Distinct sex-dependent behavioral responses induced by two positive allosteric modulators of alpha 5 subunit-containing GABAA receptors.

Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABAA receptors (α5-GABAAR), which are expressed mainly by pyramidal neurons in the hippocampus, have been proposed as a potential target to treat these psychiatric disorders. Here, we evaluated the effects produced by GL-II-73 and SH-053-2'F-R-CH3 (1, 5, and 10 mg/kg), two positive allosteric modulators of α5-GABAAR in behavioral tests sensitive to drugs with anxiolytic, antidepressant, and antipsychotic properties in male and female C57BL/6 mice. In both males and females, GL-II-73 produced an anxiolytic-like effect in the elevated plus-maze (EPM) and novelty-suppressed feeding and a rapid and sustained antidepressant-like effect in the forced swim test. GL-II-73 also induced antipsychotic-like effects in males indicated by attenuating MK-801-induced hyperlocomotion and prepulse inhibition (PPI) disruption. However, GL-II-73 per se increased locomotor activity and impaired fear memory extinction in males and females and PPI in males. On the other hand, SH-053-2'F-R-CH3 induced anxiolytic-like effects in the EPM and facilitated fear memory extinction in males. Contrary to GL-II-73, SH-053-2'F-R-CH3 attenuated MK-801-induced hyperlocomotion and PPI disruption in females but not in males. Neither of these drugs induced rewarding effects or impaired motor coordination. These findings suggest that GL-II-73 and SH-053-2'F-R-CH3 cause distinct sex-dependent behavioral responses and support continued preclinical research on the potential of positive allosteric modulators of α5-GABAAR for the treatment of psychiatric disorders.

Class-switched Primary Cutaneous Marginal Zone Lymphomas Are Frequently IgG4-positive and Have Features Distinct From IgM-positive Cases.

Primary cutaneous marginal zone lymphoma (PCMZL) can be subdivided into 2 groups based on immunoglobulin (Ig) heavy chain usage: IgM-positive cases that constitute a less common and more T-helper type 1-driven process, and more common heavy chain class-switched cases that are predominantly T-helper type 2-driven. Although some report a significant IgG4-positive subset, others have found a much smaller proportion. To further evaluate the proportion of IgG4-positive PCMZL, to address whether IgG4-positive cases have any distinctive characteristics, and to assess whether additional features separating IgM-positive and class-switched cases could be identified, the clinicopathologic features of 26 PCMZL obtained from 19 patients were investigated. Twenty of 26 (77%) PCMZL were heavy chain class-switched (19 IgG-positive, 1 IgA-positive), including 9 that were IgG4-positive (35%). IgG4-positive and other class-switched PCMZL were morphologically similar. IgM-positive cases occurred in older individuals (median: 69 vs. 46.5 y; P=0.0001), more often involved the subcutis (P=0.002), demonstrated plasma cells diffusely scattered versus at the periphery of the lymphoid infiltrate (P=0.005), uniformly showed follicular colonization (P=0.0001), contained more numerous B cells (P=0.0004), and were more likely to have a T-cell CD4:CD8 ratio of <3:1 (P=0.03). None of the IgM-positive PCMZL harbored a MYD88 L265P mutation. No significant differences in clinical outcome were documented. These results highlight the high frequency of IgG4-positive PCMZL, which are otherwise similar to other class-switched cases, provide additional evidence supporting the distinction between class-switched and IgM-positive cases, and emphasize the indolent nature of at least the class-switched PCMZL, which may warrant their categorization as a clonal chronic lymphoproliferative disorder.

Onlay Reconstruction of the Posterior Cruciate Ligament: Biomechanical Comparison of Unicortical and Bicortical Tibial Fixation.

