Transport of molecules across tumor vasculature

The vascular-extravascular exchange of fluid and solute molecules in a tissue is determined by three transport parameters (vascular permeability, P, hydraulic conductivity, L_p, and reflection coefficient, ); the surface area for exchange, A; and the transluminal concentration and pressure gradients. The transport parameters and the exchange area for a given molecule are governed by the structure of the vessel wall. In general, tumor vessels have wide interendothelial junctions; large number of fenestrae and transendothelial channels formed by vesicles; and discontinuous or absent basement membrane. While these factors favor movement of molecules across tumor vessels, high interstitial pressure and low microvascular pressure may retard extravasation of molecules and cells, especially in large tumors. These characteristics of the transvascular transport have significant implications in tumor growth, metastasis, detection and treatment.     

p-Dimethoxy-substituted trans-octahydrobenzo[f]- and -[g]quinolines: synthesis and assessment of dopaminergic agonist effects

The N-n-propyl homologues of the title compounds were prepared for further assessment of the ability of the "p-dimethoxy" moiety to confer dopaminergic agonism upon a variety of ring systems. Both the angularly and the linearly annulated trans-benzoquinoline ring derivatives displayed prominent DA2 dopaminergic effects on the peripheral sympathetic nerve terminal and displayed postjunctional dopamine receptor agonist properties in the striatum. It is speculated that the angular octahydrobenzo[f]quinoline derivative (but not the linear octahydrobenzo[g]quinoline derivative) may owe its dopamine-like effects to metabolic activation phenomena. In contrast, the cis-fused isomer of the angularly annulated benzoquinoline was inactive, as was the simple benzene derivative N,N-di-n-propyl-beta-(2,6-dimethoxyphenyl)ethylamine.     

Anticancer Mechanism of Curcumin on Human Glioblastoma

Glioblastoma (GBM) is the most malignant brain tumor and accounts for most adult brain tumors. Current available treatment options for GBM are multimodal, which include surgical resection, radiation, and chemotherapy. Despite the significant advances in diagnostic and therapeutic approaches, GBM remains largely resistant to treatment, with a poor median survival rate between 12 and 18 months. With increasing drug resistance, the introduction of phytochemicals into current GBM treatment has become a potential strategy to combat GBM. Phytochemicals possess multifarious bioactivities with multitarget sites and comparatively marginal toxicity. Among them, curcumin is the most studied compound described as a potential anticancer agent due to its multi-targeted signaling/molecular pathways properties. Curcumin possesses the ability to modulate the core pathways involved in GBM cell proliferation, apoptosis, cell cycle arrest, autophagy, paraptosis, oxidative stress, and tumor cell motility. This review discusses curcumin’s anticancer mechanism through modulation of Rb, p53, MAPK, P13K/Akt, JAK/STAT, Shh, and NF-κB pathways, which are commonly involved and dysregulated in preclinical and clinical GBM models. In addition, limitation issues such as bioavailability, pharmacokinetics perspectives strategies, and clinical trials were discussed.     

Gastric polyposis caused by multiple carcinoids and early carcinoma.

A case of gastric polyposis caused by multiple carcinoids with concurrent gastric carcinoma is reported in a 70 year old woman with severe atrophic gastritis and intestinal metaplasia. On microscopic examination, the carcinoids and gastric carcinoma arose separately thus representing "double primaries". Long-standing hypergastrinaemia probably plays a causative role in the development of carcinoma and carcinoids. Carcinoid tumours, although of low malignant potential, may be important as indicators of other unrelated high risk malignancies. Patients with carcinoids should be followed closely, especially as the incidence of these tumours seems to be on the increase.     

Nutritional correlates of acute respiratory infections

During October 1992 to June 1993 in eight villages covered by the Primary Health Center Machhra in Meerut District, India, interviews with mothers and examinations of 1600 children aged less than 5 years (under-fives) were conducted to examine the relationship between acute respiratory infection (ARI) and malnutrition. 42.25% of all children had an ARI within the last 15 days. Most ARIs (73.4%) were considered mild (cough and cold with no pneumonia). Pneumonia accounted for 19.5% of all ARI cases, which were considered moderate. The remaining ARI cases were severe (severe and very severe pneumonia). 57.5% of all children suffered from protein energy malnutrition (PEM). 78.6% of children aged 12-14 months had PEM. ARI was more common among malnourished children than well-nourished children (52.2% vs. 28.8%; p 0.001). The incidence of ARI increased as the nutritional status deteriorated (p 0.05). It also increased as the midarm circumference decreased (p 0.001). These findings confirm the synergistic action between malnutrition and infection, in this case ARI. Malnourished children suffer considerable impairment in immunity, especially cellular immunity, which makes them more prone to ARI. These findings reinforce the need to strengthen the quality, quantity, and accessibility of nutritional services, particularly promotion of breast feeding and vitamin A supplementation.     

