EFFECT OF SOME IMMUNOMODULATORY DRUGS ON EMBRYONIC DEVELOPMENT OF DANIO RERIO FISH.

At the current stage of healthcare development, the inclusion of immunomodulators in the complex pharmacotherapy of various immunoinflammatory and viral diseases is widely discussed, but due to the lack of sufficient research and a broad evidence base, not all drugs with similar properties are used in medicine. According to the information obtained from the instructions for the use of immunomodulators, it was obtained that the main contraindications to their use include the prescription of children, pregnant women, and women during breastfeeding. In this study, we evaluated the effects of immunomodulatory drugs: aminodihydrophthalazindione sodium and meglumine acridonacetate, on the early developmental stages of Danio rerio (Zebrafish) embryos.

Describing motivation for health and treatment decisions and communication choices of calf-care workers on western United States dairies.

On large dairy farms, animal health assessments and treatments are made by farm employees. Little is known about how employees make decisions about illness detection or treatment, information critical to improving antimicrobial stewardship. The objectives of this study were to describe calf-care employee motivations for decisions associated with preweaned calf health and treatments, describe on-farm worker communication networks, and determine information sources used by these employees to support their decisions. Personal interviews were conducted with 103 calf-care employees on 28 farms in the western United States. The interview consisted of 10 motivation source type (MST) questions and questions about training, communication and educational opportunities. A latent class analysis created a summary for MST and resulted in 4 classes. Forty-three percent of calf-care employees fell into a class where responses were a combination of internal and intrinsic (personal beliefs or values and task fulfillment, respectively) and 23% were a combination of internal and goal internal (aligned with organizational goals). This latter class aligned health decisions with internal motivation and treatment decisions with goal internal. A network analysis summarized dominant communication relationships and established that feeders and treaters perceived more communication with supervisors than was reciprocated by supervisors, and that there was less communication between workers and management for tasks relative to daily work. Employee training was primarily done by herdsman, calf manager, or coworkers, and information for skill improvement and problem solving was sought from these individuals. Although veterinarians were not often involved in employee training, when they were involved, employees were likely to use them as an information source for skill improvement and problem solving. Few participants had ever used social media, but almost all had a device that could access the internet; more than 60% indicated interest in a social media platform for work-related information. Work motivation for many calf caretakers appeared to be sourced from personal beliefs, values, and job fulfillment, particularly when deciding to treat a sick calf. Investigation and incorporation of beliefs and values in training programs could help with alignment of protocols with actual treatment and further efforts to implement judicious use of antimicrobials.

Calf care personnel on dairy farms and their educational opportunities.

As dairy herd sizes become larger and the organization of the business more complex, targeting communication and education to enhance animal care becomes more difficult. The purpose of this study was to describe selected demographics of calf care employees on large (>500 animals) and small (<501 animals) dairy farms that raise their own calves. Two to 8 individuals per farm involved with calf care, including owners, veterinarians, and calf managers, feeders, and treaters, were interviewed in either English or Spanish. Interviews were conducted in person on 53 dairy farms located in Arizona, Idaho, New York, Oregon, and Washington State. The number of preweaned calves on the farm ranged from 9 to 1,500 (median = 93). A total of 224 individuals were interviewed across 8 job titles. As farm size increased, personnel structure became more complex. Farms with >100 preweaned calves were 15 times more likely to have a calf manager title compared with farms with ≤100 preweaned calves. Eight farms designated the same person as calf manager, treater, and feeder, all with ≤100 preweaned calves. Thirty-two (60%) of the farms had at least 1 full-time calf feeder. Almost 30% of owners and over 40% of veterinarians interviewed were over 50 yr of age, whereas over 40% of the calf managers, feeders, and treaters were under 30 yr of age. Seventy-three percent of feeders and 72% of treaters spoke Spanish at home. For languages in which interviewees were comfortable speaking, more than 30% of owners and 33% of veterinarians were comfortable communicating in Spanish. For calf care employees, 60% of calf managers, 42% of feeders, and 38% of treaters were bilingual (English and Spanish), but most (72%) preferred to be interviewed in Spanish. The level of education varied by job title for those interviewed, but most of the calf care team had high school or less education. However, some diversity was observed in educational background within job title with almost 38% of the calf managers having at least some college education. The majority of feeders (88%) and treaters (83%) reported being trained by another employee and 66 and 58%, respectively, had not received any continuing education in the previous year. With the amount of diversity seen on these farms, understanding employees' educational backgrounds, language, and generational differences may be valuable when developing training for new procedures for animal health or other aspects of animal care.

