Hydrodynamic liver gene transfer mechanism involves transient sinusoidal blood stasis and massive hepatocyte endocytic vesicles

The present study contributes to clarify the mechanism underlying the high efficacy of hepatocyte gene transfer mediated by hydrodynamic injection. Gene transfer experiments were performed employing the hAAT gene, and the efficacy and differential identification in mouse plasma of human transgene versus mouse gene was assessed by ELISA and proteomic procedures, respectively. By applying different experimental strategies such as cumulative dose-response efficacy, hemodynamic changes reflected by venous pressures, intravital microscopy, and morphological changes established by transmission electron microscopy, we found that: (a) cumulative multiple doses of transgene by hydrodynamic injection are efficient and well tolerated, resulting in therapeutic plasma levels of hAAT; (b) hydrodynamic injection mediates a transient inversion of intrahepatic blood flow, with circulatory stasis for a few minutes mainly in pericentral vein sinusoids; (c) transmission electron microscopy shows hydrodynamic injection to promote massive megafluid endocytic vesicles among hepatocytes around the central vein but not in hepatocytes around the periportal vein. We suggest that the mechanism of hydrodynamic liver gene transfer involves transient inversion of intrahepatic flow, sinusoidal blood stasis, and massive fluid endocytic vesicles in pericentral vein hepatocytes.     

Postpartum depression among Neonatal Intensive Care Unit mothers and its relation to postpartum dietary intake: A review

Mothers with infants in the Neonatal Intensive Care Unit (NICU) are at a higher risk of postpartum depression (PPD). Risk factors of PPD include environmental factors, psychological factors and biological factors. In this review, the aim was to identify the prevalence of PPD and its associated risk factors among mothers with infants in NICU. The relationship between dietary intake in relation to traditional postpartum practices with PPD is also discussed. Findings showed that PPD among mothers with infants in NICU was prevalent, ranging between 12.1% and 68%. Factors such as preterm birth, long hospitalisation and maternal role alteration were the most associated risk factors contributing to PPD. Consumption of food based on traditional practices was found to influence maternal mental health. Therefore, a rational approach in addressing mental health issues and adhering traditional food practices is needed in order to promote a postpartum mother's safe and healthy well-being.     

Efficacy of the potentized homeopathic drug, Carcinosin 200, fed alone and in combination with another drug, Chelidonium 200, in amelioration of p-dimethylaminoazobenzene-induced hepatocarcinogenesis in mice

OBJECTIVES: This study was conducted to examine whether the potentized homeopathic remedy Carcinosin 200, fed alone and in combination with Chelidonium 200, has differential protective effects against p-dimethylaminoazobenzene (p-DAB)-induced hepatocarcinogenesis in mice. DESIGN: Liver tumors were induced in mice through chronic feeding of p-DAB (initiator) and phenobarbital (PB, promoter). The mice were divided into two subgroups: (1) one was fed potentized Alcohol 200 and served as controls; and (2) the other was fed Carcinosin 200 alone or in combination with Chelidonium 200 and divided into several sets. The relative efficacy of the two potentized remedies, alone or in combination, in combating hepatocarcinogenesis was assessed through several cytogenetical endpoints such as chromosome aberrations, induction of micronuclei, sperm head anomaly, and mitotic index at several intervals of fixation (days 7, 15, 30, 60, 90, and 120). Several toxicity biomarkers such as acid and alkaline phosphatases, glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and lipid peroxidation activity were also assayed in three organs of treated and control mice. In addition, recovery by the homeopathic drugs, if any, of tissue damage inflicted because of chronic feeding of p-DAB and PB was also assessed by optical, scanning, and transmission electron microscopies of liver done at days 60 and 120. RESULTS: Both Carcinosin 200 and Chelidonium 200 when administered alone show considerable ameliorative effect against p-DAB-induced hepatocarcinogenesis in mice; but the conjoint feeding of these two drugs appears to have had a slightly greater protective effect. CONCLUSIONS: These homeopathic remedies have the potential to be used as complementary and alternative medicine in liver cancer therapy, particularly as supporting palliative measures.     

