Demonstration of endothelial adhesion of sickle cells in vivo: a distinct role for deformable sickle cell discocytes.

Different morphologic and density classes of sickle cells (SS) may play distinct roles in the generation of vasoocclusion, explaining the complexity of this phenomena. The densest SS red blood cells (RBCs) (SS4) can induce vasoocculsion in ex vivo microcirculatory preparations as well as in an intact animal model. Previous studies of the interaction of SS deformable discocytes with endothelial monolayers or the rat ex vivo mesocecum preparation have shown adhesion that is desmopressin (dDAVP)-stimulated, von Willebrand factor (vWF)-mediated, and limited to the small venules. However, in vivo adhesion of SS RBCs to the endothelium has neither been demonstrated nor characterized; and, in particular, the relation of adhesion to vasoocclusion is unknown. Using an intact animal model that involves injecting saline-washed, density-defined SS RBCs into the femoral artery of a rat, we find that: (1) Quantitative studies of RBCs retained in the rat thigh using 99mTc-labeled RBCs and gamma camera imaging showed that dDAVP induces a threefold increase in retention of normal (AA) cells and deformable SS discocytes (SS2). (2) electron microscopy and Microfil injection show that the retention of SS2 cells is due to adhesion to the vascular endothelium with no evidence of obstruction. (3) H-1 magnetic resonance imaging showed that retention of SS4 cells induced a dose-dependent increase in tissue edema (presumable secondary to tissue hypoxia), while retention of AA or SS2 cells produced no change. We conclude that endothelial adhesion of deformable SS discocytes can be demonstrated in an in vivo animal model, that this adhesion is enhanced by dDAVP (presumably related to, but not necessarily limited to the release of vWF), and that this phenomenon per se does not lead to vasoocclusion. Nevertheless, adhesion of deformable SS discocytes may have consequences. We hypothesize that adhesion of SS discocytes could narrow the lumen of postcapillary venules and facilitate secondary trapping of SS4 cells and lead to subsequent vasoocclusion.     

The interferon antagonist sarcolectin in the progress of HIV-1 infection and in AIDS.

Sarcolectin (SCL) is a nonspecific stimulator of cellular DNA synthesis that was found in all animal sera tested to date. It inhibits the established interferon (IFN)-dependent antiviral state, restoring cells to their normal status. In this study, we examined the excretion/secretion of the IFN antagonist SCL in sera from healthy donors and in sera collected during different periods of human immunodeficiency virus type 1 (HIV-1) infection. We followed HIV-1-infected patients during all stages of development (seroconversion, initial and advanced phases of AIDS) and found a significant increase in SCL in sera of HIV-infected patients compared with seronegative subjects used as controls. This increase was established during seroconversion, and then the titers leveled off. In the final stage of the disease, the SCL titer increased again very significantly. We attribute this rapid rise to the virus-dependent destruction of T cells that can no longer be repaired. The high SCL level observed at this final stage, which is most predictive of the disease's progression, suggests that the action, rather than the production, of IFN is impaired.     

Multipoint linkage mapping of the Xq25-q26 region in a family affected by the X-linked lymphoproliferative syndrome

We have performed, in a large Swiss family, a study of linkage between various DNA markers in the Xq24-27 region and the locus for the X-linked lymphoproliferative syndrome (XLP). Our results indicated that the marker DXS37 in Xq25-q26 is genetically linked to the XLP syndrome. The multipoint linkage analysis showed that the disease locus is distal to DXS11, but proximal to the hypoxanthine phosphoribosyl-transferase gene (HPRT).     

Why discrepancies exist between structured diagnostic interviews and clinicians' diagnoses

Summary The authors employed empirical methods to study the causes of discrepancies between clinicians' and epidemiologists' diagnoses of cases from the general population within the homogeneous DSM-III/DIS system. Four interviewers conducted 139 interviews using the DIS, while psychiatrists completed a DSM-III checklist, after which they could then ask any questions they wanted. All kappas exceeded 0.58. Meetings were subsequently organized with all participating psychiatrists in order to point out reasons for discrepancies between DIS diagnoses and clinical judgement. The authors came to the following conclusions: (1) DSM-III ambiguities led to discrepancies, especially when reference periods were not specified. (2) Discrepancies arose when cases were difficult: symptoms pertaining to different diagnoses or multiple diagnoses and the fact that clinicians could use volunteered comments, while interviewers were obliged to keep strictly to the schedule, contributed to discrepancies. (3) Other approaches, such as CIDI for anxiety and DISSA for depression, could improve DIS performances.     

