Updates in therapeutic drug monitoring in inflammatory bowel disease

Biologics and immunomodulators (IMM) are generally considered the most effective therapies for the treatment of ulcerative colitis and Crohn’s disease. However, despite the efficacy of these therapies, many patients either have a primary lack of response or a secondary loss of response to these medications. Therapeutic drug monitoring (TDM) is a systematic approach to managing such patients. In this review, we summarize the latest data on TDM, including reactive and proactive TDM, in patients with inflammatory bowel disease on biologics and/or IMM.     

Starvation in cancer cells: circulating arginine is good for cancer but bad for patients

Introduction: Currently, basic understanding of heterogeneity and complexity of tumors is depicted at molecular, cellular, genetic, epigenetic and metabolic adaptations levels.

Areas covered: There are appreciable numbers of views to pinpoint signaling axis that support metabolic adaptations of cancer cells in response to environmental pressures including nutritional factors and drug treatments. Specifically, nutritional deprivation and autophagy in certain types of cancer are linked to the abilities of cancer cells to use arginine in an auxotrophic or prototrophic manner.

Expert opinion: Hence, this paper highlights the current scope of arginine- and autophagy-centered metabolic adaptations across tumor types and possible avenues to bring tumors towards cytotoxic or cytostatic death.     

Oculodentodigital dysplasia

Oculodentodigital dysplasia is a rare, autosomal dominant disorder with high penetrance and variable expressivity, caused by mutations in the connexin 43 or gap junction protein alpha-1 gene. It has been diagnosed in fewer than 300 people worldwide with an incidence of around 1 in 10 million. It affects many parts of the body, particularly eyes (oculo), teeth (dento), and fingers and/or toes (digital). The common clinical features include facial dysmorphism with thin nose, microphthalmia, syndactyly, tooth anomalies such as enamel hypoplasia, anodontia, microdontia, early tooth loss and conductive deafness. Other less common features are abnormalities of the skin and its appendages, such as brittle nails, sparse hair, and neurological abnormalities. To prevent this syndrome from being overlooked, awareness of possible symptoms is necessary. Early recognition can prevent blindness, dental problems and learning disabilities. Described here is the case of a 21-year-old male who presented to the ophthalmology outpatient department with a complaint of bilateral progressive loss of vision since childhood.     

Hemorrhage promotes chronic adverse remodeling in acute myocardial infarction: a T1, T2 and BOLD study

Hemorrhage is recognized as a new independent predictor of adverse outcomes following acute myocardial infarction. However, the mechanisms of its effects are less understood. The aim of our study was to probe the downstream impact of hemorrhage towards chronic remodeling, including inflammation, vasodilator function and matrix alterations in an experimental model of hemorrhage. Myocardial hemorrhage was induced in the porcine heart by intracoronary injection of collagenase. Animals (N = 18) were subjected to coronary occlusion followed by reperfusion in three groups (six/group): 8 min ischemia with hemorrhage (+HEM), 45 min infarction with no hemorrhage (I ? HEM) and 45 min infarction with hemorrhage (I + HEM). MRI was performed up to 4 weeks after intervention. Cardiac function, edema (T₂, T₁), hemorrhage (T₂*), vasodilator function (T₂ BOLD), infarction and microvascular obstruction (MVO) and partition coefficient (pre‐ and post‐contrast T₁) were computed. Hemorrhage was induced only in the +HEM and I + HEM groups on Day 1 (low T₂* values). Infarct size was the greatest in the I + HEM group, while the +HEM group showed no observable infarct. MVO was seen only in the I + HEM group, with a 40% occurrence rate. Function was compromised and ventricular volume was enlarged only in the hemorrhage groups and not in the ischemia‐alone group. In the infarct zone, edema and matrix expansion were the greatest in the I + HEM group. In the remote myocardium, T₂ elevation and matrix expansion associated with a transient vasodilator dysfunction were observed in the hemorrhage groups but not in the ischemia‐alone group. Our study demonstrates that the introduction of myocardial hemorrhage at reperfusion results in greater myocardial damage, upregulated inflammation, chronic adverse remodeling and remote myocardial alterations beyond the effects of the initial ischemic insult. A systematic understanding of the consequences of hemorrhage will potentially aid in the identification of novel therapeutics for high‐risk patients progressing towards heart failure.     

Surgical management of pygopagus conjoined twins with spinal bifida

Purpose

Conjoined twins are a rare complication of 9 monozygotic twins and are associated with high perinatal mortality. Pygopagus are one of the rare types of conjoined twins with only a handful of cases reported in the literature.

Case summary

We present the case of one-and-half month-old male pygopagus conjoined twins, who were joined together dorsally in lower lumbar and sacral region and had spina bifida and shared a single thecal sac with combined weight of 6.14 kg. Spinal cord was separated at the level of the conus followed by duraplasty. They had uneventful recovery with normal 15 months follow-up.

Conclusion

Separation of conjoined twins is recommended in where this is feasible with the anticipated survival of both or one infant.

     

Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure

The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65×10⁻⁵) and diastolic BP (P=7.61×10⁻³) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0×10⁻³). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.     

