Ontogeny of the Early Triassic Cynodont Thrinaxodon liorhinus (Therapsida): Cranial Morphology

The cranial morphology of 68 Thrinaxodon liorhinus specimens, ranging in size from 30 to 96 mm in basal skull length, is investigated using both qualitative and quantitative analyses. From this comprehensive survey, we determined that nine cranial features, including five in the temporal region, separated the sample into four ontogenetic stages. A bivariate analysis of 60 specimens indicated that the skull generally increased in size isometrically, with the exception of four regions. The orbit had negative allometry, a result consistent with other ontogenetic studies of tetrapods, whereas the length of the snout, palate, and temporal region showed positive allometry. The last trend had strong positive allometry indicating that during ontogeny the length of the sagittal crest increased at a much faster rate than the rest of the skull. The large number of changes in the temporal region of the skull of Thrinaxodon may indicate a greater development of the posterior fibres of the temporalis musculature from an early ontogenetic stage. For example, the posterior sagittal crest developed much earlier in ontogeny than the anterior crest that formed in adults, and bone was deposited dorsally creating a unified posterior sagittal crest rather than having a suture that spanned the entire depth of the skull roof. In combination with the isometric height of the zygomatic arch and the almost complete absence of the zygomatic arch angulation, these ontogenetic changes suggest that there was greater development of the temporalis relative to the masseter muscles, indicating a strong posterodorsal movement of the mandible in Thrinaxodon. Anat Rec, 298:1440–1464, 2015. © 2015 Wiley Periodicals, Inc.     

A missense mutation in the chloride/proton ClC-5 antiporter gene results in increased expression of an alternative mRNA form that lacks exons 10 and 11. Identification of seven new CLCN5 mutations in patients with Dent’s disease

Mutations in the voltage-gated chloride/proton antiporter ClC-5 gene, CLCN5, are associated with Dent’s disease, an X-linked renal tubulopathy. Our interest is to identify and characterize disease-causing CLCN5 mutations, especially those that alter the splicing of the pre-mRNA. We analyzed the CLCN5 gene from nine unrelated Spanish Dent’s disease patients and their relatives by DNA sequencing. Pre-mRNA splicing analysis was performed by RT-PCR. Seven new mutations were identified, consisting of three missense mutations (C219R, F273L, and W547G), one splice-site mutation (IVS-2A > G), one deletion (976delG), and two non-sense mutations (Y140X and W314X). We found that missense mutation W547G also led to increased expression of a new alternative isoform lacking exons 10 and 11 that was expressed in several human tissues. In addition, we describe another novel CLCN5 splicing variant lacking exon 11 alone, which was expressed only in human skeletal muscle. We conclude that missense mutation W547G can also alter the expression levels of a CLCN5 mRNA splicing variant. This type of mutation has not been previously described in the CLCN5 gene. Our results support the importance of a routine analysis at the pre-mRNA level of mutations that are commonly assumed to cause single amino acids alterations.     

Voxel-based morphometry of the thalamus in patients with refractory medial temporal lobe epilepsy

Previous research has suggested that patients with refractory medial temporal lobe epilepsy (MTLE) show gray matter atrophy both within the temporal lobes as well as in the thalamus. However, these studies have not distinguished between different nuclei within the thalamus. We examined whether thalamic atrophy correlates with the nuclei's connections to other regions in the limbic system. T1-weighted MRI scans were obtained from 49 neurologically healthy control subjects and 43 patients diagnosed with chronic refractory MTLE that was unilateral in origin (as measured by ictal EEG and hippocampal atrophy observed on MRI). Measurements of gray matter concentration (GMC) were made using automated segmentation algorithms. GMC was analyzed both voxel-by-voxel (preserving spatial precision) as well as using predefined regions of interest. Voxel-based morphometry revealed intense GMC reduction in the anterior portion relative to posterior thalami. Furthermore, thalamic atrophy was greater ipsilateral to the MTLE origin than on the contralateral side. Here we demonstrate that the thalamic atrophy is most intense in the thalamic nuclei that have strong connections with the limbic hippocampus. This finding suggests that thalamic atrophy reflects this region's anatomical and functional association with the limbic system rather than a general vulnerability to damage.     

