Factor XIII deficiency diagnosis: Challenges and tools

Factor XIII deficiency (FXIIID) is a rare hereditary bleeding disorder arising from heterogeneous mutations, which can lead to life‐threatening hemorrhage. The diagnosis of FXIIID is challenging due to normal standard coagulation assays requiring specific FXIII assays for diagnosis, which is especially difficult in developing countries. This report presents an overview of FXIIID diagnosis and laboratory methods and suggests an algorithm to improve diagnostic efficiency and prevent missed or delayed FXIIID diagnosis. Assays measuring FXIII activity: The currently available assays utilized to diagnose FXIIID, including an overview of their complexity, reliability, sensitivity, and specificity, as well as mutational analysis are reviewed. The use of a FXIII inhibitor assay is described. Diagnostic tools in FXIIID: Many laboratories are not equipped with quantitative FXIII activity assays, and if available, limitations in lower activity ranges are important to consider. Clot solubility tests are not standardized, have a low sensitivity, and are therefore not recommended as routine screening test; however, they are the first screening test in almost all coagulation laboratories in developing countries. To minimize the number of patients with undiagnosed FXIIID, test quality should be improved in less well‐equipped laboratories. Common country‐specific mutations may facilitate diagnosis through targeted genetic analysis in reference laboratories in suspected cases. However, genetic analysis may not be feasible in every country and may miss spontaneous mutations. Centralized FXIII activity measurements should also be considered. An algorithm for diagnosis of FXIIID including different approaches dependent upon laboratory capability is proposed.     

The role of 5-HT(3) receptors in the additive anticonvulsant effects of citalopram and morphine on pentylenetetrazole-induced clonic seizures in mice

Citalopram, a selective serotonin reuptake inhibitor (SSRI), is frequently used in the treatment of major depressive disorders. In addition to its antidepressant features, citalopram shows some anticonvulsive properties at lower doses, whereas higher doses, ingested in cases of suicide, have been associated with seizures. Moreover, some reports support the enhancing effect of morphine on different responses of SSRIs such as analgesic and anticonvulsant properties. Although the exact mechanisms of these additive effects are not yet fully understood, 5-HT(3) receptor has recently been shown to play an important role in the central effects of SSRIs and morphine. In this regard, we used a model of clonic seizures induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether morphine and citalopram exhibit additive anticonvulsant effects and, if so, whether this effect is mediated through modulation of 5-HT(3) receptors. In our study, citalopram at lower doses (0.5 and 1 mg/kg, ip) significantly increased the seizure threshold (P<0.01) and at a higher dose (50 mg/kg) had proconvulsive effects. Moreover, morphine at low and noneffective doses had additive effects on the anticonvulsive properties of citalopram. This additive effect was prevented by pretreatment with low and noneffective doses of tropisetron (a 5-HT(3) receptor antagonist) and augmented by 1-(m-chlorophenyl)-biguanide (mCPBG, a 5-HT(3) receptor agonist). Moreover, low doses of morphine (0.1 and 0.5 mg/kg) alone or in combination with potent doses of 5-HT(3) receptor agonist or antagonist could not alter the proconvulsive properties of citalopram at higher dose (50 mg/kg), ruling out the contribution of 5-HT(3) to this effect. In summary, our findings demonstrate that 5-HT(3) receptor mediates the additive anticonvulsant properties of morphine and low-dose citalopram. This could constitute a new approach to augmenting the efficacy and curtailing the adverse effects of citalopram.     

Inhibition of androgen receptor and Cdc25A phosphatase as a combination targeted therapy in molecular apocrine breast cancer

Molecular apocrine breast cancer is an estrogen receptor negative subtype characterized by the over-expression of steroid response genes. In this study we investigate the therapeutic effects of persistent ERK phosphorylation using a Cdc25A phosphatase inhibitor, PM-20 in combination with AR inhibition using flutamide in this subtype. Our findings demonstrate a significant synergy with this combination in reducing cell viability and growth. Furthermore, we show that the mechanism of this effect involves a cross-talk between the AR and ERK signalling pathways. Moreover, using a xenograft molecular apocrine model we demonstrate that the combination therapy results in a significantly better therapeutic response compared to monotherapy and control groups manifesting as reductions in tumor growth, proliferation index, and cellularity. This study demonstrates that the combined application of AR and Cdc25A inhibitors is a promising therapeutic strategy in molecular apocrine breast cancer.     

