Biomedical subjects

J Grover

Publications and source records attributed to J Grover.

At least 19 recordsLinked to original sources

PubMed2006

Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors.

PURPOSE: MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. METHODS: Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. RESULTS: Five dose levels of MAC-321 ranging from 25 to 75 mg/m(2) were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m(2)). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m(2); one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m(2) had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1-2 fatigue and grades 1-2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C (max) value of less than 1 h. Mean C (max) and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20-228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). CONCLUSIONS: MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m(2). The major DLT was neutropenic fever. Four subjects had disease stabilization.

Administration, Oral↗

PubMed2006

The consequence of PRELP overexpression on skin.

PRELP is a member of the small leucine-rich repeat proteoglycan family that is abundantly expressed in many cartilages compared to other connective tissues. To study the consequence of PRELP overexpression in tissues where it is normally expressed at low abundance, transgenic mice were generated in which the human PRELP transgene was placed under control of the CMV promoter. A connective tissue phenotype was observed in the skin, where the organization of collagen fibrils in the dermis was perturbed and the thickness of the hypodermal fat layer was diminished.

Adipose Tissue↗

PubMed2001

Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study.

BACKGROUND: In trials of patients with left ventricular dysfunction or heart failure, ACE inhibitor use was unexpectedly associated with reduced myocardial infarction (MI). Using the Heart Outcomes Prevention Evaluation (HOPE) trial data, we tested prospectively whether ramipril, an ACE inhibitor, could reduce coronary events and revascularization procedures among patients with normal left ventricular function. METHODS AND RESULTS: In the HOPE trial, 9297 high-risk men and women, >/=55 years of age with previous cardiovascular disease or diabetes plus 1 risk factor, were randomly assigned to ramipril (up to 10 mg/d), vitamin E (400 IU/d), their combination, or matching placebos. During the mean follow-up of 4.5 years, there were 482 (10.4%) patients with clinical MI and unexpected cardiovascular death in the ramipril group compared with 604 (12.9%) in the placebo group [relative risk reduction (RRR), 21% (95% CI) (11,30); P<0.0003]. Ramipril was associated with a trend toward less fatal MI and unexpected death [4.0% versus 4.7%; RRR, 16% (-3, 31)] and with a significant reduction in nonfatal MI [5.6% versus 7.2%; RRR, 23% (9,34)]. Risk reductions in MI were documented in participants taking or not taking beta-blockers, lipid lowering, and/or antiplatelet agents. Although ramipril had no impact on hospitalizations for unstable angina [11.9% versus 12.2%; RRR, 3% (-9,14)], it reduced the risk of worsening and new angina [27.2% versus 30.0%; RRR, 12% (5,18); P<0.0014] and coronary revascularizations [12.5% versus 14.8%; RRR, 18%; (8,26) P<0.0005]. CONCLUSIONS: In this high-risk cohort, ramipril reduced the risk of MI, worsening and new angina, and the occurrence of coronary revascularizations.

Aged↗

PubMed2001

Characterization and expression of murine PRELP.

The cDNA sequence of the murine proline/arginine-rich end leucine-rich repeat protein (PRELP) gene was cloned by PCR-based techniques. The gene encodes a protein of 378 amino acids, which is four amino acid residues shorter than its human counterpart. This difference resides mainly in the amino terminal region of the mature protein, which is five amino acids shorter in the mouse than the human and has a lower arginine content. The remainder of the protein, including the structure of the leucine-rich repeats, the potential sites for N-linked glycosylation, and the disulfide-bonded domains are well conserved between species. In common with humans, the murine gene possesses three exons, with the translation initiation codon residing in exon 2 and the termination codon in exon 3. Exons 1 and 2 are separated by an intron of approximately 6.7 kbp, whereas exons 2 and 3 are separated by an intron of approximately 1.7 kbp. Western blot analysis of mouse cartilage extracts indicates that PRELP exists as a glycoprotein of approximately 55 kDa, as in human cartilage. Immunohistochemical and in situ hybridization analysis reveal that PRELP is expressed in cartilage throughout both fetal development and post-natal life, in contrast to the human where expression in cartilage is not apparent prior to birth. Northern blot analysis indicates that PRELP mRNA is also expressed in the developing embryo prior to skeletogenesis. The promoter region of the mouse PRELP gene possesses no TATA box in its proximal region, in common with humans, and shows differences in the conservation of elements known to be involved in regulating expression of the human PRELP gene.

