'm getting ready for tutoring again this summer. I want to do more math this year with the kindergartner. I'm excited to use Smoothy Bumper Planet to work on number concepts. I also want to use Brain Toys with all three of the kids to work on comprehension and writing. I think I'll use The Whole Brain Writing Game with both the boys this summer as well.
All of these resources and materials are free for download at the WBT website!
Wow - great Idea - I have been thinking of doing some tutoring myself - it is great to hear how well these programs have been working for you!!!﻿using System;
using System.Collections.Generic;
using System.Text;

namespace _01_ListVsIEnumerable.RealWorld
{
	class Program
	{
		public static void Main(string name, Action<string> output)
		{
			var match = LogicFunctions.FindByName(name);

			if (match.Count == 1)
				output("person (" + name + ") found exactly once!");
			else
				output("person not found.");
		}
	}
}
© Litinsky et al.; Licensee Bentham Open.
Statins (3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors) exert favorable effects on lipoprotein metabolism, but appeared to possess anti-inflammatory properties among others, as suggested by their ability to inhibit collagen-induced arthritis in mice. Their activity in fibroblast-like synovial cells (FLS) has not yet been studied.
To evaluate the effect of varying doses of simvastatin on apoptosis of FLS.
Synovial tissue, obtained during total knee replacement due to osteoarthritis, was cut into small pieces and cultured in Petri dishes with test materials, as previously described. FLS were incubated for 48 hours with 1 μmol/ml, 5 μmol/ ml, 15 μmol/ml and 50 μmol/ml of simvastatin. Following incubation, apoptosis was analyzed by two-dimensional flow cytometry (FACS) using annexin V/PI staining according to the manufacturer’s instructions.
Different concentrations of simvastatin induced apoptosis of FLS. The level proportion of apoptotic cells of resting or activated with lipopolysaccharide (LPS; 3 μg/ml) FLS, not treated with simvastatin, was 21%. At 48 hours, the rate of apoptosis of activated fibroblasts, incubated with 1 μmol/ml, 5 μmol/ml, 15 and 50 μmol/ml was 22%, 32%, 48% and 41% respectively. Synovial cell viability evaluated by tetrazolium salt XXT was unaffected by the simvastatin concentration used.
Varying concentrations of simvastatin induce apoptosis of activated fibroblast-like synoviocytes, suggesting another possible mechanism of anti-inflammatory effects of statins in inflammatory conditions.
Keywords: Apoptosis, inflammation, simvastatin, fibroblast-like synoviocytes..
Statins are potent inhibitors of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the cholesterol synthetic pathway, and they are widely used to treat hyperlipidemia. The beneficial effects of statins have been attributed primarily to their ability to inhibit cholesterol synthesis. They block the conversion of HMG-CoA to mevalonate at the start of the cholesterol biosynthetic pathway with a subsequent increase in LDL-receptor expression on the hepatocyte, resulting in a further reduction of plasma LDL-cholesterol level.
Although statins are considered to be the most effective drugs for treating hypercholesterolemia, the reduction in cardiovascular events observed in patients treated with statins is not fully explained by the reduction in LDL-cholesterol: this has been in part attributed to the ability of statins to modulate several mechanisms involved in the inflammatory process. Better survival of heart transplant patients treated with statins has been attributed to their immunomodulatory effects  and reports of improvement of Rheumatoid Arthritis (RA) patients  lend support to the clinical anti-inflammatory role of statins.
Inflammatory processes are involved in atherosclerosis [3, 6]. A number of studies suggest that in addition to their lipid-lowering activity, statins may influence atherosclerosis and cardiovascular diseases through the down regulation of the inflammatory response. Statins has been shown to reduce plasma levels of TNF-alpha, sP selectin and IL-6 in long term survivors of heart transplantation and in patients with cholesterolemia, without known cardiovascular disease [8, 9].
Some in vitro experiments and studies in animal models have also found that these agents may down regulate inflammatory responses such as the production of pro-inflammatory cytokines, chemokines and adhesion molecules; these agents may also reduce the expression of inducible major histocompatibility complex (MHC) class II molecules by antigen presenting cells.