Fast and nonuniform dynamics of perisaccadic vision in the central fovea

Humans use rapid eye movements (saccades) to inspect stimuli with the foveola, the region of the retina where receptors are most densely packed. It is well established that visual sensitivity is generally attenuated during these movements, a phenomenon known as saccadic suppression. This effect is commonly studied with large, often peripheral, stimuli presented during instructed saccades. However, little is known about how saccades modulate the foveola and how the resulting dynamics unfold during natural visual exploration. Here we measured the foveal dynamics of saccadic suppression in a naturalistic high-acuity task, a task designed after primates’ social grooming, which—like most explorations of fine patterns—primarily elicits minute saccades (microsaccades). Leveraging on recent advances in gaze-contingent display control, we were able to systematically map the perisaccadic time course of sensitivity across the foveola. We show that contrast sensitivity is not uniform across this region and that both the extent and dynamics of saccadic suppression vary within the foveola. Suppression is stronger and faster in the most central portion, where sensitivity is generally higher and selectively rebounds at the onset of a new fixation. These results shed light on the modulations experienced by foveal vision during the saccade-fixation cycle and explain some of the benefits of microsaccades.

Human vision is not uniform across space. While the retina collects information from a broad field, only a minuscule fraction—less than 0.01%—is examined at high resolution. This is the area covered by the foveola, the region void of rods and capillaries, where cones are most densely packed. Because of this organization, rapid eye movements, known as saccades, are necessary to redirect gaze toward the objects of interest, abruptly translating the image across the retina every few hundreds of milliseconds. It is remarkable that the visual system appears unperturbed by these sudden visual transitions and seamlessly integrates fixations into a stable representation of the visual scene.It has long been observed that visual sensitivity is transiently attenuated around the time of saccades, a phenomenon believed to play a role in perceptually suppressing retinal image motion during eye movements. This effect, known as “saccadic suppression”, consists of the elevation of contrast thresholds to briefly flashed stimuli, which precedes the initiation of the saccade and outlasts it by as much as 100 ms (1–5). Saccadic suppression is typically investigated with stimuli that cover large portions of the visual field, often in the periphery. However, limitations in the precision of stimulus delivery, both spatial and temporal, have so far prevented mapping of the saccade-induced dynamics of visibility within the foveola. Thus, despite the disproportionate importance of foveal vision, little is currently known about its time course around the time of saccades.Studies on saccadic suppression also commonly focus on large saccades under well-controlled, but artificial, laboratory conditions. However, an examination of the time course of foveal vision needs to take into account that natural execution of high-acuity tasks—the tasks that require foveal vision—normally tends to elicit saccades with very small amplitudes (6). Microsaccades, gaze shifts so small that the attended stimulus remains within the foveola, are the most frequent saccades when examining a distant face (7), threading a needle (8), or reading fine print (9), tasks in which they shift the line of sight with surprising precision. Because of their minute amplitudes, microsaccades pose specific challenges to the mechanisms traditionally held responsible for saccadic suppression (10–19). These movements yield broadly overlapping pre- and postsaccadic images within the fovea, which would appear to provide little masking in visual stimulation (20). They also result in reduced retinal smear (21), as they rotate the eye at much lower speeds than larger saccades, delivering luminance modulations that are well within the range of human temporal sensitivity. Furthermore, it is unknown whether possible corollary discharges associated with microsaccades exert similar effects to those of their larger counterparts (22).Despite these observations, microsaccades have been found to suppress sensitivity to relatively large test stimuli (23–25). However, the only two studies that specifically examined foveal vision during microsaccades reached diametrically opposite conclusions, with one arguing for a normal reduction in sensitivity (26) and the other for a complete lack of suppression (27), leaving open the question of whether suppression extends to the foveola. While several factors could have been responsible for these discrepant results, two important considerations are worth emphasizing. First, selectively testing foveal dynamics is technically challenging, since the entire foveola is comparable in size to the region of uncertainty in gaze localization resulting from standard eye-tracking methods. Second, the common intuition gained by conceptualizing the visual signals delivered by saccades as uniform—i.e., constant-velocity—translations of the image on the retina (28) does not apply well to microsaccades, whose relatively brief durations and well-defined dynamics yield substantially lower power on the retina than predicted by a uniform translation (29). Thus, even a moderate suppression may be sufficient to prevent visibility of stationary scenes during small saccades.Recent advances in methods for gaze-contingent display control now enable determination of the line of sight with accuracy sufficient to selectively test a desired foveal region during normal eye movements. Leveraging on these recent advances, here we mapped the perisaccadic dynamics of contrast sensitivity across the foveola during natural visual exploration. We developed a gaze-contingent high-acuity task that resembles primate social grooming, a task that very naturally integrates visual search and detection of brief stimuli and that spontaneously elicits frequent microsaccades, and presented probes at desired retinal locations with high spatial and temporal resolution. Our results show that microsaccades are accompanied by an elevation of visual thresholds at the center of gaze that starts before the initiation of the movement but dissipates very rapidly as the saccade ends. The extent and dynamics of this suppression vary with eccentricity across the foveola, so that a stronger modulation occurs in the most central region, where vision is selectively enhanced after a saccade.     

