TGF-β1 Promotes Lymphangiogenesis during Peritoneal Fibrosis

Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-β1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-β1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-β type I receptor (TGFβR-I) inhibitor. TGF-β1–induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFβR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-β–VEGF-C pathway.The decrease in ultrafiltration capacity that is associated with the high peritoneal solute transport that is observed after prolonged peritoneal dialysis (PD) treatment is a major reason for its discontinuation.^1–4 Several studies have shown that a higher peritoneal solute transport rate is associated with reduced survival of PD patients.^1,2,5 The characteristic features of chronic peritoneal damage in PD treatment are associated with submesothelial fibrosis and neoangiogenesis.^6,7 Analyses of the surface peritoneum showed no significant changes in vessel density with duration of PD.^6,8 In addition, the vessel density in patients with ultrafiltration failure (UFF) was significantly higher than the vessel density in normal individuals or non-PD patients, but it was not higher than the vessel density in patients undergoing PD.⁶ These findings suggest that factors other than increased vascular density may be involved in disease states associated with increased transport of peritoneal membranes. In addition, the relationship between peritoneal fibrosis and UFF remains obscure.Blood capillaries have a continuous basal lamina with tight interendothelial junctions and are supported by pericytes and smooth muscle cells. In contrast, lymphatic capillaries are thin-walled with a wide lumen and do not contain pericytes or basement membrane. The structures of lymphatic vessels are suitable for the removal of tissue fluid, cells, and macromolecules from the interstitium.^9–11 If lymphangiogenesis develops in the peritoneal membrane, absorption of the PD fluid could be increased and lead to UFF. An increase in the number of lymphatic vessels has recently been reported in several disease conditions, including tumor metastasis,^12–15 chronic respiratory inflammatory diseases,^16–18 wound healing,¹⁹ and renal transplant rejection.^20,21 We recently reported that lymphangiogenesis had developed in tubulointerstitial fibrosis of human renal biopsy specimens,²² and we also reported the mechanisms of lymphangiogenesis in rat unilateral ureteral obstruction models.²³The lymphatic absorption rate, which is measured by the rate at which intraperitoneally administered radioactive serum albumin or macromolecule dextran 70 disappears, is significantly higher in patients with UFF, and lymphatic reabsorption is considered to be one of the causes of UFF.^24–27 However, the results from these clinical approaches have been controversial.^28,29 In addition, little is known about the pathology and the process of lymphangiogenesis in patients with UFF and peritonitis.In this study, we investigated lymphangiogenesis and the expression of vascular endothelial growth factor-C (VEGF-C), which is a potentially important mediator of lymphangiogenesis, in human peritoneal tissues, PD effluent, and peritoneal mesothelial cells. We also explored VEGF-C induction by TGF-β1 in the human mesothelial cell line (Met-5A) and cultured human peritoneal mesothelial cells (HPMCs) from the spent PD effluent of patients with varying rates of peritoneal transport. Finally, we explored the relationship between peritoneal fibrosis and lymphangiogenesis in rats that were administered chlorhexidine gluconate (CG) into the abdominal cavity, which provides a model of chemically induced peritoneal inflammation/fibrosis.^30–32 This work is the first report to show that lymphangiogenesis is linked to the peritoneal fibrosis that is often associated with a high peritoneal transport rate.     

Efficacy of endotracheal lidocaine administration with continuous infusion of remifentanil for attenuating tube-induced coughing during emergence from total intravenous anesthesia

Purpose

Although attenuation of tube-induced coughing is necessary in specific types of surgery, the best method for such attenuation is still unclear. We studied the combined intervention of endotracheal lidocaine and intravenous remifentanil compared to intravenous remifentanil alone with respect to coughing during emergence from anesthesia.

Methods

We examined 60 ASA 1–2 patients (age, 20–69 years) undergoing tympanoplasty under general anesthesia. Anesthesia was induced with propofol, remifentanil, and rocuronium. The trachea was intubated using a laryngotracheal instillation of topical anaesthetic (LITA) tracheal tube. Anesthesia was maintained with propofol and remifentanil (0.1–0.3 μg/kg/min). Propofol was discontinued and remifentanil (0.1 μg/kg/min) was continued at the end of the operation. Patients were randomly allocated to the lidocaine (n = 30) and control groups (n = 30). We administered 3 ml 4 % lidocaine via the LITA tube to patients in lidocaine group at the end of the operation. The trachea was extubated when the patient regained consciousness and followed orders. Coughing was evaluated using a 4-point scale by an observer who examined the video records at extubation.

Results

Fewer patients in lidocaine group (8 of 30) than in control group (18 of 30, p < 0.01) coughed. Fewer patients in lidocaine group (2 of 30) than in control group (12 of 30, p < 0.01) had moderate or severe cough (scale 2 or 3).

Conclusions

This study is consistent with the finding that endotracheal lidocaine administration and continuous infusion of remifentanil before extubation is useful to prevent coughing on emergence from anesthesia.     

