PubMed Health⌕ Search

Biomedical subjects

S Patel

Publications and source records attributed to S Patel.

At least 37 records · Page 2Linked to original sources
PubMed2003

Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer.

OBJECTIVE: To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases. DATA SOURCES: Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies. Foreign language papers were included. STUDY SELECTION: Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity. RESULTS: 95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted > or = 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates. CONCLUSIONS: In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.

Bone Neoplasms↗
PubMed2003

Acceptability and compliance with hip protectors in community-dwelling women at high risk of hip fracture.

OBJECTIVES: To determine acceptability and compliance with hip protectors in women at high risk of hip fracture who are living independently in the community. METHODS: Women aged 65 yr and over referred for open access bone densitometry who had femoral neck osteoporosis and a high risk of falling were asked to wear hip protectors. RESULTS: Eighty five women fulfilled the inclusion criteria of whom 32 (38%) found the hip protectors acceptable and agreed to participate. Reasons given by the remaining 53 (62%) for not finding the hip protectors acceptable included discomfort on wearing, dislike of their personal appearance with the hip protectors on, and disagreement about their fracture risk. Participants were more likely to have a family history of osteoporosis (47 vs 26%, respectively) and hip fracture (16 vs 8%) compared with non-participants. At 12 months only about half of the subjects were wearing hip protectors daily. CONCLUSIONS: Our findings suggest that only a minority of community-dwelling women at high risk of hip fracture will wear hip protectors to reduce fracture risk. Their use should be restricted to highly motivated women who should be carefully identified.

Accidental Falls↗
PubMed2003

hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan.

hAG-2 and hAG-3 are recently discovered human homologues of the secreted Xenopus laevis proteins XAG-1/2 (AGR-1/2) that are expressed in the cement gland, an ectodermal organ in the head associated with anteroposterior fate determination during early development. Although the roles of hAG-2 and hAG-3 in mammalian cells are unknown, both proteins share a high degree of protein sequence homology and lie adjacent to one another on chromosome 7p21. hAG-2 mRNA expression has previously been demonstrated in oestrogen receptor (ER)-positive cell lines. In this study, we have used real-time quantitative RT - PCR analysis and immunohistochemistry on tissue microarrays to demonstrate concordant expression of hAG-2 and hAG-3 mRNA and protein in breast tumour tissues. Tumour expression of both genes correlated with OR (hAG2, P=0.0002; hAG-3, P=0.0012), and inversely correlated with epidermal growth factor receptor (EGFR) (P=0.003). Yeast two-hybrid cloning identified metastasis-associated GPI-anchored C4.4a protein and extracellular alpha-dystroglycan (DAG-1) as binding partners for both hAG-2 and hAG-3, which if replicated in clinical oncology would demonstrate a potential role in tumour metastasis through the regulation of receptor adhesion and functioning. hAG-2 and hAG-3 may therefore serve as useful molecular markers and/or potential therapeutic targets for hormone-responsive breast tumours.

Amino Acid Sequence↗
PubMed2003

Regulation and function of spinal and peripheral neuronal B1 bradykinin receptors in inflammatory mechanical hyperalgesia.

Activation of either B1 or B2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia. Whereas B2 agonists activate sensory neurones directly, B1 agonists were thought only to have indirect actions on sensory neurones. The recent discovery of constitutive B1 receptor expression in the rat nervous system lead us to re-investigate the role of neuronal B1 receptors in inflammatory hyperalgesia. Therefore we have examined B1 bradykinin receptor regulation in rat dorsal root ganglia in a model of inflammatory hyperalgesia, and correlated it with hyperalgesic behaviour. Twenty-four hours after injection of Freund's complete adjuvant into one hindpaw, there was a significant increase in B1 protein expression (measured by immunohistochemistry) in both ipsilateral and contralateral dorsal root ganglion neurones, whereas axotomy resulted in reduction of B1 protein in ipsilateral dorsal root ganglia. In behavioural experiments, the B1 antagonist desArg10HOE140, administered by either intrathecal or systemic routes, attenuated Freund's complete adjuvant-induced mechanical hyperalgesia in the inflamed paw, but did not affect mechanical allodynia. The B1 agonist, desArg9BK, did not affect paw withdrawal thresholds in nai;ve rats following intraplantar administration into the paw, whilst intrathecal administration elicited mechanical hyperalgesia. However, after Freund's complete adjuvant-induced inflammation, desArg9BK caused a marked mechanical hyperalgesia, by either route, of the contralateral, uninflamed hindpaw, correlating with the observed contralateral and ipsilateral increases in receptor levels. Our results suggest a functional role for B1 receptors expressed both in the periphery and in the spinal cord, in mechanical hyperalgesia during inflammation.

