Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most... more
Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using...
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The American College of Sports Medicine recommends that to maintainhealth, adults should engage in 150 min of moderate/vigorous physical activity (MVPA) per week. The purpose of the current study was to investigate the lowest MVPA dose... more
The American College of Sports Medicine recommends that to maintainhealth, adults should engage in 150 min of moderate/vigorous physical activity (MVPA) per week. The purpose of the current study was to investigate the lowest MVPA dose possible to maintainfunctional fitness Functional fitness was assessed using theSenior Fitness Testin 101 women (75.0 ± 7.2 years) from two Midwestern communities. Accelerometer determined daily activity level was assessed for 7 days as participants went about their normal daily activities. MVPA was determined via proprietary filtering, and time spent in this intensity was calculated. A 5-day average of time spent in MVPA was organized into four groups. ANOVAs revealed significant differences between activity groups on all functional fitness measures except back scratch and sit and reach. Results indicate that to maintain lower body function in older women, a threshold of 20 min/day of MVPA for 5 days is needed.
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Phytoplanktons are microscopic organisms that inhabit the upper sunlit layers (the euphotic zone) of most aquatic environments. They are generally denser than water and would normally sink out of the euphotic zone. Though some species can... more
Phytoplanktons are microscopic organisms that inhabit the upper sunlit layers (the euphotic zone) of most aquatic environments. They are generally denser than water and would normally sink out of the euphotic zone. Though some species can swim or have flotation devices, most depend on the turbulence naturally present in their environment to keep them afloat for a sufficient length of
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The purpose of this study was to compare the effects of Nordic walking with conventional walking and band-based resistance exercise on functional fitness, static balance and dynamic balance in older adults. Volunteers (n = 65) were... more
The purpose of this study was to compare the effects of Nordic walking with conventional walking and band-based resistance exercise on functional fitness, static balance and dynamic balance in older adults. Volunteers (n = 65) were divided into four groups: Nordic walking (NW), conventional walking (CW), resistance (RES), and control. Each group performed activity 50-70 min·day(-1) (warm-up 10-15 min, main exercise 30-40, and cool down 10-15 min), 3 days·week(-1) (NW and CW) or 2 day·week(-1) (RES) for 12 wks. Upper-body strength improved (p < 0. 05) in the RES (22.3%) and the NW (11.6%) groups compared to the CW and control groups. Cardio- respiratory fitness improved more in the NW (10.9%) and CW (10.6%) groups compared to the RES and control groups. Upper- and lower-body flexibility also improved in all exercise groups compared to the control group. There were no improvements in balance measures in any group. While all modes of exercise improved various components of fitness, ...
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To analyze shoulder muscle activation when performing push-ups under different stability conditions and heights. Comparative study by repeated measures. Valencia University laboratory. 29 healthy males participated. Subjects performed 3... more
To analyze shoulder muscle activation when performing push-ups under different stability conditions and heights. Comparative study by repeated measures. Valencia University laboratory. 29 healthy males participated. Subjects performed 3 push-ups each with their hands at 2 different heights (10 vs. 65 cm) under stable conditions and using a suspension device. Push-up speed was controlled and the testing order was randomized. The average amplitudes of the electromyographic root mean square of the long head of the triceps brachii (TRICEP), upper trapezius (TRAPS), anterior deltoid (DELT) and clavicular pectoralis (PEC) were recorded. The electromyographic signals were normalized to the maximum voluntary isometric contraction (MVIC). Suspended push-ups at 10 cm resulted in greater activation in the TRICEP (17.14 ± 1.31 %MVIC vs. 37.03 ± 1.80 %MVIC) and TRAPS (5.83 ± 0.58 %MVIC vs. 14.69 ± 1.91 %MVIC) than those performed on the floor. For DELT and PEC similar or higher activation was found performing the push-ups on the floor, respectively. Height determines different muscle activation patterns. Stable push-ups elicit similar PEC and higher DELT muscle activation, being greater at 10 cm; whereas suspended push-ups elicit greater TRAPS and TRICEP muscle activation, being greater at 65 cm.
