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Biomedical subjects

S Dalal

Publications and source records attributed to S Dalal.

At least 19 recordsLinked to original sources
PubMed2005

Gross anatomy of the interphalangeal joint of the great toe: implications for excision of plantar capsular accessory ossicles.

Bony or cartilaginous ossicles occur at the plantar aspect of the interphalangeal joint of the great toe. The variation in pattern, prevalence, and anatomic relationships of these structures is not clearly established in the literature, especially in a Caucasian population. Without this knowledge, pathology at this joint may be underestimated and surgical approaches may be poorly planned particularly as radiographs underestimate the incidence of ossicles at this joint. The aims of this study were to determine the incidence and pattern of ossicles at this joint and to establish their anatomic relationships to aid planning the approach for their excision. The interphalangeal joint of the left hallux was dissected in 40 British Caucasian cadavers and the pattern of nodules and their anatomic relationships were established. In 27.5% of subjects, there was no identifiable ossicle and, in these specimens, the tendon of flexor hallucis longus was adherent to the joint capsule. In the remaining specimens (72.5%), a bursa separated the tendon of flexor hallucis longus from the plantar joint capsule and nodules were found embedded within the joint capsule. More than half (52.5%) of the specimens had a single nodule located centrally within the plantar capsule and the remaining 20% had two nodules lying within the capsule. This study shows that a large proportion of the population have either one or two bony or cartilaginous ossicles at this joint. It has also shown that, when present, these structures do not lie within the tendon of flexor hallucis longus and may be most safely excised from a medial approach.

Adult↗
PubMed2003

Effect of homocysteine on cytokine production by human endothelial cells and monocytes.

BACKGROUND: Hyperhomocysteinaemia is an independent risk factor in the development of cardiovascular disease. Although homocysteine has been shown to affect endothelial cell function, the mechanisms by which it induces disease states are still poorly understood. Here, we report the ability of homocysteine to influence inflammatory cytokine/chemokine production by human saphenous vein endothelial cells, peripheral blood monocytes and monocyte-derived macrophages. METHODS: Human saphenous vein endothelial cells, peripheral blood monocytes and monocyte-derived macrophages were treated with homocysteine (0.1-5 mmol/L) for 4 and/or 24h. Tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-8 production was measured in the cell culture media using commercially available enzyme-linked immunosorbent assays. RESULTS: Interleukin-6 production by human saphenous vein endothelial cells was significantly stimulated following a 24-h treatment with homocysteine, whilst IL-8 concentrations were inhibited after both 4- and 24-h treatments. Homocysteine was also found to stimulate IL-1beta production by human peripheral blood monocytes and TNF-alpha production by monocyte-derived macrophages. CONCLUSIONS: Overall, results from this study suggest that homocysteine alters the profile of cytokine/chemokine production by endothelial cells and macrophages. This altered profile may be important in the inflammatory events that initiate or enhance the development of atherosclerotic lesions.

Cell Size↗
PubMed2000

Understanding the sequence determinants of conformational switching using protein design.

An important goal of protein design is to understand the forces that stabilize a particular fold in preference to alternative folds. Here, we describe an extension of earlier studies in which we successfully designed a stable, native-like helical protein that is 50% identical in sequence to a predominantly beta-sheet protein, the B1 domain of Streptococcal IgG-binding protein G. We report the characteristics of a series of variants of our original design that have even higher sequence identity to the B1 domain. Their properties illustrate the extent to which protein stability and conformation can be modulated through careful manipulation of key amino acid residues. Our results have implications for understanding conformational change phenomena of central biological importance and in probing the malleability of the sequence/structure relationship.

Amino Acid Sequence↗
PubMed1999

Multiple functions of human papillomavirus type 16 E6 contribute to the immortalization of mammary epithelial cells.

The E6 proteins from cervical cancer-associated human papillomavirus (HPV) types such as HPV type 16 (HPV-16) induce proteolysis of the p53 tumor suppressor protein through interaction with E6-AP. We have previously shown that human mammary epithelial cells (MECs) immortalized by HPV-16 E6 display low levels of p53. HPV-16 E6 as well as other cancer-related papillomavirus E6 proteins also binds the cellular protein E6BP (ERC-55). To explore the potential functional significance of these interactions, we created and analyzed a series of E6 mutants for their ability to interact with E6-AP, p53, and E6BP in vitro. While there was a similar pattern of binding among these E6 targets, a subset of mutants differentiated E6-AP binding, p53 binding, and p53 degradation activities. These results demonstrated that E6 binding to E6-AP is not sufficient for binding to p53 and that E6 binding to p53 is not sufficient for inducing p53 degradation. The in vivo activity of these HPV-16 E6 mutants was tested in MECs. In agreement with the in vitro results, most of these p53 degradation-defective E6 mutants were unable to reduce the p53 level in early-passage MECs. Interestingly, several mutants that showed severely reduced ability for interacting with E6-AP, p53, and E6BP in vitro efficiently immortalized MECs. These immortalized cells exhibited low p53 levels at late passage. Furthermore, mutants defective for p53 degradation but able to immortalize MECs were also identified, and the immortal cells retained normal levels of p53 protein. These results imply that multiple functions of HPV-16 E6 contribute to MEC immortalization.