Animals↗
PubMed2003

Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer.

Squamous cell carcinoma (SCC) of the oral tongue is characterized by a high propensity for cervical nodal metastasis, which affects the probability of regional control and survival. Until now, elective treatment of the clinically negative neck in early lesions (T(1-2)) of the oral tongue cancer remains controversial. This study attempted to identify predictive factor(s) for cervical nodal metastasis and treatment outcomes in patients with early stage SCC of the oral tongue treated primarily by surgery. Fifty patients with previously untreated Stage I/II primary tongue carcinomas with available archival specimens treated at the Royal Marsden Hospital between 1981 and 1998 were reviewed. Clinico-pathological features including age, gender, alcohol and tobacco consumption, tumour location, histological grade, tumour-stromal border, growth pattern, tumour thickness, and clinical stage were evaluated and the correlations with cervical metastases and outcome analysis were determined. The overall occult nodal metastatic rate was 40% (20/50). Tumour thickness exceeding 5 mm was statistically significantly correlated with cervical metastases (P = 0.003; relative risk = 2.429). No statistical correlation was observed between other clinico-pathological parameters and nodal metastasis. With a median follow-up of 98 months, 5-year actuarial overall, disease-specific (DSS), and relapse-free survival were 65.71, 67.77, and 68.18%, respectively. Univariate analysis for DSS showed poorer outcomes for patients with age > 60 years (P = 0.0423) and tumour thickness > 5 mm (P = 0.0067). The effect of tumour thickness was maintained (P = 0.005) on multivariate analysis. The present study indicates that the thickness of primary tumour has a strong predictive value for occult cervical metastasis and poor outcomes in patients with Stage I/II oral tongue SCC. Thus, elective neck treatment (surgery or irradiation) is indicated for tumours exceeding 5 mm thickness.

Adult↗
PubMed2003

Proteomic analysis of the cell-surface membrane in chronic lymphocytic leukemia: identification of two novel proteins, BCNP1 and MIG2B.

B-cell-specific plasma-membrane proteins are potential targets for either small molecule or antibody-based therapies. We have sought to annotate proteins expressed at the cell surface membrane in patients with chronic lymphocytic leukemia (CLL) using plasma-membrane-based proteomic analysis to identify previously uncharacterized and potentially B-cell-specific proteins. Proteins from plasma-membrane fractions were separated on one-dimensional gels and trypsinized fractions subjected to high-throughput MALDI-TOF mass spectrometry. Using this method, many known B-cell surface antigens were detected, but also known proteins not previously described in this disease or in this cellular compartment, including cell surface receptors, membrane-associated enzymes and secreted proteins, and completely unknown proteins. To validate the method, we show that BLK, a B-cell-specific kinase, is located in the CLL-plasma-membrane fraction. We also describe two novel proteins (MIG2B and B-cell novel protein #1, BCNP1), which are expressed preferentially in B cells. MIG2B is in a highly conserved and defined gene family containing two plasma-membrane-binding ezrin/radixin/moesin domains and a pleckstrin homology domain; the Caenorhabditis elegans homolog (UNC-112) is a membrane-associated protein that colocalizes with integrin at cell-matrix adhesion complexes. BCNP1 is a completely unknown protein with three predicted transmembrane domains, with three alternatively spliced final exons. Proteomic analysis may thus define new potential therapeutic targets.

Apoptosis Regulatory Proteins↗
PubMed2003

A clinical procedure to predict the value of temporary occlusion therapy in keratoconjunctivitis sicca.

