Biomedical subjects
Publications and source records attributed to C R Johnson.
[structure: see text]. A new class of 3-hetero-13,14-dihydro prostaglandin F(1)(alpha) analogues was synthesized from a common intermediate. The latter was constructed via a two-step, three-component process. The lower chain, containing the 15-(phenoxymethyl) group, was synthesized in enantiopure form using Jacobsen's (salen)Co-catalyzed kinetic resolution of a terminal epoxide with phenol.
This open pilot study of vagus nerve stimulation (VNS) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD(28) measure, 34.0% for the Montgomery-Asberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p =.0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.
Attentional processes in individuals with high-functioning autism were compared with a matched control group. Participants for the study were 103 children and adults with autism and 103 control subjects. Measures administered corresponded to Mirsky et al.'s (1991) factor analysis of tests of attention. Diminished performance was noted on measures that loaded on the Focus-Execute and Shift factors, but not on the Sustain and Encode factors. For tests in which psychomotor speed was used as the score, and the difference between groups was significant, covariance analyses were performed, using tests of basic motor functions as covariates. This procedure led to attenuation to the point of nonsignificant differences in the case of some of the attention tests. Thus, this comprehensive analysis of attention in individuals with high-functioning autism only found differences on measures in which the task placed demands on cognitive flexibility or psychomotor speed. Thus, purported attention deficits in autism may actually be primary deficits in complex decision making or psychomotor abilities.
Two-component regulatory systems are important regulators of virulence genes in a number of bacteria. Genes encoding a two-component regulator system, with homology to the phoP/phoQ system in salmonella, were identified in the meningococcal genome. Allele replacement was used to generate a meningococcal knock-out mutant of the regulator component of this system, and its phenotype was examined. The mutant displayed many differences in protein profiles compared with wild type, consistent with it being a gene-regulatory mutation. Many of the growth characteristics of the mutant were similar to those of phoP mutants of salmonella: it was unable to grow at low concentrations of magnesium and was sensitive to defensins and other environmental stresses. Magnesium-regulated differences in protein expression were abrogated in the mutant, indicating that the meningococcal PhoP/PhoQ system may, as in salmonella, respond to changes in environmental magnesium levels. These results are consistent with the PhoP homologue playing a similar role in the meningococcus to PhoP in salmonella and suggest that it may similarly be involved in the regulation of virulence genes in response to environmental stimuli in the meningococcus. In support of this conclusion, we found the mutant grew was unable to grow in mouse serum and was attenuated in its ability to traverse through a layer of human epithelial cells. Identification of those genes regulated by the meningococcal PhoP may provide a route towards the identification of virulence genes in the meningococcus.
To evaluate the response of three tropical forage species to varying rates of nitrogen (N) fertilization [0, 39, 78, 118, 157 kg of N/(ha x cutting)] and five summer harvests, forage DM mass and nutritive value were evaluated in a randomized complete block design with a split-split plot arrangement of treatments. Plots (n = 60) were established in 1996, and five harvests were conducted every 28 d from June through September in 1997 and 1998, with fertilizer applications occuring after each harvest. Fertilization with 78 kg of N/(ha x cutting) increased forage mass in these grasses by 129% (P < 0.01) compared with no N fertilization. Additional N did not result in further increases of forage mass. Bermudagrass (Cynodon dactylon) produced more forage DM [P < 0.01; 1,536 +/- 43 kg/(ha x cutting)] than stargrass [Cynodon nlemfuensis; 1,403 +/- 43 kg/(ha x cutting)] or bahiagrass [Paspalum notatum; 1,297 +/- 43 kg/(ha x cutting)]. Peak forage mass for all species occurred in late June and July. In vitro organic matter digestibility (IVOMD) of stargrass increased (P < 0.01) linearly with fertilization. A quadratic response to N fertilization (P < 0.01) was noted in IVOMD of bermudagrass, whereas bahiagrass was not affected. Bermudagrass was more (P < 0.01) digestible (57.5 +/- 0.4) than stargrass (54.6 +/- 0.4) and bahiagrass (51.9 +/- 0.4%). As fertilization level increased, NDF decreased linearly (P < 0.01) in all three forages. Total N concentration increased (P < 0.01) linearly as N fertilization increased in all forages. Total N concentration was highest (P < 0.01) in stargrass (2.4%, DM basis) compared with bermudagrass (2.2%) and bahiagrass (2.0%). Total N concentration was depressed in all forages for late June and July harvests (P < 0.01). Fertilization increased (P < 0.05) the concentration (% of DM) of all protein fractions. In July and August, nonprotein N was reduced 11.8% (P < 0.01), whereas ADIN increased in July (P < 0.01). Bahiagrass had less N in cell contents than did bermudagrass and stargrass but had a greater concentration of N associated with the cell wall. Managerial factors, including rates of N fertilization and harvest dates, can have profound effects on the nutritional value of forage. An increased understanding of these effects is imperative to improve supplementation programs for ruminants.
