Overexpression of program death-1 in T cells has mild impact on allograft survival.

Program death-1 (PD-1), an inhibitory receptor upregulated on T cells upon TCR stimulation, has been shown to attenuate a number of immune responses in vivo, including acute allograft rejection. We tested whether constitutive expression of PD-1 would further inhibit allograft rejection. To this end, we generated transgenic mice expressing T-cell-restricted PD-1 under the control of the Lck proximal promoter and CD2 locus control. PD-1 transgenic (PD-1-Tg) mice did not develop gross abnormalities of thymic development and displayed normal numbers of thymocyte subsets and peripheral T cells. In vitro, PD-1-Tg T cells had reduced proliferative and cytokine secretion capacity upon TCR stimulation and cross-linking of PD-1 resulted in diminished phosphorylation of protein kinase C-theta and Akt, as well as increased activation of the phosphate and tensin homolog. However, only T-cell responses to minor but not major mismatches were reduced in vitro. Similarly, PD-1-Tg mice exhibited prolonged survival of cardiac allografts only in mice transplanted with heart allografts expressing multiple minor mismatches and treated with suboptimal doses of cyclosporine A. We conclude that genetic engineering of T cells to express PD-1 constitutively has only a mild impact on allograft survival.     

Insight et bipolarité

Contrarily to schizophrenia, a few studies are published on insight in bipolar disorders. In literature, it appears that the presence of psychotic symptoms and manic polarity are related to an important alteration of clinical insight. However, these two factors have not been found in several studies. There is only one study on cognitive insight with preliminary data. However, data on neurocognitive variables and clinical insight are heterogeneous and contradictory. We think that a conceptual approach on insight could help to better understand those contradictory results about insight in bipolar disorder.     

Outcome of Acute Kidney Injury in Sudanese Children — An Experience from a Sub-Saharan African Unit

♦ Background: Acute Kidney Injury (AKI) is an important cause of morbidity and mortality in developing countries. Although continuous renal replacement therapy is gaining more popularity worldwide, peritoneal dialysis (PD) in children remains an appropriate therapy for AKI in children for all age groups including neonates.♦ Methodology: We retrospectively reviewed all children who have been admitted with AKI at the pediatric nephrology unit, Soba University Hospital, Khartoum, during the period from January 2005 to December 2011.♦ Results: Over 7 years we recorded 659 children of whom 362 (54.9%) were male. The spectrum of age was variable with the majority being neonates, 178 (27.1%). The average patient admission rate was 94 patients per year, with an estimated incidence of 9.8 patients/million population/year. Common causes of AKI were sepsis 202 (30.8%), acute glomerulonephritis 75 (11.5%) and obstructive uropathy due to stones 56 (8.5%). The most common dialysis modality used was PD, 343 (52.4%), and peritonitis was reported in 53 (15.4%) patients. Recovery from AKI was achieved in 450 (68.9%) children, 37 (5.7%) went into chronic kidney disease (CKD), 33 (5.1%) referred to the pediatric surgery and 194 (29.7%) died.♦ Conclusion: In the setting of developing countries where AKI is a common cause of morbidity and mortality, reasonably equipped renal units with adequately trained medical staff may save many lives. International funding programs for communicable diseases and charity organizations should include AKI management in their programs. Acute PD remains the treatment modality of choice for AKI in developing countries.     