Amino Acid Sequence↗

PubMed2000

Analysis of the human lumican gene promoter.

The human lumican gene was shown to possess one major transcription start site, resulting in exon 1 of the gene giving rise to the first 74 base pairs (bp) of the 5'-untranslated region. About 1.6 kilobase pairs of upstream promoter sequence were sequenced and analyzed to identify elements responsible for gene expression. No typical TATAA sequence was identified in the vacinity of the transcription start site, but an atypical TATCA sequence residing 41 bp upstream was shown to be necessary for transcription, although it was incapable of supporting transcription by itself. A GC box residing 74 bp upstream of the transcription start site also was essential for the initiation of transcription. Sp3 was identified as the transcriptional activator binding to the GC box. No additional elements that significantly modulated transcription were noted in the promoter sequence analyzed, when using human adult chondrocytes as the cell source for transfection in reporter assays. In contrast, reporter assays carried out in human fetal lung fibroblasts, where lumican expression is deplete, revealed the presence of a repressor element located between 384 and 598 bp upstream of the transcription start site. A GATA-binding site located between bp -386 and -391 was identified as being necessary for repression of transcription. The mouse lumican promoter does not possess an equivalent site, and this may explain why the lumican gene is expressed in fetal murine cartilage but not in fetal human cartilage.

Animals↗

PubMed2000

The rise and fall of a hospital-sponsored group practice.

Each physician group, network, or management services organization developed as part of an "integration" strategy over the past decade is unique. The current status of each of these entities is based on a variety of factors, including the local health care economy and environment, the sponsoring organization, and the entity's leadership. Much of the current news concerning integration initiatives is negative, and significant operating losses and the disillusionment of the participants have been reported. It is important to study the failures, however, for despite the unique factors impacting each one there are universal lessons to be learned in every case. This article chronicles the causes of one integrated group practice's breakup after five years of operation and the process undertaken to return the physicians to small independent practices.

California↗

PubMed1999

Expression of the tissue inhibitor of metalloproteinases (TIMP) gene family in normal and osteoarthritic joints.

The pathophysiological and biological significance of tissue inhibitor of the metalloproteinases-3 (TIMP-3) gene compared to other TIMPs was investigated in osteoarthritic (OA) human and normal bovine joint tissues. Human OA synovial fibroblasts in culture constitutively expressed TIMP mRNAs. TIMP-3, TIMP-1 and gelatinase A mRNAs were elevated in most human OA synovia over controls, while TIMP-2 expression was similar. TIMP-3 and TIMP-1 mRNAs present in bovine cartilage were inducible by serum factors. Transforming growth factor beta (TGF-beta 1) induced TIMP-3 RNA and protein in human OA and normal bovine chondrocytes. TIMP mRNAs were low (TIMP-1) or undetectable in human fetal chondrocytes but were expressed at all other ages. Thus, the two main joint tissues, synovial membranes and cartilage, express TIMP genes. Due to their matrix protecting activities, the presence of multiple TIMPs may be beneficial for normal joints, while increased TIMP-3 and TIMP-1 expression in arthritic joints may be associated with pathological remodeling.

Aged↗

PubMed1998

Characterization of the human proline/arginine-rich end leucine-rich repeat protein (PRELP) gene promoter and identification of a repressor element.

The 5'-flanking region of the human proline/arginine-rich end leucine-rich repeat protein (PRELP) gene has been characterized for both promoter and repressor activity by using a variety of reporter gene constructs and transient transfection into chondrocytes or fibroblasts. The human PRELP gene lacks a TATA box, and in its absence a Sp1-binding site residing 29 bp upstream of the transcription start site is essential for initiating gene expression. In contrast, an Ets-binding site residing 497 bp upstream of the transcription start site can lead to the repression of gene expression. The analysis of nuclear proteins by gel retardation studies with the repressor element identified a common protein, presumably an Ets family member, present in neonatal chondrocytes and skin fibroblasts that do not express the PRELP gene. The factor was not detected in nuclear protein preparations from adult chondrocytes in which the PRELP gene is expressed.

Base Sequence↗

PubMed1998

Vitamin E deficiency and associated neurological deficits in children with protein-energy malnutrition.