The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B

The X-linked lymphoproliferative syndrome (XLP) is a genetic disorder in which affected males have a morbid or fatal response to Epstein-Barr virus infection. The XLP deficiency has been mapped to a gene encoding a 128-residue protein, SH2D1A, which is comprised principally of a Src homology 2 (SH2) domain. We now report that SH2D1A associates with Dok1, a protein that interacts with Ras-GAP, Csk, and Nck. An SH2D1A SH2 domain mutant that has been identified in XLP does not associate with Dok1, in accord with the hypothesis that this interaction is linked to XLP. The association of SH2D1A with Dok1 also depends on phosphorylation of Dok1 Y(449) in the sequence ALYSQVQK. Further, overexpression of SH2D1A is found to activate NF-kappaB in 293T cells. NF-kappaB activation by SH2D1A does not depend on the wild-type SH2 domain and is inhibited by a dominant-negative IkappaB kinase beta. Thus, SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein-Barr virus infection.     

Minilaparoscopy-assisted transrectal low anterior resection (LAR): a preliminary study

Background

Natural orifice translumenal endoscopic surgery (NOTES) represents the evolution of surgery towards less invasive procedures. The feasibility of NOTES transrectal approach has increased its clinical applicability. This report describes a first series of minilaparoscopy-assisted transrectal low anterior resection with double purse-string end-to-end circular stapler anastomoses.

Methods

Between March and April 2012 three selected patients underwent transrectal minilaparoscopy-assisted natural orifice surgery total mesorectal excision for rectal cancer. All the oncologic principles of open/laparoscopic low anterior resection for rectal cancer were strictly fulfilled. Two patients underwent neoadjuvant treatment. Laparoscopic visualization and assistance was provided through one 10-mm umbilical port and two ports, one of which was used as stoma site (5 mm) and the other as a drain site (2 mm needle port). The specimen was transected transanally followed by the confection of double purse-string lateral/end-to-end anastomoses. There were no intraoperative complications.

Results

Mean operative time was 143 min. Oral intake was initiated on the second postoperative day. Patients were discharged home by day 5. The pathology unit confirmed that distal and circumferential margins were free of tumor invasion, and quality of mesorectum resection was reported satisfactory. One patient had to be readmitted because of severe dehydration due to increased ileostomy output. The patient was discharged at the third day after the readmission without renal failure.

Conclusions

In this preliminary report, transrectal minilaparoscopy-assisted low anterior resection was feasible and safe. Lateral/end-to-end anastomoses can be considered an interesting alternative to the double-stapling technique. However, it is necessary to further study and develop these procedures, along with careful patient selection, before transrectal low anterior resection may be considered for routine clinical use.     

Comparison of Fracture Prediction Tools in Individuals Without and With Early Chronic Kidney Disease: A Population-Based Analysis of CARTaGENE

Whether fracture prediction tools developed for the management of osteoporosis can be used in chronic kidney disease (CKD) is poorly known. We aimed to compare the performance of fracture prediction tools in non-CKD and CKD. We analyzed CARTaGENE, a population-based survey of 40-year-old to 69-year-old individuals recruited between 2009 and 2010. Renal function was assessed using baseline creatinine and categorized according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines (non-CKD, stage 2, stage 3). Individuals without creatinine measurements or with advanced CKD (stage 4 or 5; prevalence <0.25%) were excluded. Predicted 5-year fracture probabilities (using Fracture Risk Assessment Tool [FRAX], QFracture, and Garvan) were computed at baseline. Fracture incidence (major fracture [MOF] or any fracture) was evaluated in administrative databases from recruitment to March 2016. Discrimination (hazard ratios [HRs] per standard deviation [SD] increase in Cox models; c-statistics) and calibration (standardized incidence ratios [SIRs] before and after recalibration) were assessed in each CKD strata. We included 19,393 individuals (9522 non-CKD; 9114 stage 2; 757 stage 3). A total of 830 patients had any fracture during follow-up, including 352 MOF. FRAX (HR = 1.89 [1.63–2.20] non-CKD; 1.64 [1.41–1.91] stage 2; 1.76 [1.10–2.82] stage 3) and QFracture (HR = 1.90 [1.62–2.22] non-CKD; 1.57 [1.35–1.82] stage 2; 1.86 [1.19–2.91] stage 3) discriminated MOF similarly in non-CKD and CKD. In contrast, the discrimination of Garvan for any fracture tended to be lower in CKD stage 3 compared to non-CKD and CKD stage 2 (HR = 1.36 [1.22–1.52] non-CKD; 1.34 [1.20–1.50] stage 2; 1.11 [0.79–1.55] stage 3). Before recalibration, FRAX globally overestimated fracture risk while QFracture and Garvan globally underestimated fracture risk. After recalibration, FRAX and QFracture were adequately calibrated for MOF in all CKD strata whereas Garvan tended to underestimate any fracture risk in CKD stage 3 (SIR = 1.31 [0.95–1.81]). In conclusion, the discrimination and calibration of FRAX and QFracture is similar in non-CKD and CKD. Garvan may have a lower discrimination in CKD stage 3 and underestimate fracture risk in these patients. © 2020 American Society for Bone and Mineral Research.