Nitric oxide-donating nonsteroidal anti-inflammatory drugs inhibit the growth of various cultured human cancer cells: evidence of a tissue type-independent effect

The novel nitric oxide (NO)-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs), which are safer than their NSAID counterparts, inhibit the growth of colon cancer cells with far greater potency than traditional NSAIDs. We examined whether NO-NSAIDs inhibit the growth of cancer cells arising from other human tissues. Human pancreatic, colon, prostate, lung, and tongue cancer cell lines were treated with NO-aspirin, -sulindac, -ibuprofen, and -indomethacin or their traditional counterparts. We determined IC(50) values, cell proliferation, apoptosis, cell cycle, cyclooxygenase (COX) protein levels, and morphological changes (light and electron microscopy). All NO-NSAIDs inhibited the growth of all cancer cell lines studied. The potency of NO-NSAIDs was 11- to 6000-fold greater than that of their counterparts (except for the effect of sulindac on lung cancer cells). NO-aspirin was consistently the most potent NO-NSAID in all cell lines tested (except for the lung cancer cell line), sometimes in excess of 100-fold over the other three NO-NSAIDs. NO-NSAIDs inhibited cell proliferation, induced apoptosis, and altered cell cycle phase distribution (G2/M to G0/G1 block). All altered cellular morphology, whereas NO-aspirin induced nuclear disintegration ("atypical" cells) established by electron microscopy. NO-aspirin showed similar effects on two pancreatic cancer cell lines, BxPC-3 (expresses COX) and MIA PaCa-2 (no COX expression), suggesting a COX-independent effect. NO-NSAIDs showed a tissue-type-independent effect. Their pleiotropic effects involve cell renewal, cell death, and cell cycle phase transitions. These results raise the possibility that NO-NSAIDs possess chemopreventive and/or chemotherapeutic activity against a wide variety of human cancers.     

Investigation of the Impact of Graphene Nanoplatelets (GnP) on the Bond Stress of High-Performance Concrete Using Pullout Testing

Efficient load transmission between concrete and steel reinforcement by bonding action is a key factor in the process of the design procedure of bar-reinforced concrete structures. To enhance the bond strength of steel/concrete composites, the impact of graphene nanoplatelets (GnP) on the bond stress and bond stress–slip response of deformed reinforcement bars, embedded in high-performance concrete (HPC), was investigated using bar pullout tests. In the current study, 36 samples were produced and examined. The main variables were the percentages of GnP, the steel reinforcement bar diameter, and embedded length. Bond behavior, failure mode, and bond stress-slip response were studied. Based on the experimental findings, the inclusion of GnP had a significant favorable influence on the bar-matrix interactions due to the bridging action of GnP as a nano reinforcement. For 0.02 wt.% of GnP, the bond strength was enhanced by more than 41.28% and 53.90% for steel bar diameters of 10 and 16 mm, respectively. The HPC-GnP mixture displayed a reduction in the initial slippage in comparison to the control sample. The test findings were compared to the prediction models created by other researchers and the ACI 408R-12 code.     

Efficacy and safety of rituximab in patients with multiple sclerosis: An observational study at a tertiary center in Makkah,Saudi Arabia

Objectives:To assess the efficacy and safety of rituximab for multiple sclerosis (MS) treatment in terms of reduction in clinical relapses, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) score and adverse events.Methods:This is a retrospective cross-sectional study conducted at King Abdullah Medical City, from January 2017 to August 2021, involving patients with MS given rituximab, with 1-year follow-up. Clinical parameters were noted pre- and post-treatment to determine efficacy; adverse events were noted to analyze safety. A paired samples t-test was used to compare responses pre- and post-treatment. A p-value<0.05 was considered significant.Results:Among 31 patients, 6 (19.4%) had progressive MS, and 25 (80.6%) had relapsing-remitting MS (mean disease duration=8.12±5.65 years). The annual relapse rate reduced from 1.67±0.97 to 0.06±0.25 (p<0.001), the EDSS score from 3.16±2.14 to 2.80±2.28 (p=0.141) and the MRI activity score from 1.84±1.03 to 1.03±0.18 (p<0.001). Only one patient had enhancing lesion activity post-treatment. The commonest side effect was urinary tract infection (25.8%). Only 2 patients discontinued the drug.Conclusion:Rituximab is an efficient drug in reducing the annual relapse rate and MRI activity of patients with MS, with few tolerable side effects not leading to drug discontinuation or any lethal outcome.