Comparative Approach of MRI-Based Brain Tumor Segmentation and Classification Using Genetic Algorithm

The detection of a brain tumor and its classification from modern imaging modalities is a primary concern, but a time-consuming and tedious work was performed by radiologists or clinical supervisors. The accuracy of detection and classification of tumor stages performed by radiologists is depended on their experience only, so the computer-aided technology is very important to aid with the diagnosis accuracy. In this study, to improve the performance of tumor detection, we investigated comparative approach of different segmentation techniques and selected the best one by comparing their segmentation score. Further, to improve the classification accuracy, the genetic algorithm is employed for the automatic classification of tumor stage. The decision of classification stage is supported by extracting relevant features and area calculation. The experimental results of proposed technique are evaluated and validated for performance and quality analysis on magnetic resonance brain images, based on segmentation score, accuracy, sensitivity, specificity, and dice similarity index coefficient. The experimental results achieved 92.03% accuracy, 91.42% specificity, 92.36% sensitivity, and an average segmentation score between 0.82 and 0.93 demonstrating the effectiveness of the proposed technique for identifying normal and abnormal tissues from brain MR images. The experimental results also obtained an average of 93.79% dice similarity index coefficient, which indicates better overlap between the automated extracted tumor regions with manually extracted tumor region by radiologists.     

Regulatory T cell abundance and activation status before and after priming with HIVIS-DNA and boosting with MVA-HIV/rgp140/GLA-AF may impact the magnitude of the vaccine-induced immune responses

Background

Little is known about regulatory CD4 T cells (Tregs) in the context of HIV vaccines. Tregs can be differentiated into resting (FoxP3⁺CD45RA⁺ – rTregs), activated (FoxP3^HighCD45RA^? – aTregs) and memory (FoxP3^LowCD45RA^? – mTregs). Tregs, as CD4 T cells, are also frequent targets for HIV infection. We studied how the abundance and phenotypes of Tregs in terms of activation status and expression of HIV-1 binding molecules would have changed during vaccination in healthy volunteers participating in a phase IIa HIV vaccine clinical trial. Subjects were primed three times with HIVIS-DNA and boosted twice with MVA-CMDR-HIV alone (n?=?12) or MVA-CMDR combined with protein CN54rgp140 (n?=?13). The proportions of β7 integrin in all CD4 T cells and in the Tregs subset decreased moderately after the final vaccination (p?=?0.001 and p?=?0.033, respectively) and the rTregs proportion within the total Tregs were also decreased after the final vaccination (p?=?0.038). All these proportions returned to normal values within the three months after the final vaccination. The magnitude of HIV-Envelope-specific IFNγ?+?T cells after vaccination (r?=?0.66; p?=?0.021) correlated directly with the proportion of Tregs, and correlated inversely correlated with ratios of Th17/Tregs (r?=??0.75; p?=?0.0057) and Th17/mTregs (r?=??0.78; p?=?0.0065). Higher titers of IgG gp140 antibodies were observed in subjects with higher mTregs proportions (r?=?0.52; p?=?0.022). Interestingly, pre-vaccination levels of mTregs correlated with vaccine-induced Env-binding antibodies (r?=?0.57; p?=?0.01) and presence of neutralizing antibodies (r?=?0.61; p?=?0.01), while the pre-vaccination Th17/mTregs ratio correlated inversely with the magnitude of cellular IFN-γ ELISpot responses (r?=??0.9; p?=?0.002). Taken together, these results suggest that pre- and post-vaccination Tregs, their activation status, the Th17/Tregs ratio and other host factors affecting Treg abundance, have an impact on the magnitude of HIV vaccine-induced immune responses. Moreover, the DNA-HIVIS/MVA-HIV regimen, alone or in combination with CN54rgp140 induced moderate and temporary alterations of the Tregs activation status. We also show a decrease in expression of the HIV-1 ligand β7 integrin on Tregs and all CD4 T cells.     

Case-based discussion: an unusual manifestation of diaphragmatic hernia mimicking pneumothorax in an adult male

Diaphragmatic hernia is an important cause of emergency hospital admission associated with significant morbidity. It usually results from congenital defect or rupture in the diaphragm due to trauma. Prompt and appropriate diagnosis is necessary in patients with this condition, as surgical intervention by either abdominal or thoracic approach may be necessary. Here, we report a case of left-sided diaphragmatic hernia presenting with sudden onset of breathlessness, respiratory distress and left-sided chest pain radiating to the abdomen, mimicking pneumothorax, treated successfully with surgical intervention.     

Effectiveness of plain radiography in diagnosing hollow viscus perforation: study of 1,723 patients of perforation peritonitis

Gastrointestinal perforations remain the most common cause of surgical pneumoperitoneum since time immemorial. The aim of this study was to find out the effectiveness of plain radiography in diagnosing hollow viscous perforation. A prospective analysis of a total of 1,723 patients of perforation peritonitis between January 2009 and June 2011, confirmed by exploratory laparotomy, was worked out in the study. All these patients had undergone either an upright chest or erect abdominal or both radiographs before undergoing operative procedure. Pneumoperitoneum was evaluated, and the findings were compared with that of exploratory laparotomy. Out of the 1,723 patients of documented perforation on intraoperative finding, 1,537 patients showed pneumoperitoneum on preoperative plain radiography. The overall positivity rate of plain radiography in detecting pneumoperitoneum was 89.20%. The positivity rate was highest for stomach and duodenal perforation (94.19%) and the least for appendicular perforation (7.69%) with highly significant difference (p value, <0.001). In developing world, where there is limited availability of resources and overburden of patients, imposing a limitation in adapting advanced radiological technique as a first line of investigation, plain radiography may be considered as a valuable screening tool in detecting pneumoperitoneum with high positivity rate.