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Providing inner-city minorities with inexpensive exercise programs may be a means of reducing frailty and maintaining independent lifestyles in this population. To determine the efficacy of such a program, 22 African-American women aged... more
Providing inner-city minorities with inexpensive exercise programs may be a means of reducing frailty and maintaining independent lifestyles in this population. To determine the efficacy of such a program, 22 African-American women aged 62-94 years were recruited from a senior center in the Wichita urban community. Sixteen women (age = 74.8 +/- 8.8 yr) participated in exercise training (3 days per week for 4 weeks) and 6 women (age = 74.7 +/- 4.5 yr) served as controls. Training consisted of chair-based exercises using elastic resistance bands (upper and lower body) and dumbbells (upper body). Elastic band training improved (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) lower body strength (30-second chair stand, time for 5 stands) by approximately 20% and the combination of bands and dumbbell training improved upper body strength (30-second dumbbell curl) by 24%. Grip strength improved by 5%. Up-&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;-Go performance improved by 10% although balance and mobility exercises were not a fundamental element of the training program. Upper and lower body flexibility did not change. Changes were not observed for any variable in the control group. This study suggests that exercising with equipment that costs only a few dollars per participant improves upper and lower body fitness in older African-American women who live in an urban setting.
Research Interests: Health Education, Medicine, Activities of Daily Living, Humans, African American, and 15 moreFemale, African American Women, Exercise, Performance Improvement, Kansas, African Americans, Aged, Middle Aged, Geriatric Assessment, Control Group, Grip strength, Health services for the aged, Physical Endurance, Exercise training, and Paediatrics and reproductive medicine
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... Assoc. Prof. Hugh J. Cornell Ph. D. 1 ,; Dr. Albert W. Hoveling Ph. D. 2,* ,; Andrew Chryss B. Eng. 3 ,; Michael Rogers B. App. Sc. 4. ... Es gibt eine große Ungenauigkeit bei großen, in Wasser suspendierten Teilchen in Wasser und... more
... Assoc. Prof. Hugh J. Cornell Ph. D. 1 ,; Dr. Albert W. Hoveling Ph. D. 2,* ,; Andrew Chryss B. Eng. 3 ,; Michael Rogers B. App. Sc. 4. ... Es gibt eine große Ungenauigkeit bei großen, in Wasser suspendierten Teilchen in Wasser und Kleinkornstärke, die lange Absetzzeiten erfordern. ...
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Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P.... more
Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P &lt; 0.001), and death (P &lt; 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.
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The drug 566C80 is an investigational hydroxynaphthoquinone that is active against Pneumocystis carinii in vitro and in animal models. Initial studies in humans indicate that 566C80 is safe and has adequate bioavailability after oral... more
The drug 566C80 is an investigational hydroxynaphthoquinone that is active against Pneumocystis carinii in vitro and in animal models. Initial studies in humans indicate that 566C80 is safe and has adequate bioavailability after oral administration. We conducted an open-label trial of 566C80 in 34 adults with the acquired immunodeficiency syndrome (AIDS) and untreated pneumocystis pneumonia. All the patients had a partial pressure of arterial oxygen of at least 60 mm Hg while breathing room air. They were enrolled sequentially in three cohorts taking 566C80 at different dosages, all administered orally: 750 mg three times daily for 5 days, then twice daily for 16 days; 750 mg three times daily for 21 days; and 750 mg four times daily for 21 days. All 34 patients survived, and 27 (79 percent) were successfully treated with 566C80 alone. The mean partial pressure of oxygen in 33 patients was 78 mm Hg at entry and 93 mm Hg after the course of 566C80 (P less than 0.001). In five patients (15 percent) the drug was discontinued because of lack of response. In four patients (12 percent), the drug was discontinued because of toxicity (fever and rash in two patients each). In two of these, treatment was considered to have succeeded because 566C80 was not discontinued because of toxicity until after day 14. Five of the successfully treated patients had rashes that resolved despite continued therapy. In nine patients, serum alanine aminotransferase levels rose above 100 U per liter. During the first three months after the completion of therapy, pneumocystis pneumonia recurred in 4 of the 27 successfully treated patients, and another 3 patients had recurrences between month 3 and month 6 of follow-up. The mean (+/- SEM) steady-state plasma levels of 566C80 were similar in the three cohorts: 16.3 +/- 2.10, 20.4 +/- 2.48, and 18.9 +/- 3.08 micrograms per milliliter in the patients taking the drug twice daily, three times daily, and four times daily, respectively. From these preliminary data, the investigational compound 566C80 appears to be a safe, effective, and well-tolerated therapy for P. carinii pneumonia of mild-to-moderate severity in patients with AIDS.