Multiple sclerosis (MS) is a condition of the central nervous system carrying a chronic course and having autoimmune etiology. The disease has a prevalence of 40.4 per 100,000 people in Saudi Arabia. ¹ MS can have a relapsing-remitting course which begins with an acute attack and is then followed by full or partial recovery (also known as relapsing-remitting MS [RRMS]). Alternative clinical presentation of MS is characterized by progressive neurological worsening without any acute attack (also known as primary progressive MS). Secondary Progressive MS is another advanced stage in the course of disease where disability worsens gradually without a new relapse. ^2,3 The disease process was earlier thought to be mediated by T cells, but research has brought forth the suggestion that B cells, too, do play a role in the pathological process. ⁴ It is now well understood that antigen presentation by B cells is a necessary step in the pathogenesis of the immune-mediated process against the glycoprotein myelin found in central nervous system. ⁵ Therapies targeting T cells (for example, interferon-beta and natalizumab) have been traditionally used for MS, but not all patients improve despite treatment compliance. Moreover, interferon causes a myriad of highly stressful side effects, and natalizumab, in addition to causing minor adverse effects, has a risk of causing a serious condition like progressive multifocal leukoencephalopathy (PML). ⁶ New therapies that target B cells are increasingly being investigated. Rituximab (RTX) is one such drug that targets CD 20 expressing B cells and also reduces T cells. The drug has shown promising results in the treatment process. ^7,8 The safety of RTX usage is established by Class IV evidence. ⁹ Phase 2 trials have shown that RTX reduces magnetic resonance imaging (MRI) inflammatory lesions by up to 88% in the patients of MS. ^10,11 Off-label RTX usage in MS is further supported by several trials. ^11,12,13 One such study showed MRI activity reduce from 88% to 8.3% in only a year and annual relapse rate reduce from 0.75 to 0.36 with the use of RTX. ¹³ The common side effects of RTX usage in patients with MS include infections (36%), with urinary tract infection being the most common, and infusion reactions (8%). This CD 20 targeting drug also increases the risk for fungal infections. ^14,15 Studies comparing the efficacy of RTX to conventional therapies have concluded that RTX has better performance in MS, especially in newly diagnosed cases of RRMS. ¹⁶ Our aim was to study the reduction in MRI inflammatory lesions, disability changes and relapses in patients with MS presenting at King Abdullah Medical City as a result of RTX therapy.     

Soft tissue sarcomas and therapeutic management: is there a place for systemic chemotherapy in an adjuvant setting?

Introduction

Extremity soft tissue sarcomas (STS) represent a rare, heterogeneous malignancy. Surgery is the primary treatment for patients with no evidence of metastatic disease but 50% of patients with high-risk tumors will relapse and develop metastatic disease. Adjuvant chemotherapy aims to lessen the recurrence of cancer after surgery with or without radiotherapy. The objective of this review was to assess the effect of adjuvant chemotherapy in adults with resectable soft tissue sarcoma after such local treatment.

Materials and methods

Pub Med searches were done to identify all randomized controlled phase III trials (RCTs) published, and presented in various international conferences, comparing surgery plus adjuvant systemic chemotherapy to surgery alone (S) for resectable soft tissue sarcoma. The following keywords: adjuvant therapy, chemotherapy, soft tissue sarcoma were used to access the principal phase III study and meta-analysis based on individual and published data.

Results

Three randomized phase III trials and three meta-analyses were identified, comparing adjuvant chemotherapy to observation after curative resection. The majority of studies indicate some benefit with chemotherapy, particularly in the relapse-free survival rate, but no survival benefit was observed in the chemotherapy group relative to the control group. Quality of initial surgery is the most important prognostic and predictive factor for Relapse Free Survival (RFS) and Overall Survival (OS).

Conclusion

Compared to surgery alone, the role and value of adjuvant chemotherapy have not yet been established and cannot be recommended outside the context of a clinical trial.