Bile-duct diameter at the porta hepatis and liver biopsies in Indian children with biliary atresia

Fibrous remnants from the porta hepatis and wedge biopsies of the liver were studied in 60 patients with biliary atresia. The patients were divided into three groups on the basis of bile duct diameter — I: no ducts; II: <50 m; III: >50 m. The liver damage was classified into three grades on the basis of ductular and parenchymal histopathologic changes and extent of inflammatory pathology. There was no correlation between severity of hepatic damage and duct diameter, although the levels of serum bilirubin and alkaline phosphatase varied in direct proportion to the degree of hepatic damage. There was an inverse relationship between age and duct diameter, but neither correlated with bile flow at surgery or in the postoperative period. The data suggest that Indian children with biliary atresia follow a different clinical course compared to those from Japan and Western countries. Correspondence to: V. Bhatnagar     

Sperm Quality Improvement in Cryopreserved Human Semen

Purpose

We determined if separation of spermatozoa (washed) on a discontinuous colloidal suspension of silica (Percoll^†) density gradient before cryopreservation improves post-thaw motility compared to an unprocessed (raw) cryopreserved sample.

Materials and Methods

Ten normal healthy volunteers recruited into the andrology laboratory donor program were studied. Raw and washed cryopreserved spermatozoa were compared for loss of motility with time, motion characteristics, viability and membrane integrity after incubation for 1, 6 and 24 hours. Within group comparisons were made to baseline measurements (0 hours before incubation).

Results

Raw and washed cryopreserved spermatozoa showed statistically significant decreases in motility and other motion characteristics after thawing. There were significant decreases in motility and other motion characteristics after incubation periods of 1, 6 and 24 hours, and significant decreases in viability and membrane integrity at 6 and 24 hours in the unprocessed spermatozoa. Although, motility and motion characteristics of washed samples decreased significantly with longer incubation periods, loss of motility with time (longevity) was greater in raw samples. Washed samples retained greater sperm motility for up to 24 hours (p less than 0.03).

Conclusions

Specimens prepared by Percoll separation techniques before freezing offer the possibility of selecting spermatozoa that retain motility for up to 24 hours. This finding can be of benefit for couples undergoing intrauterine insemination to achieve pregnancy.     

Pharmacokinetics of methotrexate in leukemia cells: Effect of dose and mode of injection

A lumped compartmental model has been derived to predict methotrexate concentration as a function of time for L1210 cells in BD2F ₁ female mice at doses ranging from 3 mg/kg to 400 mg/kg. Using standard methods of parameter estimation as well as experimental determinations, an integrated approach was derived to account for the differences between the subcutaneous (s.c.) and intraperitoneal (i.p.) modes of injection. It was found that a single generalized forcing function can be used to fit plasma concentration after s.c. injection for all doses. Adequate fits (average error<20% while the standard deviation of experimental determinations was±22%) of L1210 cell data after s.c. injection were obtained. The best results were for a maximum facilitated influx constant V_max of 0.424 g/min/ml, a Michaelis influx constant K_m of 1,42 g/ml, and a first-order efflux constant of 0.047 min^–1.The model simulations were not sensitive to V_max, K_m,and so long as the ratio V_max/was approximately 9g/ml. The values of V _max ,K _m ,and which were obtained from our analysis of the in vivodata can be explained on the basis of previously performed in vitroexperiments. The parameters obtained from modeling the s.c. data were then applied for i.p. injection data. The resulting fits were adequate (average error<20% while the standard deviation of experimental determinations was±22%). A single generalized forcing function for drug concentration in the peritoneal cavity after i.p. injection for all doses was derived. The application of these results enables the prediction of methotrexate concentration in neoplastic cells at other doses after either s.c. or i.p. injection.