Chronic Systemic Infection of Mice with Leishmania infantum Leads to Increased Bone Mass

Vector-borne infections of humans with the protozoan parasite Leishmania (L.) infantum can cause a systemic and potentially lethal disease termed visceral leishmaniasis. In the corresponding mouse model, an intravenous infection with L. infantum leads to the persistence of parasites in various organs, including bone marrow (BM). Considering the anatomical proximity between the BM and the cortical bone, we investigated whether a chronic infection with L. infantum affected bone homeostasis. Unexpectedly, chronic infection with L. infantum caused an increase in bone mass in mice. In vivo, an increased number of osteoblasts and osteocytes and a decreased maturation of osteoclasts characterized the phenotype. Confocal laser scanning fluorescence microscopy confirmed the infection of BM macrophages but also revealed the presence of parasites in osteoclasts. In vitro, mature osteoclasts took up L. infantum parasites. However, infection of osteoclast progenitors abolished their differentiation and function. In addition, secretory products of infected BM–derived macrophages inhibited the maturation of osteoclasts. Both in vitro and in vivo, infected macrophages and osteoclasts showed an enhanced expression of the anti-osteoclastogenic chemokine CCL5 (RANTES). Neutralization of CCL5 prevented the inhibition of osteoclast generation seen in the presence of culture supernatants from L. infantum-infected macrophages. Altogether, our study shows that chronic infection with Leishmania increases bone mass by inducing bone formation and impairing osteoclast differentiation and function. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Peroxisome proliferator-activated receptor beta/delta exerts a strong protection from ischemic acute renal failure

Ischemic acute renal failure is characterized by damages to the proximal straight tubule in the outer medulla. Lesions include loss of polarity, shedding into the tubule lumen, and eventually necrotic or apoptotic death of epithelial cells. It was recently shown that peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) increases keratinocyte survival after an inflammatory reaction. Therefore, whether PPARbeta/delta could contribute also to the control of tubular epithelium death after renal ischemia/reperfusion was tested. It was found that PPARbeta/delta+/- and PPARbeta/delta-/- mutant mice exhibited much greater kidney dysfunction and injury than wild-type counterparts after a 30-min renal ischemia followed by a 36-h reperfusion. Conversely, wild-type mice that were given the specific PPARbeta/delta ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na+. This protective effect was accompanied by a significant reduction in medullary necrosis, apoptosis, and inflammation. On the basis of in vitro studies, PPARbeta/delta ligands seem to exert their role by activating the antiapoptotic Akt signaling pathway and, unexpectedly, by increasing the spreading of tubular epithelial cells, thus limiting potentially their shedding and anoikis. These results point to PPARbeta/delta as a remarkable new target for preconditioning strategies.     

Relevance of Toll-like receptor-4 polymorphisms in renal transplantation

BACKGROUND: Polymorphisms in Toll-like receptor-4 (TLR4) have been reported to be associated with a blunted immune response to microbial pathogens, as well as a decreased risk of atherosclerosis in the general population. We assessed the impact of the two TLR4 variants on the risk of severe infection, the incidence of acute rejection, and the occurrence of atherosclerotic complications in renal transplant recipients (RTR). METHODS: TLR-4 polymorphisms were assessed in a cohort of 238 RTR. Post-transplant atherosclerotic events, acute rejection, severe bacterial infection, cytomegalovirus (CMV) disease, and opportunistic infections were evaluated as outcomes. RESULTS: The patients were followed for a mean duration of 95 +/- 29 months after transplant. TLR4 polymorphism was observed in 27 (11.3%) RTR. Subjects with TLR4 polymorphisms were less likely to experience post-transplant atherosclerotic events (RR 0.44; 95% CI 0.21 to 0.93; P= 0.02) and acute rejection (RR 0.41; 95% CI 0.30 to 0.83; P= 0.01), but presented severe bacterial infections (RR 1.33; 95% CI 1.12 to 1.67; P= 0.01) and opportunistic infections (RR 3.03; 95% CI 1.72 to 8.29; P= 0.008) more frequently. TLR4 polymorphism was marginally associated with CMV disease (RR 1.47; 95% CI 0.95 to 2.64; P= 0.08). CONCLUSION: RTR with TLR4 polymorphism present a lower risk of post-transplant atherosclerotic events and acute allograft rejection, but experience severe infectious episodes more frequently. This subset of RTR may benefit from a less potent immunosuppression regimen, along with increased preventive measures against infectious agents.     