Inhibition of carrageenin-induced pedal oedema in rats by immobilisation stress

The effect of immobilisation stress on acute pedal inflammation induced by carrageenin, and the mechanism of stress-induced anti-inflammatory effect, were investigated in male Wistar strain albino rats. Carrageenin-induced pedal inflammation oedema was attenuated by immobilisation stress in a time-dependent manner, when the rats were restrained for 30 min, 1 h, and 2 h immediately after the induction of the inflammation. Pentobarbitone exhibited significant anti-inflammatory effect of its own in an anaesthetic dose and also inhibited stress (1 h)-induced attenuation of the inflammation. Likewise, lignocaine, injected behind the knee joint of the inflamed limb, attenuated the inflammation and also inhibited the stress-induced anti-inflammatory effect. These findings indicate the importance of the central nervous system (CNS) and the afferent/efferent neural pathways from and to the inflammatory site, in inflammation and in stress-induced anti-inflammatory effect. Earlier studies from this laboratory have shown that the central noradrenergic, histaminergic, serotonergic and GABA-ergic neurotransmitter systems have a modulatory anti-inflammatory effect on carrageenin-induced pedal oedema. Since all these neurotransmitter systems have been reported to be activated by stress, their role was assessed in the inflammation-attenuation effect of immobilisation stress. The present studies indicate that, of these neurotransmitters, only the central noradrenergic system is involved in the anti-oedema effect of stress. Endogenous opioid peptides may also be involved in the stress-inflammation interaction, since naloxone inhibited the stress effect. Bilateral adrenalectomy and peripheral chemical sympathectomy, induced by i.p. administration of 6-hydroxydopamine, augmented carrageenin oedema and antagonised the stress-induced anti-inflammatory effect. However, metyrapone, an inhibitor of endogenous corticoid synthesis, failed to inhibit the stress effect. These findings indicate that the sympatho-medullary system, which is known to be activated during stress, is responsible for the observed anti-inflammatory effect of immobilisation stress, rather than augmented release of adrenal corticoids. It is suggested that the observed inflammation reducing effect of immobilisation stress is a consequence of increased central noradrenergic and peripheral sympatho-medullary activity.     

Central Lymph Node Metastasis in Gastric Cancer Is Predictive of Survival After Preoperative Therapy

Background

It is unclear how preoperative therapy for gastric cancer affects the metastasis rate of lymph nodes (LNs) and whether the location of positive LNs affects survival after preoperative therapy. Therefore, we determined the association between positive central lymph nodes (CnLNs) and disease stage and overall survival (OS).

Methods

We reviewed a prospectively maintained database to identify patients who had undergone resection of gastric adenocarcinoma at our institution from 2005 to 2015. CnLNs were defined as common hepatic, celiac, and proximal splenic artery LNs (stations no. 8, 9, and 11p). The frequency of CnLN metastases and risk factors affecting OS were examined.

Results

We identified 356 patients. Preoperative therapy was administered to 66% of patients. D2 LN dissection was performed in 80% of patients, and the median number of LNs examined was 25 (IQR, 18–34). In 243 patients (68%), CnLNs had undergone separate pathologic examination; the CnLN-positive rate was 9.1% (22 of 243; station no. 8, 4.5%; no. 9, 2.1%; and no. 11p, 4.8%). CnLN metastasis was associated with shorter 3-year OS in patients with pN2/3 disease (33 vs. 62%; p?=?0.004). Among patients who had undergone preoperative therapy, ypT3–4 stage (HR 2.44; p?=?0.01) and positive CnLNs (HR 5.44; p?<?0.001) were negatively associated with OS by multivariate analysis.

Conclusions

CnLN metastases are uncommon in gastric cancer and have an adverse effect on OS in patients who have undergone preoperative therapy. Larger multi-institutional studies are needed to determine whether CnLN positivity requires a separate staging category after preoperative therapy.

     

Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice

In vivo models have demonstrated that interleukin-13 (IL-13) plays an important role in asthma; however, few studies have evaluated the effect of inhibition of IL-13 on established and persistent disease. In the present study, we have investigated the effect of a therapeutic dosing regimen with an anti-IL-13 monoclonal antibody (mAb) in a chronic mouse model of persistent asthma. BALB/c mice were sensitized to allergen [ovalbumin (OVA); on days 1 and 8] and challenged with OVA weekly from day 22. Anti-IL-13 mAb or vehicle dosing was initiated following two OVA challenges when disease was established. At this time, mice exhibited airway hyperresponsiveness (AHR), increased mucus production, inflammation, and initiation of subepithelial fibrosis compared with saline-challenged mice. Mice received four additional OVA challenges. Treatment with anti-IL-13 mAb inhibited AHR and prevented the further development of subepithelial fibrosis and progression of inflammation. Furthermore, mAb treatment reversed the mucus hyperplasia to basal levels. These effects were associated with an inhibition of cytokines, chemokines, and matrix metalloproteinase-9. These data demonstrate that neutralization of IL-13 can inhibit the progression of established disease in the presence of repeated allergen exposures.