy only. It is evident from this study that a significant proportion ( reverse similar 20%) of patients who present with cutaneous infiltration by B-cell lymphoma have systemic disease. Staging is therefore mandatory in these patients. Approximately 1/3 patients with primary cutaneous DLBCL or MZL ultimately relapse, and relapse rates appear higher in those patients receiving local therapy only. Systemic or combined modality therapy may therefore be the most appropriate treatment at presentation. This should be assessed prospectively in randomized trials.

A population based, case control study of non-Hodgkin's lymphoma in patients with rheumatoid arthritis.

OBJECTIVE: Epstein-Barr virus (EBV) associated lymphoproliferative disorders (LPD) similar to those that occur in immunosuppressed solid organ recipients have been reported in patients with rheumatoid arthritis (RA). These LPD cause significant morbidity and/or mortality in a state of sustained immunosuppression, but may spontaneously regress if immunocompetence is restored. We determined the population based frequency of EBV associated LPD relative to all non-Hodgkin's lymphomas (NHL) that occur in the general population of patients with RA. METHODS: Forty-two case patients with NHL and RA and 49 control patients with NHL and no RA were identified in a population based, case control study of NHL that occurred in a 6 county Northern California area during the years 1988-94. The lymphoma tissue specimens were reviewed and the diagnosis of NHL was confirmed. In addition, the specimens were analyzed for NHL grade, histologic subtype, histopathologic features associated with immunosuppression, immunophenotype, and the presence of EBV genome in the tumor cells. RESULTS: No significant differences were identified between NHL in the RA case group and the control group (no RA) with respect to any variables investigated. One patient (2%) in the case group and one (2%) in the control group developed LPD containing EBV. CONCLUSION: Our findings reveal that EBV associated lymphomas represent only a small fraction of all NHL in the general RA patient population. EBV associated LPD should be recognized when they occur because they require a special approach to patient management. However, these data indicate that the majority of NHL that occurs in patients with RA is probably coincidental with RA and not the result of significant immunosuppression.

xid mice reveal the interplay of homeostasis and Bruton's tyrosine kinase-mediated selection at multiple stages of B cell development.

Human X-linked agammaglobulinemia (XLA) and murine X-linked immune defect (XID) are both immunodeficiencies mediated by mutations in Bruton's tyrosine kinase (Btk), yet the developmental stage(s) affected remain controversial. To further refine the placement of the XID defect(s), we used bromodeoxyuridine labeling to determine turnover, production and transition rates of developing B cell subsets in normal, xid and xid mice expressing a human Bcl-2 transgene (xid/bcl-2). We find the xid mutation manifest at two stages of B cell development. The first is early, reducing pre-B cell production by restricting pro-B to pre-B cell transit. Surprisingly, this impairment is offset by increased survival of cells progressing from the pre- to immature B cell pool, suggesting that Btk-independent homeostatic mechanisms act to maintain this compartment. The second point of action is late, substantially reducing mature B cell production. Together, these findings reconcile apparent discrepancies in the developmental stage affected by the murine versus human lesions and suggest previously unappreciated homeostatic processes that act at the pre-B to immature B cell transition. Finally, Btk likely functions differently at these two checkpoints, since ectopic Bcl-2 expression fails to directly complement the early xid lesion, yet reverses the defect impeding final B cell maturation.