Detection and quantification of valvular heart disease with dynamic cardiac MR imaging.

Magnetic resonance (MR) imaging is rapidly gaining acceptance as an accurate, reproducible, noninvasive method for optimal assessment of structural and functional parameters in patients with valvular heart disease. The severity of valvular regurgitation can be evaluated with cine gradient-echo MR imaging, which allows measurement of the area of the signal void corresponding to the abnormal flow jet. Alternatively, this modality can be used to obtain ventricular volumetric measurements and calculate the regurgitant fraction, or velocity-encoded cine (VEC) MR imaging can be used to quantify regurgitant blood flow. The severity of valvular stenosis can be determined by evaluating the flow jet and associated findings with either modality or by using VEC MR imaging to calculate the transvalvular pressure gradient and valve area. Dynamic MR imaging allows accurate assessment of ventricular function and comprehensive evaluation of pathophysiologic changes. In addition, good interstudy reproducibility suggests a role for VEC MR imaging in assessing the effects of therapeutic intervention and monitoring regurgitant fraction, thereby helping in surgical planning and the prevention of ventricular dysfunction. With greater cost-effectiveness and the increasing availability of new hardware and more advanced techniques, MR imaging will become a routine procedure in valvular heart disease.     

The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease

The course of autosomal dominant polycystic kidney disease (ADPKD) varies among individuals, with some reaching ESRD before 40 years of age and others never requiring RRT. In this study, we developed a prognostic model to predict renal outcomes in patients with ADPKD on the basis of genetic and clinical data. We conducted a cross-sectional study of 1341 patients from the Genkyst cohort and evaluated the influence of clinical and genetic factors on renal survival. Multivariate survival analysis identified four variables that were significantly associated with age at ESRD onset, and a scoring system from 0 to 9 was developed as follows: being male: 1 point; hypertension before 35 years of age: 2 points; first urologic event before 35 years of age: 2 points; PKD2 mutation: 0 points; nontruncating PKD1 mutation: 2 points; and truncating PKD1 mutation: 4 points. Three risk categories were subsequently defined as low risk (0–3 points), intermediate risk (4–6 points), and high risk (7–9 points) of progression to ESRD, with corresponding median ages for ESRD onset of 70.6, 56.9, and 49 years, respectively. Whereas a score ≤3 eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%, a score >6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%. This new prognostic score accurately predicts renal outcomes in patients with ADPKD and may enable the personalization of therapeutic management of ADPKD.     

Could post-liver transplantation course be helpful for the diagnosis of so called cryptogenic cirrhosis?

Cryptogenic cirrhosis (CC) is diagnosed in 5-30% of cirrhotic patients overall and 7% of patients who undergo liver transplantation for cirrhosis. In our series of patients transplanted for CC, pre-transplant clinical and histological data and the post-transplant course were reexamined in an attempt to identify the aetiology. Among the 881 patients transplanted in our centre between 1987 and 2000, 28 patients with a median age of 46 yr (range: 18-69) at transplantation were initially classified as having CC. Two patients were excluded because of intense ischaemic lesions caused by chemoembolization prevented histological analysis of the native liver (n = 1) and because of cryptic HBV infection (n = 1). Among the remaining 26 patients, four groups were individualized: (i) patients with chronic inflammatory liver disease with autoimmune features (n = 14, 54%); (ii) patients with features suggestive of non-alcoholic fatty liver disease (n = 3, 11.5%); (iii); patients with incomplete septal cirrhosis (ISC) and vascular liver disease (n = 3), and (iv) patients with unresolved CC (n = 6, 23%). In the autoimmune liver disease group, the median International Autoimmune Hepatitis score was 12.5 (range: 11-19) after reevaluation and review of the post-transplantation course was helpful to confirm the diagnosis with the occurrence of active graft hepatitis in nine patients, with autoantibodies in five patients. The vascular group was characterized by lesions of obliterative portal venopathy and ISC in all native livers. Diagnosis of NAFLD was based on the clinical background of obesity and/or type 2 diabetes and the presence of steatosis or steatohepatitis in native livers and graft biopsies. A definite aetiological diagnosis can be achieved in the majority of patients initially diagnosed with CC. Autoimmune liver disease emerged as the main aetiology (14 of 26 patients, 54%) and frequently recurred on the grafted liver (nine cases). In all cases a precise diagnosis is obviously of practical interest for better management of post-transplant survey and treatment.     