Vitamin E is important in maintaining normal neurological structure and function. In this study, 100 children with protein-energy malnutrition (PEM) were studied and compared to a suitably age-matched control group. Posterior column deficits, cerebellar deficits, and problems with fine motor coordination were present to a significant degree in the PEM subjects. The presence of neurological signs was correlated with various parameters of vitamin E deficiency, including low serum alpha-tocopherol levels and a low tocopherol/total lipid ratio which was present in 92 per cent of subjects. There was good concordance between vitamin E levels and vitamin E to serum lipid ratio in assessing vitamin E deficiency. We conclude that vitamin E deficiency is prevalent, to a hitherto unsuspected degree, in children with PEM and that these malnourished children have significant neurological deficits attributable to low vitamin E levels. This observation is of clinical significance as the neurological deficits are potentially reversible with vitamin E supplementation.

Case-Control Studies↗

PubMed1998

Prolonged formation of methemoglobin following nitroethane ingestion.

BACKGROUND: Artificial nail removers containing nitroethane pose a serious risk of toxicity when ingested. CASE REPORTS: We report 3 cases of children under 3 years of age who developed prolonged methemoglobinemia following ingestions of small quantities of these nitroethane-containing products. Methylene blue therapy reduced the methemoglobin level in all 3 children; however, in 2 of these children methemoglobin levels increased again several hours later and required additional methylene blue. Accurate substance identification is essential for appropriate management of ingestions of fingernail products. The availability of nitroethane products for home use should be questioned.

Antidotes↗

PubMed1997

The structure and chromosome location of the human chondroadherin gene (CHAD).

The cDNA sequence of the human chondroadherin gene was cloned using PCR-based techniques. The gene encodes a protein of 359 amino acids, of which the first 21 amino acids represent a putative signal peptide sequence and which possesses 11 leucine-rich repeats flanked by cysteine-rich regions. The cDNA possesses a 5' untranslated region of 149 bp, a coding region of 1080 bp including the stop codon, and a 3' untranslated region of 561 bp terminating in a poly(A) tail. The cDNA hybridizes with a single messenger RNA of 1.9 kb, which is present in chondrocytes at all ages. Analysis of genomic DNA revealed that the chondroadherin gene possesses two introns, both of which reside within the coding region. The first intron has a length of about 2.3 kb and separates the codons for lysine(258) and phenylalanine(259). The second intron has a length of about 0.5 kb and splits the codon for tryptophan(314). This genomic organization results in exon 1 encoding the signal peptide, the amino-terminal cysteine-rich region, and the first 9 leucine-rich repeats; exon 2 encoding the last 2 leucine-rich repeats and part of the carboxy-terminal cysteine-rich region; and exon 3 encoding the remainder of the carboxy-terminal cysteine-rich region. The gene does not possess a TATA box prior to its transcription start site. Isolation of a cosmid clone spanning the chondroadherin gene enabled its chromosome location to be established. The gene was shown to reside at chromosome 17q21.33.

Amino Acid Sequence↗

PubMed1997

Three-dimensional method for determination of amniotic fluid volume in intrauterine pockets.

BACKGROUND: Although current ultrasound techniques provide a linear (amniotic fluid index; AFI) or two-dimensional area index of amniotic fluid (AF), these indices have limited correlation with actual AF volume. We sought to quantify the three-dimensional volume of ultrasound-identified AF pockets, as assessed by the AFI and two-dimensional area methods. The BVI 2500 (Bladder Volume Instrument 2500; Diagnostic Ultrasound Corp., Redmond, WA) has been used to quantify the volume of residual urine in the bladder. INSTRUMENT AND METHOD: The BVI 2500 (Diagnostic Ultrasound Corp.) ultrasound uses a rotating 2-MHz transducer, computer-defined fluid interface, and computer integration of 12 cross-sectional images to calculate three-dimensional fluid volume. After providing written informed consent, 14 term pregnant patients (36-42 weeks) were evaluated using the BVI 2500 and an Ultramark 8 sector scan (Advanced Technology Laboratory, Bothell, WA). The largest vertical fluid pocket in each quadrant of the abdomen was identified with the sector scan, and vertical and horizontal measurements for AFI and two-dimensional area were recorded. Simultaneous AF volume measurements of each pocket were performed three times with the bladder volume instrument, and maximum values were used. Three-dimensional volume, two-dimensional area, and AFI values were compared by correlation analysis, with P < or = .05 considered statistically significant. EXPERIENCE: Among all patients, the average (+/- standard deviation) AFI was 7.6 +/- 4.1 (range 1.5-16.4) cm, and the average two-dimensional area was 30.9 +/- 21.1 (range 4.3-81.3) cm2. This corresponded to an average three-dimensional volume of 215 +/- 134 (range 23-497) cm3. Three-dimensional volume correlated highly with both AFI (r = 0.9; P < .001) and two-dimensional area (r = 0.86; P < .001). One AFI centimeter was equivalent to a volume of 30 cm3. CONCLUSION: There are highly significant linear correlations of three-dimensional amniotic fluid volumes with AFI and two-dimensional area. The four pockets used in AFI determination account for only 50% of total AF volume. Three-dimensional determinations may aid in clinical assessments of AF volume.