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Mutations in distinct sites of epidermal keratins, in particular in the helix initiation and termination regions, cause human genodermatoses due to faulty intermediate filament formation. Extension of this observation to human hereditary... more
Mutations in distinct sites of epidermal keratins, in particular in the helix initiation and termination regions, cause human genodermatoses due to faulty intermediate filament formation. Extension of this observation to human hereditary hair and nail diseases includes population analyses of human hair keratin genes for natural sequence variations in the corresponding sites. Here we report on a large-scale genotyping of the short helix termination region (HTR) of the human type I cortical hair keratins hHa1, a3-I, and a3-II, and the cuticular hair keratin hHa2. We describe two polymorphic loci, P1 and P2, exclusively in the cuticular hHa2 gene, both creating dimorphic protein variants. P1 is due to a C to T mutation in a CpG element leading to a threonine to methionine substitution; P2 concerns a serine codon AGT that also occurs as an asparagine coding variant AAC. A third polymorphism, P3, is linked with a C to T point mutation located at the very beginning of intron 6. The three polymorphic sites are clustered in a 39-nucleotide sequence of the hHa2 gene. Both allelic frequency calculations in individuals of different races and pedigree studies indicate that the two-allelic hHa2 variants resulting from P1 and P2 occur ubiquitously in a ratio of about 1:1 (P1) and 2:1 (P2) respectively in our survey, and are clearly inherited as Mendelian traits. A genotype carrying both mutations simultaneously on one allele could not be detected in our sampling, and there was no association of a distinct allelic hHa2 variant with the known ethnic form variations of hairs. Sequence comparisons of the HTR of hHa2 with those of other type I hair keratins including the hHa2-ortholog from chimpanzee provide evidence that the P1- and P2-linked mutations must have occurred very early in human evolution and that the two P2-associated codon variants may be the result of two independent point mutations in an ancestral AGC serine codon. These data describe natural polymorphisms in the HTR of a member of the keratin multigene family.
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Analysis of the EBI/GeneBank database using nonhuman hair keratin associated protein (KAP) gene sequences as a query resulted in the identification of two human KAP gene domains on chromosome 21, one of which, located at 21q22.1, has... more
Analysis of the EBI/GeneBank database using nonhuman hair keratin associated protein (KAP) gene sequences as a query resulted in the identification of two human KAP gene domains on chromosome 21, one of which, located at 21q22.1, has recently been characterized. The second domain presented here, an approximately 90 kb domain on chromosome 21q23, harbored 16 KAP genes and two KAP pseudogenes. By comparison with known sheep and mouse KAP families, these genes could be assigned to two KAP families, KAP10 and KAP12, with the KAP10 family (12 members) being distinctly larger than the KAP12 family (four members). Systematic cDNA/3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; rapid amplification of cDNA ends isolation studies using human scalp mRNA led to the identification of eight KAP10 and two KAP12 cDNA sequences. In situ hybridization analyses of human anagen hair follicles using specific 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-noncoding sequences of the various KAP10/KAP12 genes revealed mRNA expression of nearly all KAP10 and KAP12 members exclusively in a narrow region of the middle portion of the hair fiber cuticle. Bioinformatic analyses of the promoter regions of the KAP10/KAP12 genes demonstrated several enhancer elements that were present in nearly all of the KAP genes. Primary among these were binding elements for the ETS, heat shock factor, AML, and HOX families of transcription factors.