Isolated thoracic spine lesion: is this the presentation of a SAPHO syndrome? A case report

A case of an isolated lesion of the thoracic spine attributed to SAPHO syndrome is presented. A 51-year-old man was referred for inflammatory pain in the thoracic spine. The general examination was normal (especially cutaneous and rheumatologic examinations). Laboratory analysis showed only a mild inflammatory reaction. Standard radiographs showed partial condensation of T8. Computed tomography showed osteolysis of the anterior corner of T8, and MRI revealed an abnormal signal of T8, with enlargement of the prevertebral soft tissue. Percutaneous and thoracoscopic biopsies showed a nonspecific inflammatory process, and cultures were sterile. Initially, several diagnoses were advanced: infectious spondylitis, malignant tumor, lymphomas, Paget disease, seronegative spondyloarthropathies and finally atypical SAPHO syndrome. Three months later, the patient experienced more pain. General examination was still normal. The radiological findings worsened, while the inflammatory blood tests were normal. A new thoracoscopic biopsy revealed a nonspecific inflammatory process. A diagnosis of SAPHO syndrome was made, despite the lack of typical lesions. Dramatically improving with anti-inflammatory therapy, the patients condition was favorable at 3-year follow-up. This atypical presentation of an isolated lesion in the spine makes the diagnosis of a SAPHO syndrome difficult but possible. Spine surgeons must be aware of this rare entity, to avoid misdiagnosis and unnecessary repeated surgical biopsies.     

Treatment of anterior communicating artery aneurysms: complementary aspects of microsurgical and endovascular procedures

OBJECT: Endovascular and surgical treatment must be clearly defined in the management of anterior communicating artery (ACoA) aneurysms. In this study the authors report their recent experience in using a combined surgical and endovascular team approach for ACoA aneurysms, and compare these results with those obtained during an earlier period in which surgical treatment was used alone. Morbidity and mortality rates, causes of unfavorable outcomes, and morphological results were also assessed. METHODS: The prospective study included 223 patients who were divided into three groups: Group A (83 microsurgically treated patients, 1990-1995); Group B (103 microsurgically treated patients, 1996-2000); and Group C (37 patients treated with Guglielmi Detachable Coil [GDC] embolization, 1996-2000). Depending on the direction in which the aneurysm fundus projected, the authors attempted to apply microsurgical treatment to Type 1 aneurysms (located in front of the axis formed by the pericallosal arteries). They proposed the most adapted procedure for Type 2 aneurysms (located behind the axis of the pericallosal arteries) after discussion with the neurovascular team, depending on the physiological status of the patient, the treatment risk, and the size of the aneurysm neck. In accordance with the classification of Hunt and Hess, the authors designated those patients with unruptured aneurysms (Grade 0) and some patients with ruptured aneurysms (Grades I-III) as having good preoperative grades. Patients with Grade IV or V hemorrhages were designated as having poor preoperative grades. By performing routine angiography and computerized tomography scanning, the causes of unfavorable outcome (Glasgow Outcome Scale [GOS] score < 5) and the morphological results (complete or incomplete occlusion) were analyzed. Overall, the clinical outcome was excellent (GOS Score 5) in 65% of patients, good (GOS Score 4) in 9.4%, fair (GOS Score 3) in 11.6%, poor (GOS Score 2) in 3.6%, and fatal in 10.3% (GOS Score 1). Among 166 patients in good preoperative grades, an excellent outcome was observed in 134 patients (80.7%). The combined permanent morbidity and mortality rate accounted for up to 19.3% of patients. The rates of permanent morbidity and death that were related to the initial subarachnoid hemorrhage were 6.2 and 1.5% for Group A, 6.6 and 1.3% for Group B, and 4 and 4% for Group C, respectively. The rates of permanent morbidity and death that were related to the procedure were 15.4 and 1.5% for Group A, 3.9 and 0% for Group B, and 8 and 8% for Group C, respectively. When microsurgical periods were compared, the rate of permanent morbidity or death related to microsurgical complications decreased significantly (Group A, 11 patients [16.9%] and Group B, three patients [3.9%]); Fisher exact test, p = 0.011) from the period of 1990 to 1995 to the period of 1996 to 2000. The combined rate of morbidity and mortality that was related to the endovascular procedure (16%) explained the nonsignificance of the different rates of procedural complications for the two periods, despite the significant decrease in the number of microsurgical complications. Among 57 patients in poor preoperative grade, an excellent outcome was observed in 11 patients (19.3%); however, permanent morbidity (GOS Scores 2-4) or death (GOS Score 1) occurred in 46 patients (80.7%). With regard to the correlation between vessel occlusion (the primary microsurgical complication) and the morphological characteristics of aneurysms, only the direction in which the fundus projected appeared significant as a risk factor for the microsurgically treated groups (Fisher exact test: Group A, p = 0.03; Group B, p = 0.002). The difference between endovascular and microsurgical procedures in the achievement of complete occlusion was considered significant (chi2 = 6.13, p = 0.01). CONCLUSIONS: The direction in which the fundus projects was chosen as the morphological criterion between endovascular and surgical methods. The authors propose that microsurgical clip application should be the preferred option in the treatment of ACoA aneurysms with anteriorly directed fundi and that endovascular packing be selected for those lesions with posteriorly directed fundi, depending on morphological criteria.     