Poliovirus infection of COS-1 and T47D cells caused a rapid decrease in total cell respiration, and this was attributed to an inhibition of mitochondrial respiration. The stimulation of mitochondrial respiration by pyruvate plus malate or succinate was impaired in saponin-permeabilised cells. However, this inhibition could be overcome by the addition of N,N,N',N'-tetramethyl-1, 4-phenylenediamine and ascorbate. The activity of succinate dehydrogenase was impaired in parallel with the inhibition of mitochondrial respiration during poliovirus infection. This shows that mitochondrial function is profoundly altered during poliovirus infection and that this occurs primarily through inhibition of electron flow at complex II of the mitochondrial respiratory chain.
[formula: see text] (R and S)-alpha-Amino alcohols and alpha-amino acids, including 4-methoxyhomophenylalanine, with a variety of unnatural side chains have been synthesized via palladium-catalyzed cross-coupling Suzuki reactions. The key building blocks 1 and 2, synthesized from the common achiral precursor 2-butene-1,4-diol, were made enantiopure utilizing a Pseudomonas cepacia lipase-catalyzed kinetic resolution. The optimal conditions for the Suzuki cross-coupling and the subsequent oxidations of the resultant alpha-amino alcohols are described.
OBJECTIVE: To determine clinical and radiographic findings, treatment, and outcome for llamas with long-bone fractures. DESIGN: Retrospective study. ANIMALS: 6 llamas. PROCEDURE: Medical records of llamas admitted between 1993 and 1998 because of long-bone fractures were reviewed. Data collected included age, sex, type of fracture, method of fracture repair, and postoperative complications. The Fisher exact test was used to compare age and sex of the llamas with long-bone fractures with those of the hospital population of llamas. All owners were contacted by telephone to determine perceived postoperative problems and whether the llamas were able to perform as expected. RESULTS: Mean age was 160.8 days (range, 23 to 365 days). There was 1 male and 5 females. Fractures were more likely to occur in young llamas (< or = 1 year old) than in adults. Five of the fractures were attributed to traumatic episodes. Long bones affected included the tibia (n = 2), radius (2), femur (1), and humerus (1). Internal fixation with lag screws, plating, or both was performed on fractures of all llamas except 1; that llama was treated by use of confinement to a stall. None of the llamas had intraoperative complications, but postoperative complications were reported in 2 llamas. All fractures healed eventually, and clients were pleased with outcomes. CONCLUSIONS AND CLINICAL RELEVANCE: Long-bone fractures in llamas are uncommon. Several types of long bone fractures can be successfully repaired by use of internal fixation, resulting in few complications and minimal convalescent time.