Adult↗

PubMed1997

Hospitalizing the suicidal adolescent: decision-making criteria of psychiatric residents.

OBJECTIVE: The primary purpose of this research is to investigate the criteria used by general psychiatric residents in determining the appropriateness of hospitalization. METHOD: A questionnaire containing 64 vignettes describing adolescent suicide attempts was completed by a sample of 33 residents from a general psychiatry training program. Six variables known to relate to lethality of attempt were systematically varied within the vignettes: gender, depression, conduct disorder/substance abuse, previous attempts, suicidal relative, and family supports. Respondents were asked to judge the appropriateness of hospitalization for each vignette. RESULTS: Hospitalization preference was significantly predicted by all risk factors except for gender, with the presence of depression emerging as the most important predictor of hospitalization. Residents recommended hospitalization more frequently than did experienced child and adolescent clinicians. In comparison with experienced clinicians, residents placed more importance on depression, and less importance on conduct disorder/substance abuse, in making decisions to hospitalize. CONCLUSIONS: Although psychiatric residents use known risk factors for adolescent suicide in assessing need for hospitalization, there was clear support for further training initiatives for psychiatric residents concerning the assessment of suicidal adolescents.

Adolescent↗

PubMed1996

The gene organization, chromosome location, and expression of a 55-kDa matrix protein (PRELP) of human articular cartilage.

The gene corresponding to a 55-kDa matrix protein previously described in adult human articular cartilage was characterized by sequencing of genomic clones. The deduced protein sequence corresponds to the recently described matrix protein PRELP. The protein was encoded by messages of 1.7, 4.6, and 6.7 kb, whose relative abundance increased as their size decreased. The message heterogeneity appears to originate from variation in the length of the 3'-untranslated region, with the smallest message being contained within the reported sequence and the larger messages having extended 3'-untranslated regions. Two introns were identified within the genomic sequence encoding the smallest message. The first intron of about 6.7 kb resides 16 nucleotides prior to the translation initiation codon, and the second intron of about 2.6 kb resides 173 nucleotides prior to the translation termination codon. The gene, which encompasses at least 16 kb of genomic DNA, was shown to reside on chromosome 1q32. Primer extension techniques were used to establish that the coding sequence commences 199 bp downstream from the major transcription start site. Analysis of the DNA sequence upstream from the transcription start site reveals the presence of numerous potential transcription factor binding sites, but no CAAT or TATA box. At the message level, gene expression was at a high level in juvenile and adult cartilage, but not in the fetus or neonate. The presence of protein in the cartilage matrix was also much lower in the neonate than in the adult. In noncartilagenous tissues appreciable message levels were observed only in the adult lung.

Adult↗

PubMed1996

The effect of a flexion contracture of the elbow on the ability to transfer in patients who have quadriplegia at the sixth cervical level.

We studied six patients (twelve upper extremities) who had quadriplegia at the sixth cervical level. Our purpose was to evaluate how the loss of terminal extension of the elbow adversely affected the ability of the patient to perform transfers with a sliding board and so-called depression raises (lifting of the body with use of the extended upper extremities to reduce the pressure on the ischial tuberosities). Function of the triceps muscle was considered to be absent in eight upper extremities and present in four. A flexion contracture of the elbow was simulated with use of a specially fabricated, hinged elbow brace. Terminal extension was progressively limited, in 5-degree increments, until the patient was no longer able to perform the transfer or the depression raise. The mean flexion contracture at which the patient could not perform the transfer or the depression raise was approximately 25 degrees when function of the triceps was absent and approximately 50 degrees when function of the triceps was intact. The results of this study emphasize the importance of maintaining the full range of motion of the elbow in a patient who has high-level quadriplegia. In a patient who has quadriplegia at the sixth cervical level who otherwise would be independent with regard to transfer skills and mobility in bed, a flexion contracture of the elbow of approximately 25 degrees or more can result in the loss of a functional level and render the patient as dependent as one who has quadriplegia at the fifth cervical level.