Biochemical pathways of apoptosis: nicotinamide adenine dinucleotide-deficient cells are resistant to tumor necrosis factor or ultraviolet light activation of the 24-kD apoptotic protease and DNA fragmentation.

The function of nicotinamide adenine dinucleotide (NAD) and adenosine diphosphate (ADP) ribosylation reactions in the mechanism of apoptotic cell death is controversial, although one theory postulates an essential role for NAD depletion by poly-ADP-ribose polymerase. The present study examined the role of intracellular NAD in tumor necrosis factor (TNF) and ultraviolet (UV) light-induced activation of the 24-kD apoptotic protease (AP24) leading to internucleosomal DNA fragmentation and death. Our results demonstrate that nutritional depletion of NAD to undetectable levels in two leukemia lines (U937 and HL-60) renders them completely resistant to apoptosis. This was attributed to a block in the activation of AP24 and subsequent DNA cleavage. Normal cells show an elevation of ADP-ribosyl transferase (ADPRT) in both the cytosol and nucleus after exposure to TNF, but before DNA fragmentation. ADPRT activity as well as cell death was suppressed by an inhibitor specific for mono-ADPRT. Nuclei from NAD-depleted cells were still sensitive to DNA fragmentation induced by exogenous AP24, indicating a selective function for NAD upstream of AP24 activation in the apoptotic pathway. We confirmed a requirement for intracellular NAD, activation of ADPRT, and subsequent NAD depletion during apoptosis in KG1a, YAC-1, and BW1547 leukemia cell lines. However, this mechanism is not universal, since BJAB and Jurkat leukemia cells underwent apoptosis normally, even in the absence of detectable intracellular NAD. We conclude that TNF or UV light-induced apoptotic cell death is not due to NAD depletion in some leukemia cell lines. Rather, NAD-dependent reactions which may involve mono-ADPRT, function in signal transduction leading to activation of AP24, with subsequent DNA fragmentation and cell death.

Purification of a 24-kD protease from apoptotic tumor cells that activates DNA fragmentation.

We report the purification of a protease from tumor cells undergoing apoptosis that is involved in activating DNA fragmentation. Initial studies revealed that two inhibitors of serine proteases, N-1-tosylamide-2-phenylethylchloromethyl ketone and carbobenzoxy-Ala-Ala-borophe (DK120), suppressed tumor necrosis factor or ultraviolet (UV) light-induced DNA fragmentation in the U937 histiocytic lymphoma as well as UV light-induced DNA fragmentation in the BT-20 breast carcinoma, HL-60 myelocytic leukemia, and 3T3 fibroblasts. The protease was purified by affinity chromatography with DK120 as ligand and showed high activity on a synthetic substrate preferred by elastase-like enzymes (Ala-Ala-Pro-Val p-nitroanilide), but was inactive on the trypsin substrate, N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester, or the chymotrypsin substrate, Ala-Ala-Pro-Phe p-nitroanilide. The activity of the DK120-binding protease purified from U937 cells undergoing apoptosis was increased approximately 10-fold over that recovered from normal cells. Further purification to homogeneity by heparin-Sepharose affinity chromatography followed by reverse phase high-performance liquid chromatography revealed a single band of 24 kD on a silver-stained sodium dodecyl sulfate gel. In addition to protease activity, the purified enzyme induced DNA fragmentation into multiples of 180 basepairs in isolated U937 nuclei. These findings suggest the 24-kD protease is a novel enzyme that activates DNA fragmentation in U937 cells undergoing apoptosis.

Activation of CPP32-like proteases is not sufficient to trigger apoptosis: inhibition of apoptosis by agents that suppress activation of AP24, but not CPP32-like activity.