Thirteen children (ages 5.6 to 11.2 years) with autism and symptoms of attention-deficit hyperactivity disorder (ADHD) participated in a double-blind, placebo-controlled crossover study of methylphenidate (0.3 and 0.6 mg/kg per dose). Eight subjects responded positively, based upon a minimum 50% decrease on the Conners Hyperactivity Index. Ratings of stereotypy and inappropriate speech, which are often associated with autistic core features, also decreased. However, no changes were found on the Child Autism Rating Scale, a global assessment of autistic symptomotology. Significant adverse side effects occurred in some children including social withdrawal and irritability, especially at the 0.6 mg/kg dose. Results suggest that methylphenidate can be efficacious for children with autism and ADHD symptoms. However, this group of children seems to be particularly susceptible to adverse side effects.
Increasingly, progress in the radiotherapy of carcinomas of the head and neck is being driven by principles of radiobiology. This article discusses some of the major advances in head and neck radiotherapy, including altered fractionation, concomitant chemotherapy, and intensity-modulated radiotherapy, in the context of radiobiologic rationale, potential impact on tumor control, and normal tissue complications.
Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.
Phenanthrene mineralization rates were found to vary widely among four soils; differences in soil nutrient levels was one hypothesis to explain this variation. To test this hypothesis, phenanthrene mineralization rates were measured in these soils with, and without, added nitrogen and phosphorus. Mineralization rates either remained unchanged or were depressed by the addition of nitrogen and phosphorus. Phenanthrene degradation rates remained unchanged in the soil which had the highest indigenous levels of nitrogen and phosphorus and which showed the largest increase in phosphorus levels after nutrients were added. The soils in which degradation rates were depressed had lower initial phosphorus concentrations and showed much smaller or no measurable increase in phosphorus levels after nutrients were added to the soils. To understand the response of phenanthrene degradation rates to added nitrogen and phosphorus, it may be necessary to consider the bioavailability of added nutrients and nutrient induced changes in microbial metabolism and ecology.
"As a consequence of diminished exercise tolerance, a large and increasing number of elderly people will be living below, at, or just above 'thresholds' of physical ability, needing only minor intercurrent illness to render them completely dependent" (Astrand, 1992, p. 1231S). The NP can play a crucial role in educating motivating, and encouraging geriatric clients to continue or initiate a fitness program. The exercise program that is prescribed by NPs for their patients "depends on their needs, goals, physical and health status, personal preference, and available time, equipment, and facilities" (Pollack et al., 1994, p. 588). Fitness is a goal for all geriatric patients, that they might remain healthy and physically fit longer, and therefore continue to lead active, fulfilling lives.
We recently demonstrated that physiological induction of apoptosis by cytotoxic sphingolipid messengers proceeds via activating protein-1 (AP1)-dependent and AP1-independent mechanisms in U937 human monoblastic leukemia cells. Here we examine involvement of the stress-activated protein kinase (SAPK) cascade and AP1 in the initiation of apoptosis in U937 cells by podophyllotoxin-derived inhibitors of topoisomerase II. Induction of apoptotic cell death and DNA damage by treatment of U937 cells with etoposide (100 microM) was associated with phosphorylation and activation of the c-Jun NH(2)-terminal kinase (JNK1) SAPK enzymes p46 and p54-JNK2 and transient increases in expression of the transcription factor c-Jun, a primary JNK substrate. These responses were accompanied by a modest, but sustained, recruitment of the mitogen-activated protein kinases p42-extracellular signal receptor-activated kinase (ERK)1 and p44-extracellular signal receptor-activated kinase 2. The capacity of etoposide to promote double-stranded DNA degradation and cell death was unaffected by manipulations that interfere with SAPK signaling outflow through c-Jun/AP1, including: 1) pharmacological inhibition of AP1 activity by diferuloylmethane and 2) molecular ablation of normal c-Jun function by the Jun dominant-negative mutant TAM-67. Cytotoxicity of the structurally related compound teniposide was similarly unaffected. In parallel trials, the lethal actions of ceramide (but not of sphingosine) were markedly diminished by pretreatment with diferuloylmethane or expression of TAM-67, confirming the effectiveness of these interventions in suppression of SAPK/AP1-dependent apoptosis. The involvement of AP1 in the proapoptotic actions of other inhibitors of topoisomerase II activity was also evaluated. Induction of cell death by the anthracyclines daunorubicin, daunorubicin, and idarubicin was found to be insensitive to pretreatment with diferuloylmethane or expression of TAM-67. Collectively, the present data indicate that induction of apoptosis by etoposide and related inhibitors of topoisomerase II is mediated through a cell death pathway that does not require SAPK-dependent recruitment of AP1. These findings additionally suggest that activation of the SAPK represents a consequence, rather than an underlying cause, of etoposide-induced apoptosis in myeloid leukemia cells.