Activities of Daily Living↗

PubMed1995

The human lumican gene. Organization, chromosomal location, and expression in articular cartilage.

A human lumican cDNA sequence was derived by polymerase chain reaction techniques from RNA obtained from intestine, placenta, and articular cartilage. A contiguous sequence of 1729 bases was obtained corresponding to an observed message size of 1.8 kilobases (kb). The cDNA sequence consists of an 80-base pair (bp) 5'-untranslated region, a 1014-bp coding sequence, and a 618-bp 3'-untranslated region terminating in a 17-bp poly(A) tail. The deduced lumican protein sequence has 338 amino acids, including a putative 18-residue signal peptide. The human lumican gene was shown to be spread over about 7.5 kb of genomic DNA and to be located on chromosome 12q22. The gene consists of 3 exons separated by introns of 2.2 and 3.5 kb. The shorter 5'-intron resides 21 bases prior to the translation initiation codon, and the 3'-intron resides 152 bases prior to the translation termination codon. The lumican message is expressed at high levels in adult articular chondrocytes but at low levels in the young juvenile. This age-related trend in message level is not, however, common to all tissues in which the lumican gene is expressed. Lumican is present in the extracellular matrix of human articular cartilage at all ages, although its abundance is far greater in the adult. In the adult cartilage lumican exists predominantly in a glycoprotein form lacking keratan sulfate, whereas the juvenile form of the molecule is a proteoglycan.

Aged↗

PubMed1995

Expression of cell-surface proteoglycan mRNA by human articular chondrocytes.

The expression of six cell-surface proteoglycans (syndecan, fibroglycan, amphiglycan, glypican, betaglycan and CD44) was studied at the mRNA level. Analysis was performed by Northern blotting using total RNA preparations from freshly isolated articular chondrocytes obtained from both juveniles and adults. Similar results were obtained for both age groups. By far the most abundant message was that for amphiglycan, CD44 message was next in relative abundance, and the messages for fibroglycan, glypican and betaglycan were all expressed at low levels. Syndecan message could not be detected by this technique. This pattern of expression was different to that observed in cultured skin fibroblasts, where the messages for amphiglycan, CD44, fibroglycan and glypican were all expressed at a similar level. In contrast with the fibroblasts, where the amphiglycan message exhibits no size polymorphism, the chondrocyte amphiglycan message is present in three polymorphic forms, due to the use of alternative polyadenylation signals. When the newly isolated chondrocytes are maintained in monolayer culture for several passages, the amphiglycan message heterogeneity reverts to that characteristic of the fibroblasts. Thus human articular chondrocytes are characterized by both their high level of amphiglycan message expression and their use of alternative polyadenylation signals.

Adult↗

PubMed1995

Lisinopril versus placebo in the treatment of heart failure: the Lisinopril Heart Failure Study Group.

Lisinopril, a long-acting, angiotensin-converting enzyme inhibitor, was compared with placebo in a randomized, parallel, double-blind, 12-week study of 193 patients with heart failure. All patients were New York Heart Association Functional Class II, III, or IV and had remained symptomatic despite optimal dosing with digoxin and diuretics. After 12 weeks of therapy, the improvement in treadmill exercise duration was greater in the lisinopril group (113 seconds) compared with the placebo group (86 seconds). This improvement in exercise duration was particularly evident in patients with left ventricular ejection fractions less than 35% (lisinopril = 130 seconds; placebo = 94 seconds). In patients receiving lisinopril, the increase in exercise duration was accompanied by an improvement in quality of life as measured by the Yale Scale Dyspnea/Fatigue Index and in signs and symptoms of heart failure. In addition, the lisinopril group had a larger mean increase (3.7%) in left ventricular ejection fraction when compared with the placebo group (1.3%). Thus, lisinopril, administered once daily for 12 weeks, was well tolerated and efficacious in the treatment of heart failure when used concomitantly with diuretics and digoxin.

Aged↗