Association of Long-Term Atorvastatin with Escalated Stroke-Induced Neuroinflammation in Rats

Statins are widely used in high-risk patients to reduce the stroke incidence. However, little has been investigated about the impact of chronic pretreatment with statins on cerebral ischemic insult following defined arterial occlusion. To address this in experimental rats, in the present work, atorvastatin was orally dosed for 1 month to evaluate the outcomes of the subsequent occlusive stroke induced by middle cerebral artery occlusion (MCAO). Our data was suggestive of potential escalating impact of chronic atorvastatin (Atv; 10 mg/kg) on neurological function, but not infarct volume. According to our immunoblotting data, such escalations were consistent with the prominent rise in TNF-α and IL-6 which paralleled with augmented Bax/Bcl2 ratio and Caspase-9 activation; however, these were not enough to worsen acute neurodegeneration determined by Fluoro Jade B staining. Noteworthy, such deteriorating effects were also partly detected in non-ischemic animals. Conclusively, our data are indicative of cerebral proinflammatory effects of chronic Atv which might overwhelm the beneficial pliotropic of the drug and predispose animals’ brain to ischemic insult. Further studies on different statins with discrete pharmacokinetic properties are highly suggested to precisely explore stroke outcomes following long term prophylactic treatment particularly in primates.     

Morphologic and radiologic anatomy of the occipital bone.

Several diseases may cause craniovertebral instability warranting occiput-cervical fusion. As occipital screw and rod constructs are becoming more popular, requiring that screws be placed either medially or laterally in the occipital bone, the need for clearer anatomical and computed tomography (CT)-confirmed data regarding the relative thickness of the occiput in its various localities has become more critical. In 18 cadaveric specimens, the occipital bone was divided into 35 measurable segments. Transversely, the occipital bone was divided into five lines starting at the level of the inion; horizontal lines then proceeded inferiorly in 1-cm segments, 1, 2, 3, and 4 cm below the level of inion. In a comparable fashion, the occipital bone was divided vertically, starting at the midline, and proceeding laterally also in 1-, 2-, and 3-cm segments. Anatomical measurements of thickness were directly performed using a Vernier caliper. Results were directly correlated with axial CT measurements of bony thickness. Anatomical and CT measurements closely correlated within the same specimen, but there was significant interspecimen variability. The marked differences in the occipital bone anatomy noted between specimens indicates that patients undergoing occipital screw placement for cranial-cervical instability would benefit from preoperative occipital CT evaluations.