A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were found to be nonsteroidal antiinflammatory and analgesic agents. These compounds are inhibitors of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) with selectivity for the COX-2 isoform. A series of analogues were prepared to investigate the scope of this lead. Five ketone side chains from active DHDMBFs were used to investigate the effects of changes in the DHDMBF "core": the size and identity of the heterocycle and the substituent requirements of the heterocycle and phenyl ring. Biological testing showed that a variety of structural changes can be accommodated, but no structure was clearly superior to the DHDMBF structure.
Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion.
Although traditional recommendations for the management of bulky cervical lymphadenopathy (AJCC categories N2-3) with definitive radiotherapy call for postradiotherapy neck dissection regardless of treatment response, recent data suggests that this policy can be modified on the basis of tumor regression rate. In a series of 130 patients with stage III-IV squamous cell carcinoma of the head and neck managed with a concomitant boost-accelerated hyperfractionated radiotherapy schedule, 81 cases had cervical lymphadenopathy at the time of referral. Patients were analyzed with respect to regional control outcomes for those having complete and incomplete clinical responses during the initial 3-month follow-up interval. The general management policy has been close observation of patients demonstrating complete clinical responses to radiation rather than postradiotherapy neck dissection. Failure patterns were examined in the 58 patients classified as complete responders. Failure occurred in the primary site in 16 (28%) of these patients, while isolated neck failure occurred in only 3 (5%). Neck recurrence rates for patients with maximum lymph node size < or = 3 cm vs. > 3 cm were not statistically different at 3-year follow-up (94% vs. 86%). Among the 23 incomplete clinical responders, 18 had incomplete neck responses. Five of these patients underwent salvage neck dissection; 4 remain clinically free of recurrence. The remaining 13 patients who either refused or were not eligible for salvage surgery ultimately succumbed with persistent loco-regional disease. The policy of observation after complete response to the radiotherapy schedule employed here was associated with a very low incidence of isolated neck failures and was safe and appropriate in patients who can be followed reliably. The prognosis for patients who failed to respond in the neck was poor except for those who underwent salvage surgery.
A newly synthesized cyclic hydroxamic acid compound, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was found to induce the apoptotic death of cultured prostate cancer cells by activating caspase-3. Orally administered BMD188 significantly inhibited the primary growth of prostate cancer cells (Du145) orthotopically implanted into SCID mice. Mechanistic studies indicated that BMD188 did not alter the protein levels of several Bcl-2 family members. In contrast, the BMD188 effect required three essential factors: reactive oxygen species (ROS), the mitochondrial respiratory chain function, and proteases. First, the apoptosis-inducing effect of BMD188 could be blocked by ROS scavengers such as Desferal. Second, both BMD188-induced PARP cleavage as well as PC3 cell apoptosis could be dramatically inhibited by several complex-specific mitochondrial respiration blockers. The involvement of mitochondria was also supported by the observations that BMD188 dramatically altered the mitochondrial distribution and morphology without affecting the cellular ATP levels. Finally, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors (TPCK and TLCK) as well as by caspase inhibitors (zVAD-fmk and DEVD-CHO). Collectively, the present study suggests that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.