A nationwide analysis of renal and patient outcomes for adults with lupus nephritis in Japan

Clinical and Experimental Nephrology - The prognosis of lupus nephritis (LN) has improved following the introduction of effective immunosuppressive therapy and progress in supportive care. This...     

Chronic Hyponatremia Causes Neurologic and Psychologic Impairments

Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancer may also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3–CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality.     

Dehydropropylpantothenamide isolated by a co-culture of Nocardia tenerifensis IFM 10554T in the presence of animal cells

Journal of Natural Medicines - A new amide, named dehydropropylpantothenamide (1), was obtained by a co-culture of Nocardia tenerifensis IFM 10554T in the presence of the mouse macrophage-like cell...     

Recovery of genomic DNA from lingual mucosal cells in sufficient quantity and quality

PURPOSE: To investigate whether genomic DNA can be purified in sufficient quantity and quality from the oral cavity. METHODS: One milliliter of peripheral blood and saliva were collected. The buccal and lingual mucosal cells were also obtained using 10 strokes with a swab or a toothbrush, respectively. All materials were centrifuged and the cells were lysed by adding sodium dodecyl-sulfate and proteinase K. The DNAs were extracted with phenol and precipitated with ethanol followed by electrophoresing on 0.8% agarose gel. The purified DNAs were digested with restriction enzyme Dpn I and Mbo I, respectively. Amplification of the IL-1A gene by PCR was carried out using the purified DNAs and electrophoresing on polyacrylamide gel. RESULTS: DNA was obtained from lingual mucosal cells collected with a toothbrush. Only about one-thirtieth of the recovered DNA was of non-human origin (bacterial contaminants from the oral cavity). Judging from the PCR amplifications of the IL-1A gene, the DNA extracted from lingual cells was of sufficient quality, in all respects indistinguishable from the DNAs extracted from the other specimen, such as peripheral blood, saliva and buccal mucosal cells collected with a swab, and in sufficient quantity. Our results indicate that it is possible to purify DNAs from lingual mucosal cells collected with a toothbrush in a simple and safe manner. Compared to DNA samples from patients by blood extraction, the described method also had the advantage of being painless and not inducing mental distress.     

Cytochemical analysis of storage materials in cultured skin fibroblasts from patients with I-cell disease

BACKGROUND: In cultured fibroblasts from I-cell disease patients the transport of many lysosomal enzymes is defective, and affected cells contain inclusion bodies filled with undegraded substrates. However, the contents of these inclusion bodies have not been well characterized yet. We attempted to identify accumulated substances in cultured I-cell disease fibroblasts cytochemically. METHODS: Cultured fibroblasts from I-cell disease patients were double-stained with a monoclonal antibody to lysosome-associated membrane protein-1 (LAMP-1) and that to GM2 ganglioside, or a series of lectins that specifically bind to sugar moieties. RESULTS: The patients' cells were granularly stained with the antibody to GM2 ganglioside and the lectins including Maakia amurensis, Datura stramonium, and concanavalin A. Their localization was coincident with that of LAMP-1. CONCLUSIONS: GM2 ganglioside and various kinds of glycoconjugates having sialic acidalpha2-3galactose, galactosebeta1-4N-acetylglucosamine and mannose residues accumulate in enlarged lysosomes in I-cell disease fibroblasts.     

Successful perioperative infection control measures after gastroenterological surgery reduced the number of cases of methicillin-resistant Staphylococcus aureus or Clostridioides (Clostridium) difficile infection to almost zero over a 30-year period: a single-department experience

To investigate changes in the incidence of postoperative infections in the surgical department of a teaching hospital. During the 30-year period from September 1987 to August 2017, 11,568 gastroenterological surgical procedures were performed in our surgical department. This 30-year period was divided into seven periods (A–G), ranging from 2 to 7 years each and based on the infection control methods used in each period. We then compared the rates of incisional surgical site infection (SSI) and organ/space SSI; remote infection (RI) including respiratory tract infection (RTI), intravascular catheter-related infection, and urinary tract infection (UTI); and antibiotic-associated colitis caused by methicillin-resistant Staphylococcus aureus (MRSA) enteritis or Clostridioides (Clostridium) difficile-associated disease (CDAD) among the seven periods. In periods B (September 1990–August 1997) and E (November 2004–July 2007), when a unique antibiotic therapy devised in our department was in use, MRSA was isolated from only 0.3% and 0.4% of surgical patients, respectively, and these rates were significantly lower than those in the other periods (p < 0.05). The rate of CDAD increased during period F (August 2007–July 2014), but in period G (August 2014–August 2017), restrictions were placed on the use of antibiotics with a strong anti-anaerobic action and, in this period, the rate of CDAD was only 0.04%, which was significantly lower than that in period F (p < 0.05). Limiting the use of antibiotics that tend to disrupt the intestinal flora may reduce the rates of MRSA infection and CDAD after gastroenterological surgery.