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In an attempt to identify new members of the human type II hair keratin family by means of 3&amp;amp;amp;amp;amp;amp;#39;- and 5&amp;amp;amp;amp;amp;amp;#39;-RACE methods and cDNA from anagen hair follicles, we detected a sequence... more
In an attempt to identify new members of the human type II hair keratin family by means of 3&amp;amp;amp;amp;amp;amp;#39;- and 5&amp;amp;amp;amp;amp;amp;#39;-RACE methods and cDNA from anagen hair follicles, we detected a sequence that encoded a hitherto unknown type II cytokeratin. The novel cytokeratin comprises 251 amino acids and exhibits the highest sequence homology with K5. Comparative one- and two-dimensional western blots of keratins from anagen hair bulbs, containing or not containing the outer and inner root sheaths (ORS/IRS), and from footsole epidermis with an antibody against the new cytokeratin, revealed its comigration with K6 and its expression in the ORS/IRS complex. We have therefore named the new cytokeratin K6hf, to distinguish it from the various K6 isoforms and to indicate its expression in the hair follicle. Both in situ hybridization with a K6hf-specific cRNA probe and indirect immunofluorescence with the K6hf antibody showed that K6hf is exclusively expressed in the so-called &amp;amp;amp;amp;amp;amp;quot;companion layer&amp;amp;amp;amp;amp;amp;quot; of the hair follicle, a single layered band of flat and vertically oriented cells between the cuboidal ORS cells and the IRS that stretches from the lowermost bulb region to the isthmus of the follicle. Concomitant K17 and K16 expression studies showed that besides suprabasal ORS cells, these cytokeratins are sequentially expressed subsequent to K6hf in companion cells above the hair bulb. Our study confirms the view of a vertically oriented companion layer differentiation. The clearly delayed K17 and K16 expression relative to that of K6hf in companion cells most probably excludes these keratins as possible type I partners of K6hf and suggests the existence of a still unknown type I partner of its own. Thus, not only morphologically but also biochemically, the companion layer is different from the ORS and can therefore be regarded as an independent histologic compartment of the hair follicle.
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ABSTRACT
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Clodronate, alendronate, and other bisphosphonates are widely used in the treatment of bone diseases characterized by excessive osteoclastic bone resorption. The exact mechanisms of action of bisphosphonates have not been identified but... more
Clodronate, alendronate, and other bisphosphonates are widely used in the treatment of bone diseases characterized by excessive osteoclastic bone resorption. The exact mechanisms of action of bisphosphonates have not been identified but may involve a toxic effect on mature osteoclasts due to the induction of apoptosis. Clodronate encapsulated in liposomes is also toxic to macrophages in vivo and may therefore be of use in the treatment of inflammatory diseases. It is generally believed that bisphosphonates are not metabolized. However, we have found that mammalian cells in vitro (murine J774 macrophage-like cells and human MG63 osteosarcoma cells) can metabolize clodronate (dichloromethylenebisphosphonate) to a nonhydrolyzable adenosine triphosphate (ATP) analog, adenosine 5&#39;-(beta, gamma-dichloromethylene) triphosphate, which could be detected in cell extracts by using fast protein liquid chromatography. J774 cells could also metabolize liposome-encapsulated clodronate to the same ATP analog. Liposome-encapsulated adenosine 5&#39;-(beta, gamma-dichloromethylene) triphosphate was more potent than liposome-encapsulated clodronate at reducing the viability of cultures of J774 cells and caused both necrotic and apoptotic cell death. Neither alendronate nor liposome-encapsulated alendronate were metabolized. These results demonstrate that the toxic effect of clodronate on J774 macrophages, and probably on osteoclasts, is due to the metabolism of clodronate to a nonhydrolyzable ATP analog. Alendronate appears to act by a different mechanism.
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The low-temperature reaction of MeSiCl3 with 2-Li-C5H4N (1:3 equivalents) in thf gives [MeSi(2-C5H4N)3LiX](X = 0.2Br, 0.8Cl), containing the first example of a Si-bridged tris(pyridyl) ligand.