The 24-kD apoptotic protease (AP24) is a serine protease that is activated during apoptosis and has the capacity to activate internucleosomal DNA fragmentation in isolated nuclei. This study examined the following: (a) the functional relationship between AP24 and the CPP32-like proteases of the caspase family; and (b) whether activation of CPP32-like proteases is sufficient to commit irreversibly a cell to apoptotic death. In three different leukemia cell lines, we showed that agents that directly (carbobenzoxy-Ala-Ala-borophe (DK120) or indirectly inhibit activation of AP24 (protein kinase inhibitors, basic fibroblast growth factor, tosylphenylalaninechloromethylketone, and caspase inhibitors) protected cells from apoptosis induced by TNF or UV light. Only the caspase inhibitors, however, prevented activation of CPP32-like activity as revealed by cleavage of the synthetic substrate, DEVD-pNa, by cell cytosols, and also by in vivo cleavage of poly (ADP-ribosyl) polymerase, a known substrate of CPP32. Activation of DEVD-pNa cleaving activity without apoptosis was also demonstrated in two variants derived from the U937 monocytic leukemia in the absence of exogenous inhibitors. Cell-permeable peptide inhibitors selective for CPP32-like proteases suppressed AP24 activation and apoptotic death. These findings indicate that CPP32-like activity is one of several upstream signals required for AP24 activation. Furthermore, activation of CPP32-like proteases alone is not sufficient to commit irreversibly a cell to apoptotic death under conditions where activation of AP24 is inhibited.

Heart transplantation in the United States, 1999-2008.

This article features 1999-2008 trends in heart transplantation, as seen in data from the Organ Procurement and Transplantation Network (OPTN) and the Scientific Registry of Transplant Recipients (SRTR). Despite a 32% decline in actively listed candidates over the decade, there was a 20% increase from 2007 to 2008. There continues to be an increase in listed candidates diagnosed with congenital heart disease or retransplantation. The proportion of patients listed as Status 1A and 1B continues to increase, with a decrease in Status 2 listings. Waiting list mortality decreased from 2000 through 2007, but increased 18% from 2007 to 2008; despite the increase in waiting list death rates in 2008, waiting list mortality for Status 1A and Status 1B continues to decrease. Recipient numbers have varied by 10% over the past decade, with an increased proportion of transplants performed in infants and patients above 65 years of age. Despite the increase in Status 1A and Status 1B recipients at transplant, posttransplant survival has continued to improve. With the rise in infant candidates for transplantation and their high waiting list mortality, better means of supporting infants in need of transplant and allocation of organs to infant candidates is clearly needed.

Bcl-2-mediated resistance to apoptosis is associated with glutathione-induced inhibition of AP24 activation of nuclear DNA fragmentation.

Studies on the mechanism of apoptosis in this laboratory support a model in which signal transduction involving caspase 3 leads to activation of a serine protease called Mr 24,000 apoptotic protease (AP24), which then induces internucleosomal DNA fragmentation in the nucleus. This study examined the effect of Bcl-2 overexpression on activation of AP24 and the induction of DNA fragmentation by AP24 in isolated nuclei. It was demonstrated that overexpression of Bcl-2 in either HL-60 or PW leukemia cell lines suppressed activation of AP24 induced by either tumor necrosis factor or UV light and protected cells from apoptosis. Furthermore, nuclei isolated from Bcl-2-overexpressing cells were relatively resistant to internucleosomal DNA fragmentation induced by AP24 isolated from apoptotic cells. Bcl-2-overexpressing cells that were nutritionally depleted of glutathione (GSH) became sensitive to tumor necrosis factor- or UV light-induced activation of AP24 and underwent apoptotic cell death. Moreover, nuclei isolated from Bcl-2-overexpressing cells that were depleted of GSH became sensitive to AP24-induced DNA fragmentation. The addition of exogenous GSH blocked the proteolytic activity of AP24, as well as its ability to induce DNA fragmentation in normal isolated nuclei. These results indicate that Bcl-2 can attenuate at least two events in the AP24 apoptotic pathway: activation of AP24 and induction of DNA fragmentation by activated AP24. Furthermore, agents that deplete intracellular levels of GSH may have therapeutic use in the sensitization of Bcl-2-overexpressing cancer cells to apoptotic cell death.

Isotope or mass encoding of combinatorial libraries.

