Hua Pan

Intellectual developmental disorder, X-linked 104 (XLID104), caused by the FRMPD4 gene variant, is a rare X-linked genetic disease that primarily manifests as intellectual disability (ID) and language delay, and may be accompanied by behavioural abnormalities. Currently, only 11 patients from four families have been reported to carry FRMPD4 gene variants. Here, we report a rare case of a Chinese patient with XLID104 who was presented with severe ID and language impairment. Genetic testing results showed that the patient had a novel hemizygous variant on FRMPD4 inherited from the heterozygous variant NM_001368397: c.1772A>C (p.Glu591Ala) carried by his mother. To our knowledge, this variant has not been reported previously. Western blot results for the recombinant plasmid constructed in vitro indicated that the expression of the mutant protein may be reduced. Using molecular dynamics simulations, we predicted that the mutant protein may affect the interaction of the FRMPD4 protein with DLG4. In this study, we expand the spectrum of FRMPD4 variants and suggest that the clinical awareness of the genetic diagnosis of nonsyndromic ID should be strengthened.

Objective: : To determine if thrombin‐inhibiting nanoparticles preserve renal function when administered after onset of ischemia‐reperfusion acute kidney injury (AKI), and to determine physiologic mechanisms by which this occurs. Hypothesis: AKI therapy remains mainly supportive, as recent clinical trials of promising therapeutic agents have failed to preserve renal function. It has been previously shown that delivery of direct thrombin inhibiting nanoparticles prior to onset of AKI in mice has successfully preserved renal function. We hypothesized that inhibition of thrombin clotting and inflammatory signaling with the use of a sustained locally acting nanoparticle formulation might both preserve renal vasculature and broadly modulate pathophysiologic processes that contribute to renal ischemia reperfusion injury even after its onset. Methods: C57BL/6 mice underwent bilateral warm ischemia for 17 minutes at 37°C followed by reperfusion. Two hours after reperfusion, mice were injected with either direct thrombin‐inhibiting (n=10) or control (n=12) perfluorocarbon nanoparticles (PFC NP). The treatment PFC NP contained ~ 13650 copies per nanoparticle of the direct thrombin inhibitor, PPACK (Proline‐Phenylalanine‐Arginine‐Chloromethyl‐Ketone). After 24 hours, blood and kidneys were collected for evaluation of BUN, inflammatory eicosanoids and cytokines, histological analysis of vascular damage, endothelial activation, and cellular infiltrates. Results: : Mice treated after AKI with direct thrombin‐inhibiting PPACK NP exhibited significantly improved kidney function at 24 hours versus the control group (BUN: 62.10±8.71mg/dL vs 110.96 ±6.21mg/dL, p=0.0002). Vascular integrity was preserved as evidenced by increased expression of CD31 in both cortex (4.28±0.62% vs 1.75±0.34%, p=0.0018) and medulla (3.24±0.38% vs 1.91±0.29%; p=0.0073). Additionally, the PPACK NP group demonstrated significantly less acute tubular necrosis (ATN), further mitigating vascular damage (ATN: 24.44±1.76% vs 37.00±4.96%, p=0.035). Treatment reduced red blood cell trapping and subsequent iron accumulation in both cortex (3.37±0.50% vs 5.34±0.42%, p=0.0083) and medulla (0.50%±0.10% vs 1.01%±0.12%, p=0.006). Inflammatory markers were also reduced in the PPACK NP group, including endothelial VCAM‐1 (positive area in medulla 0.49±0.12% vs 1.41±0.60%, p=0.0073), ICAM‐1 (positive area in medulla 3.07±0.51% vs 4.46±0.35%, p=0.030). and serum M‐CSF and IL‐6. Mast cell infiltration and prostaglandin D2 (PGD2) were also decreased. Conclusion: Nanoparticle delivery of local thrombin inhibitors that have a known minimal effect on systemic clotting parameters successfully protects renal function by preserving renal vasculature, reducing ATN and iron accumulation, and broadly attenuating thrombin‐induced inflammatory mechanisms even when delivered after onset of AKI.

This study was based on 95391 participants (18–98 years old) from the Kailuan study, which assessed all-cause mortality in a community-based population in northern China according to estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and proteinuria estimated from urine dipstick results. Data were analysed based on Cox proportional hazards models with adjustment for relevant confounders, and the results were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). During eight years of follow-up, a total of 6024 participants died. The two indicators, eGFR < 45 ml/min/1.73 m² and the presence of proteinuria, were independently associated with all-cause mortality. Compared with eGFR ≥45 ml/min/1.73 m² with negative proteinuria, HRs of all-cause mortality were 1.26 (95% CI 1.10–1.44) for eGFR < 45 ml/min/1.73 m² without proteinuria, 1.95 (1.78–2.14) for eGFR ≥45 ml/min/1.73 m² with proteinuria, and 2.63 (2.14–3.23) for eGFR < 45 ml/min/1.73 m² with proteinuria. The all-cause mortality risk of eGFR and/or proteinuria was much higher in females than in males (P for interaction < 0.01). In conclusion, both severely decreased eGFR and proteinuria are independent predictors of all-cause mortality in the general northern Chinese population. A combination of severely decreased eGFR and proteinuria increases the risk of all-cause mortality, which is even over 5-fold higher in females.

Testis tissue from immature mammalian donor animals, grafted ectopically to immunodeficient mouse hosts, can undergo complete spermatogenesis with the production of fertilization‐competent spermatozoa. To further characterize testis tissue xenografts as a model for testis function in situ, the objective of this study was to compare gene expression between porcine testis tissue xenografts and testis tissue in situ. Pieces of testis tissue from 1‐week‐old piglets were grafted onto immunodeficient male mice and a littermate piglet was raised for comparison as control. Complete spermatogenesis was present in the testis tissue xenografts at 8 months after transplantation into mouse hosts and in the 8‐month‐old control porcine testis tissue. Total RNA was isolated from xenografts and control tissue, and the RNA was labeled and hybridized to the porcine genome array. By analyzing the expression of 23,256 transcripts, we found that 71 genes were differentially expressed with at least a fourfold difference between xenografts and control tissue. Interestingly, none of the 56 transcripts present on the array that were annotated in porcine testis showed differential expression between xenografts and control testis. This analysis indicates that global gene expression in porcine testis xenografts appears comparable to testis tissue in situ. These findings support the hypothesis that testis tissue xenografts can provide a representative model to study mammalian spermatogenesis. Mol. Reprod. Dev. 74: 674–679, 2007.