High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations

Type 1 citrullinemia (CTLN1) often presents as a hyperammonemic encephalopathy in the neonatal period, but it can also develop in the late-infantile period and in adults. In addition, some patients can be identified in the presymptomatic period by neonatal or family member screening. In this study, twenty Korean patients with CTLN1 (19 families) were examined; fourteen patients with neonatal-onset, three with late-onset, and three that were identified presymptomatically. The 13 patients with hyperammonemic encephalopathy received continuous venovenous hemofiltration (CVVH) or peritoneal dialysis (PD). Although the hyperammonemia was relieved more effectively in the six patients on CVVH than the seven on PD, most of these patients suffered from severe neurologic deficits. Recurrent hyperammonemic episodes (7 pts, 35%), recurrent and reversible acute hepatic dysfunction (5 pts, 25%), and focal cerebral infarction (2 pts, 10%) were noted. The neonates with hyperammonemic encephalopathy had extensive brain injuries at the onset of hyperammonemia, followed by encephalomalacia and brain atrophy at quite an early age. Genetic testing for the ASS1 gene revealed a different mutation spectrum from those of other ethnicities; Three common mutations, c.421-2A > G (37.8%), c.1128-6_1188dup67 (18.9%), and p.Gly324Ser (16.2%), accounted for 73% of the mutations. The poor outcome was expected in patients with the peak ammonia level at onset over 600 μmol/L, whose proportion was higher in the neonatal presentation group than in the presymptomatic/late presentation group. Our findings add to the current understanding of the ethnic diversity of CTLN1 from both clinical and genetic perspectives.     

Effect of combined mulberry leaf and fruit extract on liver and skin cholesterol transporters in high fat diet-induced obese mice

Obesity is an epidemic disease characterized by an increased inflammatory state and chronic oxidative stress with high levels of pro-inflammatory cytokines and lipid peroxidation. Moreover, obesity alters cholesterol metabolism with increases in low-density lipoprotein (LDL) cholesterols and triglycerides and decreases in high-density lipoprotein (HDL) cholesterols. It has been shown that mulberry leaf and fruit ameliorated hyperglycemic and hyperlipidemic conditions in obese and diabetic subjects. We hypothesized that supplementation with mulberry leaf combined with mulberry fruit (MLFE) ameliorate cholesterol transfer proteins accompanied by reduction of oxidative stress in the high fat diet induced obesity. Mice were fed control diet (CON) or high fat diet (HF) for 9 weeks. After obesity was induced, the mice were administered either the HF or the HF with combination of equal amount of mulberry leaf and fruit extract (MLFE) at 500mg/kg/day by gavage for 12 weeks. MLFE treatment ameliorated HF induced oxidative stress demonstrated by 4-hydroxynonenal (4-HNE) and modulated the expression of 2 key proteins involved in cholesterol transfer such as scavenger receptor class B type 1 (SR-B1) and ATP-binding cassette transporter A1 (ABCA1) in the HF treated animals. This effect was mainly noted in liver tissue rather than in cutaneous tissue. Collectively, this study demonstrated that MLFE treatment has beneficial effects on the modulation of high fat diet-induced oxidative stress and on the regulation of cholesterol transporters. These results suggest that MLFE might be a beneficial substance for conventional therapies to treat obesity and its complications.     

Effect of Hominis Placenta on cutaneous wound healing in normal and diabetic mice

BACKGROUND/OBJECTIVES

The number of diabetic patients has recently shown a rapid increase, and delayed wound healing is a major clinical complication in diabetes. In this study, the wound healing effect of Hominis placenta (HP) treatment was investigated in normal and streptozotocin-induced diabetic mice.

MATERIALS/METHODS

Four full thickness wounds were created using a 4 mm biopsy punch on the dorsum. HP was injected subcutaneously at the middle region of the upper and lower wounds. Wounds were digitally photographed and wound size was measured every other day until the 14th day. Wound closure rate was analyzed using CANVAS 7SE software. Wound tissues were collected on days 2, 6, and 14 after wounding for H/E, immunohistochemistry for FGF2, and Masson''s trichrome staining for collagen study.

RESULTS

Significantly faster wound closure rates were observed in the HP treated group than in normal and diabetes control mice on days 6 and 8. Treatment with HP resulted in reduced localization of inflammatory cells in wounded skin at day 6 in normal mice and at day 14 in diabetic mice (P < 0.01). Expression of fibroblast growth factor (FGF) 2 showed a significant increase in the HP treated group on day 14 in both normal (P < 0.01) and diabetic mice (P < 0.05). In addition, HP treated groups showed a thicker collagen layer than no treatment groups, which was remarkable on the last day, day 14, in both normal and diabetic mice.

CONCLUSIONS

Taken together, HP treatment has a beneficial effect on acceleration of cutaneous wound healing via regulation of the entire wound healing process, including inflammation, proliferation, and remodeling.     