BACKGROUND: Combinatorial chemistry using solid-phase synthesis is a rapidly developing technology that can result in a significant reduction in the time required to find and optimize lead compounds. The application of this approach to traditional medicinal chemistry has led to the construction of libraries of small organic molecules on resin beads. A major difficulty in developing large combinatorial libraries is the lack of a facile encoding and decoding methodology to identify active compounds. RESULTS: Several encoding schemes are described which use the ability of mass spectrometry to ascertain isotopic distributions. Molecular tags are attached to resin beads in parallel or on the linker used for chemical library synthesis. The tags are encoded via a controlled ratio of a number of stable isotopes on the tagging molecules, and range from a single to a complex isotopic distribution. CONCLUSIONS: A novel coding scheme is described that is useful for the generation of large encoded combinatorial libraries. The code can be cleaved after assay and analyzed by mass spectrometry in an automated fashion. An important element of the combinatorial discovery process is the ability to extract the structure-activity relationship (SAR) information made available by library screening. The speed and sensitivity of the mass-encoding scheme has the potential to determine the full SAR for a given library.

Acylamino boronic acids and difluoroborane analogues of amino acids: potent inhibitors of chymotrypsin and elastase.

A series of 1-acylamino boronic acids (IA-VA), analogues of the amino acids phenylalanine, phenylglycine, alanine, valine, and isoleucine, were prepared as potential transition-state inhibitors of the serine proteases alpha-chymotrypsin and elastase, by a boronate homologation reaction. The corresponding difluoroboranes (IB-VB), produced from the boronic acids by treatment with HF, were more easily purified than the boronic acids. Since the difluoroboranes readily hydrolyze in water, they proved to be convenient precursors for the boronic acids. The phenylalanine and phenylglycine analogues I and II were good competitive inhibitors of alpha-chymotrypsin (Ki = 0.3-8 microM), and the alanine, valine, and isoleucine analogues (III-IV) proved to be good inhibitors of elastase (Ki = 0.1-35 microM). On the basis of their high affinity and the tendency of boronic acids to form borate complexes, these acylamino boronic acids may be behaving as transition-state inhibitors.

Analogues of carbamyl aspartate as inhibitors of dihydroorotase: preparation of boronic acid transition-state analogues and a zinc chelator carbamylhomocysteine.

Dihydroorotase (DHO) catalyzes the conversion of carbamyl aspartate (CA) to dihydroorotate (DO) in the de novo pyrimidine biosynthetic pathway. Few effective inhibitors of DHO have been reported, and thus blockade of this reaction has not been widely pursued as a strategy for development of antitumor agents. Utilizing two mechanism-based strategies, we have designed and prepared potential DHO inhibitor analogues of CA. One strategy replaced the gamma-carboxyl moiety of CA with a boronic acid. This substitution yields compounds which form stable charged tetrahedral intermediates and mimic the enzyme-substrate transition state. Preparation of the boronic acid analogues of CA and its carboxylic acid esters focused on a Curtius rearrangement as a key step following a malonic ester synthesis. This was followed by carbamoylation of the free amine under nonaqueous neutral conditions with Si(NCO)4. The ethyl ester was a competitive inhibitor of DHO with an apparent Ki of 5.07 microM, while the nonesterified analogue and the methyl ester were not effective inhibitors. None of the compounds were cytotoxic against L1210 cells in culture. An active-site-directed sulfhydryl-containing zinc chelator was also prepared. This analogue irreversibly inhibited the enzyme, but it also was ineffective in L1210 growth inhibition.

Chemically reactive estrogens: synthesis and estrogen receptor interactions of hexestrol ether derivatives and 4-substituted deoxyhexestrol derivatives bearing alkylating functions.

A series of chemically reactive derivatives of the nonsteroidal estrogen hexestrol have been synthesized as potential affinity labels for the estrogen receptor or as cytotoxic agents with selective activity against receptor-containing cells. These compounds are hexestrol ethers with halo ketone, halohydrin, or epoxide functions or 4-substituted deoxyhexestrols with halo ketone, benzyl halide, nitro, azide, sulfonyl fluoride, or sulfonyl azide groups. The alkylating activity of the electrophilic derivatives was measured using the colorimetric reagent nitrobenzylpyridine, the bromo derivatives being considerably more reactive than the chloro ones. Their reversible binding to the lamb uterine estrogen receptor was measured by competitive binding assays, and their irreversible reaction with receptor was measured by exchange assays that determine the rate and extent of receptor inactivation. In general, monoetherification of hexestrol or substitution of deoxyhexestrol produces compounds with relatively low affinity for the estrogen receptor (0.3-10% that of estradiol). Most of the electrophilic derivatives are rapid and effective inactivators of receptor (24-70% inactivation within 0.5-5 h at 25 degrees C). Of the photosensitive derivatives, 4-azidodeoxyhexestrol appears to be the most efficient receptor inactivator (49%). The high reactivity of these compounds toward the estrogen receptor and the lack of interference by their reaction with other cellular nucleophiles suggest that these compounds may be useful as affinity-labeling agents or as selective cytotoxic agents in intact systems.