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The amprenavir (APV) early or expanded access program was designed to provide open-label APV to patients who would potentially receive benefit beyond that expected from currently available protease inhibitors (PIs) and who were at risk of... more
The amprenavir (APV) early or expanded access program was designed to provide open-label APV to patients who would potentially receive benefit beyond that expected from currently available protease inhibitors (PIs) and who were at risk of disease progression before the drug&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s expected time of regulatory approval. This study was conducted as part of an early access program to assess the safety profile and tolerability of APV in adults and children (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =4 years of age) who were either intolerant to or, in the opinion of the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s physician, virologically failing a previous PI-containing antiretroviral regimen. Specific CD4+ cell count and viral load limits were not imposed by this early access protocol. This open-label, nonrandomized study was conducted at multiple sites throughout the United States. Adults received APV at a dosage of 1200 mg BID. Patients weighing &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 kg received APV at a dosage of 20 mg/kg BID for the solid formulation or 1.5 mL/kg BID for the liquid formulation. A total of 489 physicians registered for this program; 364 (74.4%) enrolled patients. The safety population of 2217 patients (2048 males [92.4%] and 169 females [7.6%] aged 2 to 74 years) received APV for a median duration of 85 days (range, 2-218 days). Patients in the intent-to-treat population (n = 1427) had extensive experience with antiretroviral therapy. Drug-related treatment-emergent adverse events reported in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;3% of patients in the safety population were nausea in 279 patients (12.6%), diarrhea in 197 patients (8.9%), rash in 177 patients (8.0%), vomiting in 148 patients (6.7%), and fatigue in 89 patients (4.0%). Adverse events and laboratory test abnormalities were graded for severity on a scale of 1 to 4 in accordance with AIDS Clinical Trials Group guidelines. Grade 3 treatment-emergent abnormal laboratory values regardless of causality occurring in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;3% of patients were neutropenia in 69 of 1887 patients (3.7%; grade 3 toxicity = 500-749/mm3) and elevated triglycerides in 80 of 1593 patients (5.0%; grade 3 toxicity = 751-1200 mg/dL). Most common grade 4 treatment-emergent laboratory abnormalities were elevated serum creatine phosphokinase levels in 36 of 1266 patients (2.8%; grade 4 = &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;6 times upper normal limit), elevated triglycerides in 39 of 1593 patients (2.4%), and neutropenia in 41 of 1887 patients (2.2%). The results of this large cohort of patients support the data from the phase II/III clinical development program and suggest that APV has an acceptable safety profile and is generally well tolerated when used in combination with other antiretroviral drugs in a heavily treatment-experienced, heterogeneous patient population.
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Research Interests: Marine Biology, Adolescent, Biological Sciences, Humans, Child, and 15 moreFemale, Animals, Fluconazole, Male, Visceral Leishmaniasis, Naphthoquinones, Middle Aged, Adult, ATOVAQUONE, Antifungal Agents, Combination drug therapy, Pilot Projects, Clinical Infectious Diseases, Child preschool, and Medical and Health Sciences
Research Interests: Drug interactions, HIV, Biological Sciences, Humans, Drug Resistance, and 15 moreMale, Hiv Infection, Human immunodeficiency virus, Genotype, Adult, Combination drug therapy, Base Sequence, Antiviral Activity, Drug Interaction, Carbamates, Area Under Curve, Clinical Infectious Diseases, Antiviral Agents, Combination Therapy, and HIV infections
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Cement slurries which have their application in the oilfield industry have been evaluated on an oscillating rheometer. Viscoelastic properties were observed in four slurries; a neat slurry, a polymer modified, a polymer/sodium silicate... more
Cement slurries which have their application in the oilfield industry have been evaluated on an oscillating rheometer. Viscoelastic properties were observed in four slurries; a neat slurry, a polymer modified, a polymer/sodium silicate modified slurry and a sodium silicate modified slurry. ...