Posterior cruciate ligament (PCL) injuries are generally associated with high-energy trauma. There are many controversies regarding optimal surgical technique in regard to graft selection and fixation methods. The recently described onlay technique allows for direct fixation of a hamstring autograft to the posterior aspect of the tibia with cancellous screw and spiked washer, while protecting the neurovascular structures and avoiding the so-called "killer turn." The objective of this study was to compare immediate postimplantation biomechanics of unicortical versus bicortical tibial fixation of onlay PCL grafts. Eight knees were randomly assigned to one of two onlay PCL techniques (n = 4 knees/technique), performed by a single experienced surgeon. Testing consisted of a posterior-directed force at four knee flexion angles, 10, 30, 60, and 90 degrees, to measure load to 5 mm of posterior displacement, maximum displacement (at 100 N load), and stiffness. For statistical analyses, data for each knee were normalized to the native PCL-intact knee and were then grouped into unicortical or bicortical groups accordingly. Data for load to 5 mm (strength), displacement at 100 N, and stiffness were compared among PCL-intact, PCL-deficient, unicortical fixation, and bicortical fixation categories using one-way analysis of variance to assess for statistically significant (p < 0.05) differences. When compared with PCL-deficient knees, both fixation techniques had less laxity. When compared with PCL-intact knees, unicortical had more laxity at all angles, and bicortical had more laxity only at 90 degrees (p < 0.001). For relative graft strength, intact knees required significantly higher loads than both treatment groups. Bicortical, however, outperformed unicortical at all angles (p < 0.001) for relative strength. Regarding stiffness, there were no significant differences between unicortical and bicortical, and both were superior to PCL-deficient and inferior to PCL-intact knees. Based on cadaveric biomechanical testing, none of the reconstructed PCL knees was able to replicate the intact native PCL, but both techniques were superior to PCL-deficient knees. The bicortical tibial fixation technique appears to have biomechanical advantages when opting for onlay PCL reconstruction.

Convergent structure of multitrophic communities over three continents.

Ecological theory predicts that communities using the same resources should have similar structure, but evolutionary constraints on colonisation and niche shifts may hamper such convergence. Multitrophic communities of wasps exploiting fig fruits, which first evolved about 75MYA, do not show long-term 'inheritance' of taxonomic (lineage) composition or species diversity. However, communities on three continents have converged ecologically in the presence and relative abundance of five insect guilds that we define. Some taxa fill the same niches in each community (phylogenetic niche conservatism). However, we show that overall convergence in ecological community structure depends also on a combination of niche shifts by resident lineages and local colonisations of figs by other insect lineages. Our study explores new ground, and develops new heuristic tools, in combining ecology and phylogeny to address patterns in the complex multitrophic communities of insect on plants, which comprise a large part of terrestrial biodiversity.

Pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue associated with granulomatous inflammation in a child with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome).

Patients with immunodeficiency disorders have an increased incidence of lymphoproliferative disorders; however, only 4 such patients with DiGeorge/chromosome 22q11.2 deletion syndrome have been reported. We report a case of a pulmonary Epstein-Barr virus-negative extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in a child with this syndrome.

EBV-positive extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in the posttransplant setting: a distinct type of posttransplant lymphoproliferative disorder?

The 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues defines monomorphic posttransplant lymphoproliferative disorders (M-PTLDs) as lymphoid or plasmacytic proliferations that fulfill the criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent patients. However, indolent B-cell lymphomas, such as extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), are specifically excluded from this category. In this study, we describe the clinicopathologic features of 4 posttransplant lymphoma-like proliferations that were Epstein-Barr virus (EBV) positive, but were otherwise completely typical for a MALT lymphoma. The 4 patients (age, 12 to 71 y) had received solid organ transplants (2 hearts, 1 kidney, 1 kidney/pancreas) at a median of 116 months before presentation, and had been maintained on varying immunosuppressive regimens that included cyclosporine, azathioprine, tacrolimus, and sirolimus. Three of the 4 patients presented with solitary subcutaneous masses, whereas the fourth patient presented with a solitary orbital soft tissue mass. All the 4 cases were morphologically typical for MALT lymphoma, demonstrated plasmacytic differentiation with IgA heavy chain restriction (3 cases κ positive, 1 case λ positive), and were diffusely EBV-encoded small RNA positive. Patients were followed for a median of 44.9 months, and all achieved a complete response following various regimens that included reduced immunosuppression with or without antiviral therapy, local surgical excision, rituximab, or local radiation therapy. The uniform EBV positivity and response to immune reconstitution in some cases suggest that EBV-positive MALT lymphomas arising in the posttransplant setting should be included among PTLDs. Whether their distinctive subcutaneous/soft tissue localization and IgA positivity are uniform features will require identification of additional cases.