PURPOSE: To evaluate the effects of dissolvable collagen punctal plugs on the symptoms, tear stability and volume in aqueous deficient dry eyes. METHODS: Sixty-two aqueous deficient dry eye patients of mixed aetiology underwent lacrimal punctal occlusion with dissolvable collagen plugs. The subjects were randomly allocated to one of two treatment groups: group I (n = 36) had their lower puncta occluded and group II (n = 26) had both their upper and lower puncta occluded. The effectiveness of this treatment was clinically assessed by (1). scoring subject symptoms and (2). measuring the tear parameters of tear thinning time (TTT) and tear meniscus height (TMH) as indicators of tear stability and volume, respectively. Following baseline measurements, patients were reviewed at time intervals of 5 and 12 days post-occlusion. A group of age- and gender-matched normals (n = 45) was recruited for comparison (group III). RESULTS: Tear volume and stability were significantly higher in group III compared with I and II at baseline. In the treated groups on both days 5 and 12: (1). symptom score reduced significantly from a median value of 7 to 3 (p = <0.001); (2). tear stability increased significantly from a median value of 3 to 5 s by day 5 (p <or= 0.001); reduced between days 5 and 12 (p < 0.05) and remained below the stability in group III at all times; (c). tear volume increased significantly by day 5 in both treatment groups from a median value of 0.13 to 0.20 mm (p<or=0.001), remained stable by day 12 in group II but reduced in group I (p < 0.05); (d). the increase in tear volume was negatively correlated with pre-treatment tear volume; (e). symptom score correlated with both baseline tear volume and stability. CONCLUSION: Collagen plugs improved tear status in the aqueous deficient dry eyes. Occluding both upper and lower puncta with temporary collagen plugs offers no practical beneficial gain compared with occluding just the lower punctum.

Adult↗
PubMed2003

Developmental binge exposure to ethanol and artificial rearing do not affect the social transfer of diet preference.

BACKGROUND: A previous study reported no effect of binge exposure to ethanol during the brain growth spurt on the social acquisition of enhanced diet preference in male rats. The objective of this study was to replicate this finding by using the artificial rearing technique and to investigate whether delay-dependent mnemonic deficits previously observed in the water maze would extend to social memory of diet preference. We also addressed whether this naturalistic behavior was dependent on the presentation of diet odor in the context of a rat-produced component in ethanol-exposed rats, as it is in normal controls. METHODS: Male rat pups were reared artificially from postnatal days 5 to 18, during which (postnatal days 6-9) they were fed either 6.5 g/kg/day of ethanol in a binge model or an isocaloric maltose-dextrin solution (gastrostomy controls). A third suckled control group was reared normally. These test rats were allowed to interact with conspecifics that had previously consumed a distinctive diet, X. Subsequently, the experimental rats were provided a choice between two novel diets, one of which was X, after delays of 0 hr (experiment 1), 24 hr, and 4 weeks (experiment 2). In experiment 3, the rats were again given the two-choice preference test, but after exposure to the diet odor alone. RESULTS: All groups demonstrated a significant preference for the socially cued diet in experiments 1 and 2, and the strength of this inclination remained consistent across the 0-hr, 24-hr, and 4-week retention intervals. Moreover, all groups demonstrated sensitivity to the social context of this task, as shown by a lesser preference for the diet exposed alone in experiment 3. CONCLUSIONS: Intact performance on the ethologically meaningful diet-preference test supports specificity in the cognitive/behavioral effects of developmental exposure to ethanol. Interestingly, early isolation, as experienced in the artificial-rearing procedure, also did not impair performance on this social task.

Animals↗
PubMed2003

On the sensitivity of wall stresses in diseased arteries to variable material properties.

Accurate estimates of stress in an atherosclerotic lesion require knowledge of the material properties of its components (e.g., normal wall, fibrous plaque, calcified regions, lipid pools) that can only be approximated. This leads to considerable uncertainty in these computational predictions. A study was conducted to test the sensitivity of predicted levels of stress and strain to the parameter values of plaque used in finite element analysis. Results show that the stresses within the arterial wall, fibrous plaque, calcified plaque, and lipid pool have low sensitivities for variation in the elastic modulus. Even a +/- 50% variation in elastic modulus leads to less than a 10% change in stress at the site of rupture. Sensitivity to variations in elastic modulus is comparable between isotropic nonlinear, isotropic nonlinear with residual strains, and transversely isotropic linear models. Therefore, stress analysis may be used with confidence that uncertainty in the material properties generates relatively small errors in the prediction of wall stresses. Either isotropic nonlinear or anisotropic linear models provide useful estimates, however the predictions in regions of stress concentration (e.g., the site of rupture) are somewhat more sensitive to the specific model used, increasing by up to 30% from the isotropic nonlinear to orthotropic model in the present example. Changes resulting from the introduction of residual stresses are much smaller.

Anisotropy↗
PubMed2003

Angiotensin-converting enzyme genotype and the ventilatory response to exertional hypoxia.