CD4 cell lymphopenia and atherosclerosis in renal transplant recipients

Several animal studies suggest that T cell-mediated immunodeficiency may play a role in the progression of atherosclerosis. This study examined the association between lymphocyte subsets and atherosclerotic events in renal transplant recipients. A total of 302 consecutive renal transplant recipients were enrolled in this prospective study. Peripheral blood lymphocyte subsets were quantified and analyzed with respect to other known cardiovascular risk factors. The patients were followed for a mean duration of 23.5 +/- 4.5 mo. Mean CD4, CD8, and CD19 cell levels were 511 +/- 290/mm(3), 553 +/- 596/mm(3), and 66 +/- 62/mm(3), respectively. CD4 levels were positively related to transplant duration (r = 0.32; P = 0.02) and inversely related to age (r = 0.35; P = 0.01). Twenty-five atherosclerotic events (AE) occurred in 25 patients (8.3%). CD4 levels were lower in patients who experienced CVE (288 +/- 170/mm(3) versus 531 +/- 290/mm(3); P < 0.0001). Cox regression analysis showed that patients in the three upper quartiles of CD4 cell count had a decreased risk of CVE compared with those in the lowest quartile. There was a linear increase in risk of CVE with decreasing CD4 cell count (P < 0.0001). A CD4 cell count in the highest quartile (>663/mm(3)) divided the risk of CVE by 10 as compared with the lowest quartile. In conclusion, CD4 lymphocytopenia is an independent risk factor for the development of cardiovascular complications in renal transplant recipients, suggesting that impaired immune response promotes accelerated atherogenesis in this population.     

Cochlear implant benefits in deafness rehabilitation: PET study of temporal voice activations.

Cochlear implants may improve the medical and social prognosis of profound deafness. Nevertheless, some patients have experienced poor results without any clear explanations. One correlate may be an alteration in cortical voice processing. To test this hypothesis, we studied the activation of human temporal voice areas (TVA) using a well-standardized PET paradigm adapted from previous functional MRI (fMRI) studies. METHODS: A PET H(2)(15)O activation study was performed on 3 groups of adult volunteers: normal-hearing control subjects (n = 6) and cochlear-implanted postlingually deaf patients with >2 y of cochlear implant experience, with intelligibility scores in the "Lafon monosyllabic task" >80% (GOOD group; n = 6) or <20% (POOR group; n = 6). Relative cerebral blood flow was measured in 3 conditions: rest, passive listening to human voice, and nonvoice stimuli. RESULTS: Compared with silence, the activations induced by nonvoice stimuli were bilaterally located in the superior temporal regions in all groups. However these activations were significantly and similarly reduced in both cochlear implant groups, whereas control subjects showed supplementary activations. Compared with nonvoice, the voice stimuli induced bilateral activation of the TVA along the superior temporal sulcus (STS) in both the control and the GOOD groups. In contrast, these activations were not detected in the POOR group, which showed only left unilateral middle STS activation. CONCLUSION: These results suggest that PET is an adequate method to explore cochlear implant benefits and that this benefit could be linked to the activation of the TVA.