Synthesis, pharmacological studies and molecular modeling of some tetracyclic 1,3-diazepinium chlorides.

Seven new 1,3-diazepinium chlorides exhibiting some structural similarities to the 1,4-benzodiazepines were synthesized. In a Hippocratic screen using mice, three of these salts, 3-methoxy-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8a), 3-methoxy-9-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8c) and 3-methoxy-11-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8e) were examined for their effect on the central nervous system, and their activities compared to that of diazepam. On their own, salts 8a, 8c and 8e solicited no sedative effects on the behaviour of the animals. However, they elicited significant effects in combination with diazepam on diazepam-induced activities such as decreased motor activity, ataxia and loss of righting reflex. Compounds 8a and 8c were fitted into the pharmacophore/receptor model developed by Cook et al. with interaction at the L(1), H(1) and A(2) sites indicating that they are potential inverse agonists of the Bz receptor. The compounds displayed some affinity for the alpha1 isoform of the GABA(A)/BzR (L(Di) interaction) but are non-selective for alpha5 (no L(2) interaction). Results of binding affinity studies showed that compound 8a is mildly selective for the alpha1 receptor although not very potent (K(i)=746.5nM). The significant potentiation of diazepam-induced ataxia and decreased motor activity by compounds 8a and 8c in the Hippocratic screen may be associated with alpha1 selectivity.

The influence of high-altitude living on body iron.

The quantitative assessment of body iron based on measurements of the serum ferritin and transferrin receptor was used to examine iron status in 800 Bolivian mothers and one of their children younger than 5 years. The survey included populations living at altitudes between 156 to 3750 m. Body iron stores in the mothers averaged 3.88 +/- 4.31 mg/kg (mean +/- 1 SD) and 1.72 +/- 4.53 mg/kg in children. No consistent effect of altitude on body iron was detected in children but body iron stores of 2.77 +/- 0.70 mg/kg (mean +/- 2 standard error [SE]) in women living above 3000 m was reduced by one-third compared with women living at lower altitudes (P < .001). One half of the children younger than 2 years were iron deficient, but iron stores then increased linearly to approach values in their mothers by 4 years of age. When body iron in mothers was compared with that of their children, a striking correlation was observed over the entire spectrum of maternal iron status (r = 0.61, P < .001). This finding could provide the strongest evidence to date of the importance of dietary iron as a determinant of iron status in vulnerable segments of a population.

Convergent incidences of Wolbachia infection in fig wasp communities from two continents.

Wide surveys suggest that Wolbachia bacteria infect ca. 20% of all insect species, but particular taxonomic or ecological groups may display significantly higher or lower incidences. We studied 61 fig wasp species in Australia and found the highest known incidence (67%) of infection in a targeted study of this nature. A comparable study in Panama reported a similar figure (59%), confirming the exceptionally high incidence of Wolbachia in fig wasps. Importantly, these are two independent estimates of Wolbachia incidence in fig wasp communities, because no host species, or even genera, are shared between localities. The high level of infection may reflect enhanced opportunities for horizontal transmission inside fig fruits. Although incidence was similar in Panama and Australia, the actual strains involved were different and region-specific. Local strains were shared by several host species, although there was often no obvious (direct) ecological link between two hosts with the same infection.

The quantitative assessment of body iron.