The "insertion" (I) rather than "deletion" (D) variant of the human angiotensin-converting enzyme (ACE) gene is associated with both lower tissue ACE activity and elite performance at high altitude. Three genotypes, II, ID and DD, are thus represented in the population. The authors examined whether an improved ventilatory response to hypoxic exercise may contribute to this effect. Subjects (n=60; 37 male, mean+/-SEM age 23.6+/-0.6 yrs, 14 II, 30 ID, 16 DD) underwent incremental cardiopulmonary exercise testing to establish maximal oxygen uptake and ventilatory threshold (VT). Four hours later, subjects exercised for 6 mins at 50% of the workload at VT. The protocol was repeated 15 mins later while breathing 12.5+/-0.5% oxygen in nitrogen. All subject characteristics were independent of genotype, as were data during normoxic exercise. However, the hypoxia-induced rise in minute ventilation was significantly greater among those of II genotype (39.6+/-4.1% versus 27.9+/-2.0% versus 28.4+/-2.2% for II versus ID versus DD, respectively). These data are supported by a significantly greater decrease in end tidal carbon dioxide (consistent with an increase in alveolar ventilation) among those homozygous for the I allele (II -18.7+/-1.3%, ID -15.7+/-0.4%, DD -15.1%+/-1.1). The ventilatory response to hypoxic exercise is influenced by angiotensin-converting enzyme genotype. Potential implications concern high altitude performance and the pathogenesis and management of hypoxic lung disease.

Adult↗
PubMed2002

Structural enzymology of Li(+)-sensitive/Mg(2+)-dependent phosphatases.

Li(+)-sensitive/Mg(2+)-dependent phosphatases have attracted considerable attention since they have been proposed as targets for lithium therapy in the treatment of manic-depressive patients. The members of this enzyme superfamily display low levels of sequence identity while possessing a common fold and active site. Extensive structural and biochemical data demonstrate the direct involvement of two metal ions in catalysis, and show that lithium exerts its inhibitory action by blocking the products at the active site. By exploiting the different inhibitory properties of magnesium and calcium, we have been able to solve the X-ray structures of the Li(+)-sensitive/Mg(2+)-dependent 3'-phosphoadenosine-5'-phosphatase in complex with its substrate and with its products. The structural comparison of these complexes provides a 3D picture of the different stages of the catalytic cycle. This gives new insights into the understanding of the biological function of this group of enzymes and their lithium inhibition, and should assist in the design of improved inhibitors of therapeutic value.

Amino Acid Sequence↗
PubMed2002

Temperature-induced beta-aggregation of fibronectin in aqueous solution.

Fibronectin structural reorganization induced by temperature has been investigated by Fourier-transform infrared (FT-IR) spectroscopy and light-scattering experiments. At 20 degrees C, from resolution enhanced by FT-IR spectra, 43% of beta sheet, 31% of turn and 26% of unordered structures were estimated. Static and quasi-elastic light-scattering results do not change significantly between 20 and 34 degrees C. Just below 50 degrees C, a decrease of 1/3 of beta sheet structures contents is observed, concomitantly with a corresponding increase of turn. The contribution of disordered structures is found to be temperature-independent. Above 50 degrees C, our data reveals the formation of intermolecular hydrogen bonding leading to the formation of intermolecular beta sheet structures. The IR band absorption at 1618 cm(-1) increases strongly as a function of temperature. The scattered intensity increases and becomes strongly q(2)-dependent. The dynamic structure factor is not a single exponential decay and becomes strongly dependent on the scattering angle. These results demonstrate that aggregation occurs in fibronectin solution. When temperature decreases, this aggregation is found irreversible. Fibronectin aggregation is driven by the formation of intermolecular hydrogen bonds responsible for intermolecular beta sheet structures.

Fibronectins↗
PubMed2002

Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3'-phosphoadenosine-5'-phosphate phosphatase activities: a novel target of lithium therapy.

Lithium cations exert profound and selective psychopharmacological effects on ameliorate manic-depressive psychosis. Although lithium is an effective drug for both treatment and prophylaxis of bipolar disorder, the precise mechanism of action is not well understood. Lithium acts as both an uncompetitive and non-competitive inhibitor of several lithium- sensitive phosphatases with regard to substrate and magnesium cofactor, respectively. In this work, we report the crystal structure and reaction mechanism of Rattus norvegicus 3'-phosphoadenosine 5'-phosphate and inositol 1,4-bisphosphate phosphatase (RnPIP), a recently identified target of lithium therapy. This Li(+)-sensitive enzyme plays a crucial role in several cellular processes, such as RNA processing, sulphation reactions and probably inositol recycling. RnPIP specifically removes the 3'-phosphate group of 3'-phosphoadenosine 5'-phosphate (PAP) and the 1'-phosphate group of inositol 1,4-bisphosphate (I(1),(4)P(2)) producing AMP and inositol 4'-phosphate, respectively. The crystal structure of RnPIP complexed with AMP, Pi and magnesium ions at 1.69 A resolution provides insight into the reaction mechanism of the hydrolysis of PAP. The core fold of the enzyme is equivalent to that found in other Li(+)-sensitive phosphatases, such as inositol monophosphatase, but molecular modelling of I(1),(4)P(2) in the RnPIP active site reveals important structural determinants that accommodate this additional substrate. RnPIP is potently inhibited by lithium and, as the accumulation of PAP inhibits a variety of proteins, including sulphotransferases and RNA processing enzymes, this dual specificity enzyme represents a potential target of lithium action, in addition to inositol monophosphatases.