Pediatric submersions: prehospital predictors of outcome.

This retrospective cohort study was conducted to test prehospital prognostic indicators in pediatric submersion victims. The authors studied all less than 20 years old victims submerged in the non-icy waters of King County, WA who were treated by Seattle or King County Emergency Medical Services between 1985 and 1989 and were hospitalized or died. Seventy-seven victims were identified from emergency medical services incident logs, hospital discharge records, and medical examiner's registries. Outcome predictors were correlated with the victim's condition at hospital discharge. Of 29 victims in cardiac arrest, 13 had return of spontaneous circulation following field resuscitation. Of these, 6 (21%) survived, with mild (n = 2) and severe (n = 4) neurologic impairment at hospital discharge. The best outcome predictors were obtained in the field. These were, for death or severe neurologic impairment, submersion durations > 10 minutes (6/6) and resuscitation durations > 25 minutes (17/17), and for good outcome, sinus rhythm (37/37), reactive pupils (43/43), and neurologic responsiveness (40/40) at the scene. Field-determined factors were reproducibly good outcome predictors. Aggressive emergency medical services may save the lives of pediatric victims in cardiac arrest following short submersion durations. The data support pronouncing dead in the field those pediatric victims of non-icy submersions who do not respond to advanced life support within 25 minutes.

Solid-phase synthesis of hydroxyethylamine angiotensin analogues.

Three hydroxyethylamine analogues of angiotensins II, III, and IV were prepared by solid-phase methods. The resin-bound peptide was alkylated with the iodomethylketone derivative of the N-terminal amino acid, followed by reduction to the alcohol using sodium borohydride. The iodomethylketones can be made in good yields from commercially available N-protected amino acids. The compounds were evaluated for their ability to displace labeled angiotensins from bovine adrenal membranes, and their metabolic stability tested in kidney homogenates and aminopeptidase M preparations. The hydroxyethylamine amide bond replacement reduced the affinity of the analogues; however, they were substantially more stable to enzymatic degradation.

Preclinical pharmacologic studies of the new antitumor agent carmethizole (NSC-602668) in the mouse and beagle dog.

The chemical breakdown of carmethizole [1-methyl-2-methylthio-4,5-bis-(hydroxymethyl)imidazole-4',5'- bis(N-methylcarbamate)hydrochloride] and its pharmacokinetics in the mouse and beagle dog were studied. Carmethizole was relatively unstable in aqueous media, having a half-life of less than or equal to 1 h in 0.9% sodium chloride, human whole blood, human plasma, and dog urine at 37 degrees C. Its major breakdown product in 0.9% sodium chloride and pH 5.0 sodium phosphate buffer was carmethizole diol. When carmethizole was added to pH 7.0 or pH 9.0 sodium phosphate buffer, the major breakdown product was carmethizole diol-4'-monophosphate. Carmethizole reacted directly with glutathione at pH 8.0, forming a glutathione adduct of carmethizole monocarbamate. Elimination of the drug from the plasma of the beagle dog following i.v. bolus doses of 22.4 and 4.3 mg/kg was biphasic. At these doses the terminal half-life was 39 and 46 min, respectively, and the respective total body clearance was 4.6 and 7.7 ml/min per kg. The 22.4 mg/kg dose was lethal to the beagle dog by day 4. Elimination of carmethizole from the plasma of mice following an i.v. bolus dose of 115 mg/kg was monoexponential, with a half-life of 11.6 min and a total body plasma clearance of 43.6 ml/min per kg. When the drug was infused at 230 mg/kg over 8 h into mice, the total body clearance was 40.8 ml/min per kg. Following the i.v. bolus administration of carmethizole to mice, 30% of the total dose was excreted in urine over 3 h as carmethizole diol, 10%, as carmethizole diol-sulfate, 3.4%, as carmethizole 4'-monocarbamate, and 2.4%, as unchanged drug.

Vascularized muscle fibers: etiopathogenesis and clinical significance.