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial proliferation and abnormal immune responses, eventually causing erosion of the affected joint. Marked infiltration of lymphocytes, macrophages, and plasma cells is observed in the synovial tissue of RA. Apoptosis of macrophages and fibroblast-like synoviocytes has been observed in rheumatoid synovium [12, 13]. It has been suggested that reduced apoptosis contributes to the synovial inflammatory process. In vitro statins were shown to exert a cytotoxic effect on human T, B and myeloma cells by promoting their apoptosis  and also modifying apoptosis of smooth muscle and endothelial cells leading to altered vascular function and neovascularisation.
We studied the effects of different doses of simvastatin on apoptosis of fibroblast–like synoviocytes (FLS).
Synovial tissue was obtained during surgery from 3 patients undergoing total knee replacement because of osteoarthritis (OA). Synovial cells derived from small pieces (~ 2mm diameter) of human synovial tissue was first grown in T 15 culture flasks, by methods described by Castor et al.. Then the cells identified as fibroblasts by the method of Castor  originating from the tissue samples were inoculated in T-15 culture flasks and incubated at 37ºC. Cell were grown as monolayers in 6 or 7 day growth (between on trypsinization and another), then trypsinized and replated until there were enough cells for an experiment to be performed. the culture medium consisted of RPMI 1640 supplemented by L-glutamine (2 mM) (Sigma, Israel), penicillin (100 U/ml), and streptomycin sulphate (100 U/ml) and 10% fetal calf serum (FCS, Bet-Haemek, Israel). Experiments were performed in 96 well plates containing 15-20×105 cells/well in a serum free medium for 48 hours at 370C (in 5% CO2).
The LPS and simvastatin treatments were carried out with isolated cells in tissue culture cells and were incubated for 48 hours, using different concentrations of simvastatin: 1, 5, 15 and 50 μmol/ml. Stimulation of the cell culture (FLS) with lipopolysaccharide (LPS) was performed as previously described. After collection of the cells, the incubation period of the cells with simvastatin lasted 48 hours.
The clinical research was conducted in accordance with guidelines for human experimentation specified by the Tel Aviv Sourasky Medical Center. The study was approved by the Ethics Committee of the Medical Center.
After 48 hours incubation in varying concentrations of simvastatin, fibroblast-like synovial cells were detached and placed in a serum free medium for 48 hours. Apoptosis was analyzed by two-dimensional flow cytometry, using annexin V and propidium iodide according to the manufacturer’s instructions (Biotest). Flow cytometry was then performed using a Becton Dickinson FACSort flow cytometer (Becton Dickinson, San Jose, CA, USA). Events accumulating at the top and bottom right-hand quadrates simulated apoptotic cells.
Cell viability in the presence of statins was determined in human synovial cultures by tetrazolium salt XTT assay at the end of the experiment.
XTT is a tetrazolium derivative that measures cell viability based on the activity of mitochondria enzymes in live cells that reduce XTT and are inactivated shortly after cell death. XTT is readily reduced to a highly water-soluble orange colored. The amount of water-soluble product generated from XTT is proportional to the number of living cells in the sample and can be quantified by measuring absorbance at wavelength of 475 nm.
Statistical analysis was evaluated by analysis of variance and by Student's t test. P values of less than 0.05 were considered statistically significant. Individual experiments were performed in triplicates. Results represent the findings from several separate experiments.
Simvastatin induced apoptosis of human fibroblasts in a dose dependent manner. The proportion of apoptotic cells of resting or activated human fibroblasts lipopolysaccharide (LPS; 3μg/ml) not treated with simvastatin was 21% (Fig. 1). At 48 hours, the proportion of apoptosis of fibroblasts activated by LPS and incubated with 1, 5, 15 and 50 μmol/ml was 22%, 32%, 48% and 41% respectively (Fig. 2).
The level of apoptosis of human fibroblasts, resting or activated with LPS in the absence of simvastatin. The level of apoptosis is among 19% to 21%.
The level of apoptosis of resting or activated with lipopolysaccaride (LPS; 3µg/ml) human fibroblasts in the medium of synovial culture tissue not treated with simvastatin. Apoptosis was analyzed by two-dimensional flow cytometry using annexin V and propidium iodide according to the manufacturer’s instructions (Biotest). Events accumulating at the top and bottom right-hand quadrates simulate apoptotic cells.
The levels of apoptosis of human fibroblasts activated by LPS, treated with different doses of simvastatin. A dose dependent apoptosis of FLS