Dimensional study of prostate cancer using stereological tools

This study analyzes the dimensional changes of the glands from prostate cancer by applying stereology to estimate the variations in volume, length, surface, and cellular densities of tumor acini. Normal and tumor acini were visualized using immunohistochemistry for cytokeratin18. On immunostained sections, parameters related to the dimensions and cell population of prostate acini were measured. The immunohistochemical expression of proliferative cell nuclear antigen was also measured to correlate the quantitative changes estimated with the proliferative activity of the epithelium. The average cell volume in normal and tumor epithelium was estimated using the method of the nucleator. The relative size of the acini was similar in the carcinoma compared with the normal prostate. Within the acini, the fraction of acinar volume occupied by the epithelium was significantly higher in cancer than in the nontumor prostate. Conversely, the glandular lumen of the cancer acini is lower than in the normal acini. The significant increase of acinar length density in the carcinoma indicates that the glandular tree's growth in the carcinoma is higher and with more branches than in the case of nonneoplastic glands. The basal surface density is higher in the carcinoma than in the controls. The number of epithelial cells per unit length of acini was significantly decreased in the neoplastic glands. This "dilution" of the cell population along the cancer acinus can be explained by the significant increase in the tumor cell's mean cell volume.     

Expert opinion: defining response to omalizumab in patients with chronic spontaneous urticaria

Omalizumab (a recombinant, humanized anti-immunoglobulin-E anti-body) has been shown in three pivotal Phase III trials (ASTERIA I, II and GLACIAL) and real-world studies to be effective and well-tolerated for the treatment of chronic spontaneous urticaria (CSU), and is the only licensed third-line treatment for CSU. However, the definition of response to omalizumab treatment often differs between clinical trials, real-world studies, and daily practice of individual physicians globally. As such, a consensus definition of “complete”, “partial” and “non-response” to omalizumab is required in order to harmonize treatment management and compare data. Here, it is proposed that a disease measurement tool, for example, the 7-Day Urticaria Activity Score (UAS7) or Urticaria Control Test (UCT) is required for defining response. The addition of quality of life measurements is helpful to gain insight into a patient’s disease burden and its changes during treatment. A potential omalizumab treatment approach based on speed and pattern of response at 1-3 and 3-6 months is suggested. In cases where there is no response during the first 1-3 months, physicians should consider reassessing the original CSU diagnosis. Moreover, in patients showing partial response at 12 weeks, treatment with omalizumab should be continued in order to maximize the possibility of achieving symptom control. If patients have a UAS7>6 and/or UCT<12, then continued treatment is advised, dependent on physician judgement and patient expectations. In treatment responders, omalizumab treatment can be resumed at a later stage after discontinuation with the same degree of symptom control.     

Treat-to-target strategy in patients with rheumatoid arthritis: Audit of adherence from real world clinical data

IntroductionThe current paradigm of the management of rheumatoid arthritis (RA) recommends achieving a state of remission or low disease activity through the treat-to-target strategy. Our study assesses adherence to this strategy.MethodPatients with RA (ACR-EULAR 2010 criteria) were included. From each centre, 19 patients were randomly selected. Clinical histories (CH) were assessed by independent auditors, checking compliance with predefined quality criteria. The study was approved by ethics committees.ResultsWe included 856 patients (mean age 54 years; 71% women). The use of a combined index (CI) was recorded in 61% of cases. Visits were recorded every 4 weeks using a CI in 4% of CH while attempts were made to achieve remission. Monitoring of disease activity every 6–8 months after reaching the target was recorded in 73% of cases.ConclusionsThe implementation of the treat-to-target strategy is barely recorded in patients with RA in routine clinical practice.     

The thickness of facial alveolar bone overlying healthy maxillary anterior teeth

Background: A facial bone (<2 mm) overlying maxillary anterior teeth may be prone to resorptive processes after extraction and immediate implant placement. A thin bone contributes to risk of bone fenestration, dehiscence, and soft‐tissue recession. This study measures the distance between the cemento‐enamel junction (CEJ) and alveolar bone crest and the thickness of facial alveolar bone at points 1 to 5 mm from the bone crest for the six maxillary anterior teeth. Methods : Sixty‐six tomographic scans (31 males and 35 females; aged 17 to 69 years; mean age: 39.9 years) of intact anterior maxilla were randomly selected and evaluated by two calibrated and independent examiners (MG and TP). Results: A high variation of CEJ–bone crest (0.8 to 7.2 mm) was detected. A significantly larger CEJ–bone crest was measured in smokers (P <0.05) and patients who were ≥50 years old (P <0.05). The average bone thickness at 3 mm from the CEJ for the maxillary right central incisor was 1.41 mm and for the maxillary left central incisor was 1.45 mm. For the maxillary right and left lateral incisors, the crestal bone thickness averaged 1.73 and 1.59 mm, respectively. For the maxillary right and left canines, the crestal bone thickness averaged 1.47 and 1.60 mm, respectively. Conclusions : The present study supports the finding of a predominantly thin facial bone overlying the six maxillary anterior teeth. Therefore, it is essential to make informed treatment decisions based on thorough site evaluation before immediate implant placement.