Norepinephrine provides short-term neuroprotection against Aβ1–42 by reducing oxidative stress independent of Nrf2 activation

Pathophysiological evidence correlating locus ceruleus neuron loss with increased Alzheimer's disease pathology suggests that norepinephrine (NE) is neuroprotective. Here, we evaluated the effects of NE on amyloid-β (Aβ)1-42–induced neurotoxicity and determined how NE exerts its actions in human SK-N-SH neurons. NE protected SK-N-SH cells against Aβ1-42–induced neurotoxicity only after a 4-hour treatment. The ability of NE to reduce Aβ1-42–induced neurotoxicity was independent of the adrenoceptor signaling pathway. Notably, NE downregulated Aβ1-42–mediated increases in intracellular reactive oxygen species (ROS) production. However, NE did not affect Aβ1-42–induced activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) redox signaling pathway, known to be involved in oxidative stress. Among the antioxidants tested, N-acetyl cysteine and glutathione, which are not only ROS scavengers but also thiol-reducing agents, mimicked the protective effects of NE. Consistently, Kelch-like ECH-associating protein 1 inhibitors, which activated the Nrf2 pathway, failed to decrease Aβ1-42–induced ROS generation and elicited no protection against Aβ1–42. Taken together, these findings suggest that NE could exert neuroprotective function against Aβ1–42 via redox cycling and reduction of intracellular oxidative stress regardless of downstream activation of the Nrf2 pathway.     

Possible pathophysiology of ketamine‐related cystitis and associated treatment strategies

Ketamine‐related cystitis is characterized by ketamine‐induced urinary frequency and bladder pain. It has become a serious problem in recent years. The most typical grossly pathological bladder change with ketamine related cystitis is a contracted bladder and bladder wall thickening. Ulcerative cystitis with an easily bleeding mucosa is a common cystoscopic finding. Microscopically, the urothelium is denuded and is infiltrated by inflammatory cells, such as mast cells and eosinophils. The pathogenesis of ketamine‐related cystitis is complicated and involves many different pathways. Past evidence suggests a direct toxic effect, bladder barrier dysfunction, neurogenic inflammation, immunoglobulin‐E‐mediated inflammation, overexpression of carcinogenic genes, abnormal apoptosis and nitric oxide synthase‐mediated inflammation contribute to the pathogenesis of ketamine‐related cystitis. The first step to managing ketamine‐related cystitis is always asking patients to cease ketamine. Medical treatment might be helpful in patients with early ketamine‐related cystitis and abstinence from ketamine. Several case studies showed that the intravesical installation of hyaluronic acid and intravesical injection of botulinum toxin type A were effective for symptom relief in selected patients. For patients with irreversible pathological change, such as contracted bladder, augmentation enterocystoplasty might be the only solution to increase bladder capacity and relieve intractable bladder pain.     

CA 125 levels in the preoperative assessment of advanced-stage uterine cancer

OBJECTIVE: The purpose of this study was too evaluate preoperative levels of CA 125 in for the prediction of advanced uterine cancer. STUDY DESIGN: We conducted a retrospective analysis of the correlation of preoperative CA 125 with grade, depth of invasion, lymph vascular space involvement, lymph node status, and stage. RESULTS: High CA 125 levels correlated with advanced-stage (P <.0001) and positive (P <.0001) lymph node status. High levels of CA 125 also correlated with the deepest myometrial invasion, the presence of lymph vascular space involvement, and the highest grade. Receiver-operator characteristic curves demonstrated that depth of invasion, lymph vascular space involvement, and grade accurately predicted advanced-stage disease 73%, 77% and 80% of the time, respectively. CA 125 levels, however, correctly predicted advanced stage 94% of the time. The sensitivity and specificity of a CA 125 cutoff level of 37 IU/mL were 95% and 90%, respectively, with a positive predictive value of 78% and a negative predictive value of 97%. CONCLUSION: CA 125 appears to be a significant independent predictor of positive lymph node status and the extrauterine spread of disease.     

Lung vitamin E transport processes are affected by both age and environmental oxidants in mice

Despite the physiological importance of alpha-tocopherol (AT), the molecular mechanisms involved in maintaining cellular and tissue tocopherol levels remain to be fully characterized. Scavenger receptor B1 (SRB1), one of a large family of scavenger receptors, has been shown to facilitate AT transfer from HDL to peripheral tissues via apo A-1-mediated processes and to be important in the delivery of AT to the lung cells. In the present studies the effects of age and two environmental oxidants ozone (O(3)) (0.25 ppm 6 h/day) and cigarette smoke (CS) (60 mg/m(3) 6 h/day) for 4 days on selected aspects of AT transport in murine lung tissues were assessed. While AT levels were 25% higher (p<0.05) and 15% lower (p<0.05) in plasma and lung tissue, respectively, in aged versus young mice, acute environmental exposure to O(3) or CS at the doses used had no effect. Gene expression levels, determined by RT-PCR of AT transport protein (ATTP), SRB1, CD36, ATP binding cassette 3 (ABCA3) and ABCA1 and protein levels, determined by Western blots for SRB1, ATTP and ABCA1 were assessed. Aged mouse lung showed a lower levels of ATTP, ABCA3 and SRB1 and a higher level CD36 and ABCA1. Acute exposure to either O(3) or CS induced declines in ATTP and SRB1 in both aged and young mice lung. CD36 increased in both young and aged mice lung upon exposure to O(3) and CS. These findings suggest that both age and environmental oxidant exposure affect pathways related to lung AT homeostasis and do so in a way that favors declines in lung AT. However, given the approach taken, the effects cannot be traced to changes in these pathways or AT content in any specific lung associated cell type and thus highlight the need for further follow-up studies looking at specific lung associated cell types.