Current initiatives to reduce the high prevalence of nutritional iron deficiency have highlighted the need for reliable epidemiologic methods to assess iron status. The present report describes a method for estimating body iron based on the ratio of the serum transferrin receptor to serum ferritin. Analysis showed a single normal distribution of body iron stores in US men aged 20 to 65 years (mean +/- 1 SD, 9.82 +/- 2.82 mg/kg). A single normal distribution was also observed in pregnant Jamaican women (mean +/- 1 SD, 0.09 +/- 4.48 mg/kg). Distribution analysis in US women aged 20 to 45 years indicated 2 populations; 93% of women had body iron stores averaging 5.5 +/- 3.35 mg/kg (mean +/- 1 SD), whereas the remaining 7% of women had a mean tissue iron deficit of 3.87 +/- 3.23 mg/kg. Calculations of body iron in trials of iron supplementation in Jamaica and iron fortification in Vietnam demonstrated that the method can be used to calculate absorption of the added iron. Quantitative estimates of body iron greatly enhance the evaluation of iron status and the sensitivity of iron intervention trials in populations in which inflammation is uncommon or has been excluded by laboratory screening. The method is useful clinically for monitoring iron status in those who are highly susceptible to iron deficiency.

The nutritional assessment of iron status

En estudios nutricionales para evaluar la deficiencia de hierro, se han definido comunmente tres estadios de severidad creciente: agotamiento de las reservas de hierro, definido por bajos niveles de ferritina sérica, deficienccia de hierro moderada sin anemia basada en evidencia de laboratorio de eritropoyesis deficiente en hierro (EDH) y anemia por deficiencia de hierro (ADH). Aunque esta clasificación provee una amplia perspectiva de la alteración de estado de hierro, las principales consecuencias de la falta de hierro están asociadas con estadíos más avanzados de anemia por deficiencia de hierro. Consecuentamente, la determinación de hemoglobina puede usarse para tamizar la deficiencia de hierro nutricionalmente significativa. Una vez identificada la anemia, estudios de laboratorio más específicos son necesarios para establecer la falta de hierro como causa. Las mediciones tradicionales de eritropoyesis deficiente en hierro (EDH) tales como una baja saturación de transferrina, elevada protoporfirina eritrocitaria, o la disminución del volumen corpuscular medio se utilizan comúnmente. La principal desventaja de estos parámetros es que éstos están afectados de manera similar en individuos con la anemia de enfermedades crónicas, una forma común de anemia en poblaciones de bajo nivel socioeconómico. Debido a que las reservas de hierro se encuentran ausentes en la anemia por deficiencia de hierro sin complicaciones, una concentración de ferritina sérica por debajo de 20µg/L confirma el diagnóstico de anemia por deficiencia de hierro una vez que la anemia está presente. La principal limitación de la ferritina sérica es que puede encontrarse falsamente elevada o en límites normales cuando la anemia por deficiencia de hierro se desarrolla en individuos con infección o inflamación crónica concurrente. Cuando esto ocurre en el medio clínico, un examen de médula ósea se realiza comúnmente para identificar la ADH. Las investigaciones recientes indican que este procedimiento puede evitarse midiendo un nuevo indicador relacionado al hierro llamado receptor sérico de transferrina (RTf). Devido a que la síntesis de RTf está regulada paralelamente con la deficiencia de hierro tisular, la ADH puede identificarse rápidamente por niveles elevados de RTf. Es importante destacar que el RTf es normal en individuos con anemia por enfermedades crónicas pero aumenta si estos individuos desarrollan ADH

Evaluation of a gastric delivery system for iron supplementation in pregnancy

The present investigation was undertaken to assess the efficacy of oral iron supplementation during pregnancy by using a gastric delivery system (GDS). Three hundred seventy-six pregnant women between 16 and 35 years of age and 14 and 22 weeks gestation were selected if mild anemia was present (hemoglobin concentration 80-110 g/l). The participants were randomly assigned to one of three study groups given no iron, two FeSO4 tablets (100 mg FE) daily, or one GDS capsule (50 mg Fe) daily. Blood was obtained initially and after 6 and 12 weeks for measurement of red blood cell and iron indexes, including serum transferrin receptor. There was a significant and comparable improvement in hematologic and iron-status measurements in the two group of women given iron whereas iron deficiency evolved in women given no iron supplement. We conclude that by elimating gastrointestinal side effects and reducing the administration frequency of an iron supplement to once daily, a GDS offers significant advantages for iron supplementation of pregnant women. (AU)