Contrary to common assumption, internal vascularization of muscle fiber occurs independent of muscle fiber splitting. Review of 1091 cases who underwent muscle biopsies demonstrated muscle fibers with internal blood vessels in a wide variety of chronic neuromuscular disease states, predominantly in patients with chronic neurogenic diseases. Many of these cases show evidence of internal disorganization or focal degeneration of muscle fibers, in particular, formation of targets, targetoids or similar structural alterations. Internal vascularization of muscle fiber probably occurs as a "healing" or "reparative process" in such fibers. Myopathic features, especially secondary myopathic changes (as seen in chronic denervation-reinnervation) are common and appear to be a necessary accompaniment of this phenomena. The vascularized muscle fiber is more likely to be seen in a distal lower extremity muscle than in a proximal limb muscle biopsy.

Urokinase plasminogen activator is elevated in human astrocytic gliomas relative to normal adjacent brain.

We assayed urokinase plasminogen activator (uPA), tissue type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) in 43 human brain tumors (predominantly astrocytic gliomas) and in histologically disease-free brain tissue resected with 21 of the tumors. Levels of uPA, tPA, and PAI-1, measured by enzyme-linked immunosorbent assay, varied widely among individuals in neoplastic and in normal tissue but did not correlate with age or sex. Pairwise comparison of neoplastic and normal tissue from 21 individuals revealed that mean tumor uPA level was elevated 6-fold (P < 0.001). Mean tumor tPA and PAI-1 were 2.5-fold greater than those of normal brain, but these differences were not statistically significant. Tumor uPA was elevated 2- to 30-fold in 16/21 paired samples (76%). In contrast, tumor tPA was elevated 2- to 22-fold in 7/21 (33%) of pairs, whereas tumor PAI-1 was 2- to 13-fold greater in 10/21 (48%) of pairs. Our results demonstrate that elevation of uPA content is frequent in astroglial tumors, as is the case in other major human cancers.

Haloacetate-induced oxidative damage to DNA in the liver of male B6C3F1 mice.

Brominated and chlorinated haloacetates (HAs) are by-products of drinking water disinfection. Dichloroacetate (DCA) and trichloroacetate (TCA) are hepatocarcinogenic in rodents, but the brominated analogs have received little study. Prior work has indicated that acute doses of the brominated derivatives are more potent inducers of oxidative stress and increase the 8-hydroxydeoxyguanosine (8-OH-dG) content of the nuclear DNA in the liver. Since, DCA and TCA are also known as weak peroxisome proliferators, the present study was intended to determine whether this activity might be exacerbated by peroxisomal proliferation. Classical responses to peroxisome proliferators, cyanide-insensitive acyl-CoA oxidase activity and increased 12-hydroxylation of lauric acid, were elevated in a dose-related manner in mice maintained on TCA and clofibric acid (positive control), but not with DCA, dibromoacetate (DBA) or bromochloroacetate (BCA). Administration of the HAs in drinking water to male B6C3F1 mice for periods from 3 to 10 weeks resulted in dose-related increases in 8-OH-dG in nuclear DNA of the liver with DBA and BCA, but not with TCA or DCA. These findings indicate that oxidative damage induced by the haloacetates is, at least in part, independent of peroxisome proliferation. In addition, these data suggest that oxidative damage to DNA may play a more important role in the chronic toxicology of brominated compared to the chlorinated haloacetates.

The search for a unified social studies curriculum: does history really repeat itself?

A bulwark of democracy is an informed electorate. Recently, disturbing evidence has been presented indicating that young Americans lack the knowledge of democratic principles and history required by our democracy. One explanation for this complex problem concerns the nature of the social studies instruction that our children are receiving. In this article, common practices in social studies instruction are described and critiqued, and an alternative, more conceptually based model of history instruction that is of potential benefit to students with learning disabilities is proposed.

History strategy instruction: problem-solution-effect analysis, timeline, and vocabulary instruction.

This multiple baseline study investigated the effectiveness of history strategy instruction emphasizing the linkage of knowledge in teaching junior high students with behavior disorders. The intervention included 24 students and 3 teachers across three classes for 3-6 weeks. The strategy included a scripted curriculum involving brisk student-teacher interchanges; student note taking and constructing of timelines and vocabulary definitions; and reciprocal questioning, using a carefully selected history textbook. Results indicate that the history strategy was effective; students in each class showed immediate and educationally significant improvement compared with baseline instruction that employed traditional history instruction.