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Research Interests: Genetics, Flow Cytometry, Biology, Medicine, Humans, and 15 moreEndothelial Cells, Mice, Animals, Male, Phenotype, Endothelial cell, Cancer Cell, Biological markers, Antitumor Activity, Biological Assay, Cell Survival, Neurosciences, Angiogenesis inhibitors, Peripheral blood, and Fibroblast growth factors
This bench-scale study investigated whether strains of Escherichia coli that are resistant to two common types of antibiotics, ampicillin and trimethoprim, possess increased resistance to two common disinfectants in water and wastewater... more
This bench-scale study investigated whether strains of Escherichia coli that are resistant to two common types of antibiotics, ampicillin and trimethoprim, possess increased resistance to two common disinfectants in water and wastewater treatment, free chlorine and ultraviolet disinfection, relative to an antibiotic-sensitive strain of E. coli isolated from sewage sludge. Trimethoprim-resistant E. coli was slightly more resistant to chlorine than the antibiotic-sensitive isolate and the ampicillin-resistant E. coli under the study conditions (95% confidence), however this difference would not be important under normal chlorination conditions applied in practice. There were no statistically significant differences between the ultraviolet dose-response profiles of the antibiotic-resistant and antibiotic-sensitive E. coli strains over the ultraviolet dose range tested.
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Bisphosphonates inhibit osteoclast-mediated bone resorption by mechanisms that have only recently become clear. Whereas nitrogen-containing bisphosphonates affect osteoclast function by preventing protein prenylation (especially... more
Bisphosphonates inhibit osteoclast-mediated bone resorption by mechanisms that have only recently become clear. Whereas nitrogen-containing bisphosphonates affect osteoclast function by preventing protein prenylation (especially geranylgeranylation), non-nitrogen-containing bisphosphonates have a different molecular mechanism of action. In this study, we demonstrate that nitrogen-containing bisphosphonates (risedronate, alendronate, pamidronate, and zoledronic acid) and non-nitrogen-containing bisphosphonates (clodronate and etidronate) cause apoptosis of rabbit osteoclasts, human osteoclastoma-derived osteoclasts, and human osteoclast-like cells generated in cultures of bone marrow in vitro. Osteoclast apoptosis was shown to involve characteristic morphological changes, loss of mitochondrial membrane potential, and the activation of caspase-3-like proteases capable of cleaving peptide substrates with the sequence DEVD. Caspase-3-like activity could be visualized in unfixed, dying osteoclasts and osteoclast-like cells using a cell-permeable, fluorogenic substrate. Bisphosphonate-induced osteoclast apoptosis was dependent on caspase activation, because apoptosis resulting from alendronate, clodronate, or zoledronic acid treatment was suppressed by zVAD-fmk, a broad-range caspase inhibitor, or by SB-281277, a specific isatin sulfonamide inhibitor of caspase-3/-7. Furthermore, caspase-3 (but not caspase-6 or caspase-7) activity could be detected and quantitated in lysates from purified rabbit osteoclasts, whereas the p17 fragment of active caspase-3 could be detected in human osteoclast-like cells by immunofluorescence staining. Caspase-3, therefore, appears to be the major effector caspase activated in osteoclasts by bisphosphonate treatment. Caspase activation and apoptosis induced by nitrogen-containing bisphosphonates are likely to be the consequence of the loss of geranylgeranylated rather than farnesylated proteins, because the ability to cause apoptosis and caspase activation was mimicked by GGTI-298, a specific inhibitor of protein geranylgeranylation, whereas FTI-277, a specific inhibitor of protein farnesylation, had no effect on apoptosis or caspase activity.
Research Interests: Engineering, Enzyme Inhibitors, Apoptosis, Molecular Mechanics, Biological Sciences, and 15 moreCaspases, Humans, Bone, Animals, Osteoclasts, Nitrogen, Bone marrow, Caspase, Rabbits, Mitochondrial Membrane Potential, Bone and Bones, Bone Resorption, Prenylation, fluorescent dyes, and Medical and Health Sciences
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Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a &quot;P-C-P&quot; structure. The bisphosphonates are therefore stable analogues of... more
Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a &quot;P-C-P&quot; structure. The bisphosphonates are therefore stable analogues of naturally occuring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains. Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget&#39;s disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. In addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of new bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures. The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs. oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid-associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradual