TGF‐β induces the differentiation of human CXCL13‐producing CD4+ T cells

In the ectopic lymphoid‐like structures present in chronic inflammatory conditions such as rheumatoid arthritis, a subset of human effector memory CD4⁺ T cells that lacks features of follicular helper T (Tfh) cells produces CXCL13. Here, we report that TGF‐β induces the differentiation of human CXCL13‐producing CD4⁺ T cells from naïve CD4⁺ T cells. The TGF‐β‐induced CXCL13‐producing CD4⁺ T cells do not express CXCR5, B‐cell lymphoma 6 (BCL6), and other Tfh‐cell markers. Furthermore, expression levels of CD25 (IL‐2Rα) in CXCL13‐producing CD4⁺ T cells are significantly lower than those in FoxP3⁺ in vitro induced Treg cells. Consistent with this, neutralization of IL‐2 and knockdown of STAT5 clearly upregulate CXCL13 production by CD4⁺ T cells, while downregulating the expression of FoxP3. Furthermore, overexpression of FoxP3 in naïve CD4⁺ T cells downregulates CXCL13 production, and knockdown of FoxP3 fails to inhibit the differentiation of CXCL13‐producing CD4⁺ T cells. As reported in rheumatoid arthritis, proinflammatory cytokines enhance secondary CXCL13 production from reactivated CXCL13‐producing CD4⁺ T cells. Our findings demonstrate that CXCL13‐producing CD4⁺ T cells lacking Tfh‐cell features differentiate via TGF‐β signaling but not via FoxP3, and exert their function in IL‐2‐limited but TGF‐β‐rich and proinflammatory cytokine‐rich inflammatory conditions.     

A potentially crucial role of the <Emphasis Type="Italic">PKD1</Emphasis> C-terminal tail in renal prognosis

Background

Autosomal dominant polycystic disease (ADPKD) often results in renal failure. Recently, allelic influences of PKD1 mutation types on renal survival were extensively investigated. Here, we analyzed integrated influences of PKD1 mutation types and positions on renal survival.

Methods

We included 338 (82 pedigrees) and 72 (12 pedigrees) patients with PKD1 and PKD2 mutations, respectively, identified through comprehensive gene analysis of 101 probands with ADPKD. Genetic testing was performed using next-generation sequencing, long-range PCR, and multiplex ligation-dependent probe amplification. Pathogenic mutations were identified by a software package-integrated seven databases and provided access to five cloud-based computing systems.

Results

Mean renal survivals of carriers with PKD1 non-truncating-type mutations at positions upstream of G-protein-coupled receptor proteolytic site (GPS-upstream domain), transmembrane domain, or cytoplasmic C-terminal tail (CTT) domain were 70.2, 67.0, and 50.1 years, respectively (P < 0.0001); renal survival was shorter for mutation positions closer to CTT domain, suggesting its crucial role in renal prognosis. Furthermore, in truncating-type mutations, strong inactivation is anticipated on nucleotides downstream from the mutation site, implying CTT domain inactivation irrespective of mutation site. Shorter mean renal survival was found for PKD1 truncating-type than non-truncating-type mutation carriers (P = 0.0348); mean renal survival was not different between PKD1 3′- and 5′-region truncating-type mutation carriers (P = 0.4375), but was shorter in PKD1 3′-region than in 5′-region non-truncating-type mutation carriers (P = 0.0014). Variable strength of CTT domain inactivation might account for these results.

Conclusions

Aforementioned findings indicate that CTT domain’s crucial role in renal prognosis needs further investigation by larger studies (ClinicalTrials.gov; NCT02322385).

     

Identification of Trypanosoma cruzi sublineages by the simple method of single-stranded conformation DNA polymorphism (SSCP)

Fifty-eight stocks of Trypanosoma cruzi from Latin America were genetically characterized using the methods of the polymerase chain reaction (PCR) and the single-stranded conformation DNA polymorphism (SSCP) with four genes, mini-exon, 24Sα rRNA, 18Sr RNA, cruzipain, and a RAPD fragment DNA region, P7–P8. All the isolates examined were assigned to T. cruzi I or subgroups of T. cruzi II by these methods. From these results, the SSCP analysis, which was simple to perform and highly sensitive to sequence variation, seemed to be a good modality for characterizing T. cruzi, particularly for subgroups of T. cruzi II. However, in several isolates of T. cruzi II, the subgroups determined with the SSCP of 24Sα rRNA were not consistent with those determined with other genes, the SSCP of 18S rRNA and cruzipain, and the PCR of P7–P8, possibly because of the occurrence of rare genetic exchanges or mutations or both in natural populations of this parasite. The SSCP patterns of 24Sα rRNA and 18S rRNA were highly variable in the T. cruzi I isolates; therefore, analyses using both genes are considered to be one possible method for the characterization of isolates within T. cruzi I.     

Effect of Simulated Patient Practice on the Self-Efficacy of Japanese Undergraduate Dietitians in Nutrition Care Process Skills

Objective

To examine the effect of an adapted simulated patient (SP) intervention on self-efficacy in nutrition care process skills.

Osteoarthritis hip joints in Japan: involvement of acetabular dysplasia

Background

We conducted a nationwide epidemiologic study regarding hip osteoarthritis (OA) in Japan, and a previous report found these patients to be unique in comparison to Caucasians. This report focused on the data regarding each hip joint, and the involvement of acetabular dysplasia with hip OA was analyzed.

Methods

Seven hundred twenty OA hips were examined. Sixty-five joints with osteonecrosis of the femoral head and 215 non-OA contralateral joints of the unilateral patients were examined as controls. The revised system of stage classification for hip OA of the Japanese Orthopedic Association (JOA) was used according to the reproducibility in order to ensure reliable data from the multiple institutions. The acetabular dysplasia indexes were also chosen according to the reproducibility and measured in the radiograph of bilateral hip joints. The clinical score was assessed using the JOA scoring system. The relative risk of the grade of acetabular dysplasia indexes for hip OA was calculated as the odds ratio and the 95% confidence interval.

Results

The stage of the OA joints deteriorated with increasing age. The clinical scores also decreased. The grade of the acetabular dysplasia indexes of the OA joints was significantly higher than that of the control joints. Each index of acetabular dysplasia demonstrated significantly increased odds ratios for hip OA. Among the OA joints, the deterioration of the OA stage was found to be significantly associated with an increasing grade of acetabular dysplasia. The odds ratio for OA deterioration in the acetabular dysplasia index was also obtained. The joints of females tended to have a higher grade and prevalence of acetabular dysplasia than those of males.

Conclusions

These findings confirmed a high prevalence of acetabular dysplasia in hip OA joints in Japan. Acetabular dysplasia was one of the most important factors associated with hip OA.     

Ancient divergence of Paragonimus westermani in Sri Lanka

Adult flukes of Paragonimus species were obtained from lungs of experimental animals infected with metacercariae found in field-collected freshwater crabs in Sri Lanka. Morphological studies of adult worms under a scanning electron microscope as well as a ordinary microscope were performed in the present study. All of morphological features observed clearly indicated that this species is P. westermani. On the other hand, the shapes of metacercariae were found to be mainly oval, but semioval and spherical ones also coexisted. In spite of the variety of their morphology of the metacercariae, there is no correlation between their shapes of metacercariae and the deoxyribonucleic acid (DNA) sequences. Molecular phylogenetic analyses using two DNA regions (partial mitochondrial cytochrome c oxidase subunit 1 and second internal transcribed spacer of the nuclear ribosomal gene repeat) placed the adult flukes of P. westermani from Sri Lanka basal in a tree including all specimens of P. westermani from various areas in Asia and P. siamensis from Thailand. The present study showed that P. westermani from Sri Lanka is an ancestral form.