Adenosine Diphosphate↗
PubMed2002

A prospective double-blind randomized controlled trial comparing the suitability of KTP laser tonsillectomy with conventional dissection tonsillectomy for day case surgery.

Tonsillectomy using a KTP laser has been performed increasingly but is not a routinely practised technique in the UK. In the USA, tonsillectomy is often performed as a day case procedure but, here in the UK, it is still standard practice to admit patients for overnight stay. We present the largest prospective double-blind randomized controlled trial to date (151 patients) comparing KTP laser with standard dissection tonsillectomy and assess the suitability of both procedures for day case surgery. We found that there was significantly less peroperative haemorrhage if tonsillectomy was performed using the KTP laser, but it did cause more postoperative pain, more depression in mood and a higher rate of both reactionary and secondary haemorrhage, which was not significant when compared with conventional dissection. There was no difference in operating time, and over 40% of patients in each group needed overnight admission. We conclude that KTP laser tonsillectomy offers no benefit apart from less intraoperative bleeding over standard dissection tonsillectomy. Discharge from hospital after tonsillectomy was found to be unpredictable. Tonsillectomy is therefore an unsuitable procedure for planned surgery through a day unit, but approximately 58% of patients could be discharged on the same day from an extended day surgery unit, and the rest have one night in hospital.

Adolescent↗
PubMed2002

Non-targeted effects of radiation: bystander responses in cell and tissue models.

The standard paradigm for radiation effects in cellular systems has involved direct damage to DNA and in particular, DNA double strand breaks as the triggering lesions leading to mutation, cell death and transformation. Recently, however, a growing body of evidence has reported non-targeted effects, which are not a direct consequence of the initial lesions produced in cellular DNA. These have included bystander responses, genomic instability, gene induction, adaptive responses and low dose hypersensitivity. A common observation of these responses is that they dominate at low doses and saturate with increasing dose. Non-targeted effects may therefore have consequences for extrapolation of risk estimates to low doses if these are important in vivo. A range of experimental techniques is being used to study non-targeted responses, including microbeam approaches. Microbeams have considerable advantages in that they allow individual cells and subcellular targets to be selected within populations with precise low doses and, if required, exact dose rates. Recent advances also allow targeting of 3-D cell systems. The mechanisms underlying non-targeted responses appear to involve production of reactive oxygen species and direct cell-to-cell signalling via gap junctional intercellular communication although significant differences exist in different cell types. The triggering lesions for these responses remain unclear however. Some non-targeted responses may be inter-related, for example in the case of bystander responses and instability and may be part of a general stress response system in irradiated populations. Some non-targeted effects may also act as protective mechanisms; if they lead to the removal of potentially damaged cells from the population.

Animals↗
PubMed2002

Purification of native alpha-enolase from Streptococcus pneumoniae that binds plasminogen and is immunogenic.

Many pathogenic bacteria express plasminogen receptors on their surface, which may play a role in the dissemination of organisms by binding plasminogen that, when converted to plasmin, can digest extracellular matrix proteins. A 45-kDa protein was purified from Streptococcus pneumoniae and confirmed as an alpha-enolase by its ability to catalyse the dehydration of 2-phospho-D-glycerate to phosphoenolpyruvate and by N-terminal sequencing. The activity of alpha-enolase was found in the cytoplasm and in whole cells. Activity was also demonstrated in cell wall fractions, which confirmed that alpha-enolase is a cytoplasmic antigen also expressed on the surface of S. pneumoniae. The plasminogen-binding activity of alpha-enolase was examined by Western blot, which showed that purified alpha-enolase was able to bind human plasminogen. Immunoblots of the purified 45-kDa alpha-enolase with 22 sera from patients with pneumococcal disease showed binding in 15 cases, indicating that pneumococcal enolase is immunogenic.

Amino Acid Sequence↗