Animals↗
PubMed1998

Potentiation of opioid analgesia by psychostimulant drugs: a review.

Recent research has investigated drug combinations that enhance the analgesic effectiveness of their component substances. Many studies have examined the combination of opioids and psychostimulant drugs, such as amphetamine and methylphenidate. Despite the positive results reported in the literature, this combination is rarely used in clinical practice. The purpose of this paper is to review the literature on the opioid-amphetamine combination. Experiments with animal and human subjects provide convincing evidence that d-amphetamine or methylphenidate potentiate the analgesic effects of morphine. Psychostimulant drugs have been shown in animal studies to possess intrinsic analgesic properties and to have the ability to enhance the analgesic properties of opioids when both types of drugs are given in combination. Studies with human subjects have confirmed the enhancement of opioid analgesia by amphetamines and, in addition, have demonstrated that psychostimulant drugs produce a decrease in somnolence and an increase in general cognitive abilities. The greater cognitive alertness, moreover, allows the use of larger opioid doses, which can produce a substantial increase in analgesia. These results indicate another possible method to enhance the quality of life in patients with difficult pain problems. Although the enhanced cognitive effects are well established, the effects on pain need further study to determine the mechanisms of action and the drug combinations and administration patterns that would maximize their effects.

Analgesics, Opioid↗
PubMed1998

Psychostimulant drugs potentiate morphine analgesia in the formalin test.

Recent research has shown that the psychostimulant drug dextroamphetamine can increase the analgesia produced by opioids. Despite the strong, positive results in human clinical subjects and in animals, this combination is rarely used in clinical practice. The purpose of this paper is to investigate whether the psychostimulant drug methylphenidate (MP) can potentiate morphine analgesia in the rat formalin test, and to compare its effectiveness to that of dextroamphetamine (AMP). The formalin test was used because its long-lasting pain of moderate intensity resembles human clinical pain. Two different drug administration times were used to observe whether the early phase of the formalin response would be differentially affected by the drugs. At Drug Administration Time 1, rats received morphine 30 min prior to the formalin injection (-30 min) and MP or AMP 20 min prior to the formalin injection (-20 min). At Drug Administration Time 2, rats received morphine 10 min prior to the formalin injection (-10 min) and MP or AMP immediately prior to the formalin injection (0 min). All drugs were given subcutaneously. The results indicate that low doses of MP or AMP potentiate the analgesic effects of morphine. The clinical value of these drug combinations merits further investigation in animals and in humans.

Analgesics, Opioid↗
PubMed1997

Transmuting alpha helices and beta sheets.

Protein architecture involves two main secondary structural classes: alpha helices and beta sheets. Some natural proteins alter their fold in response to changes in solution conditions or as a consequence of mutation. Here, we discuss recent attempts to induce such conformational changes by design: specifically, the motivation and success of efforts to change one protein fold into a different one in response to the 'Paracelsus Challenge'. The results of such efforts may provide a better understanding of the processes that underlie conformational plasticity in proteins.

Amino Acid Sequence↗
PubMed1997

Protein alchemy: changing beta-sheet into alpha-helix.

For most proteins the amino acid sequence determines the tertiary structure. The relative importance of the individual amino acids in specifying the fold, however, remains unclear. To highlight this, Creamer and Rose put forth the 'Paracelsus challenge': Design a protein with 50% sequence identity to a protein with a different fold. We have met this challenge by designing a sequence which retains 50% identity to a predominantly beta-sheet protein, but which now adopts a four helix bundle conformation and possesses the attributes of a native protein. Our results emphasize that a subset of the amino acid sequence is sufficient to specify a fold, and have implications both for structure prediction and design.

Amino Acid Sequence↗
PubMed1997

The rapid diagnosis of acute promyelocytic leukaemia using PML (5E10) monoclonal antibody.

Acute promyelocytic leukaemia (APL) is characterized cytogenetically by t(15;17)(q22:q21) which results in the production of a PML/RAR alpha fusion protein. Detection of the translocation or the fusion gene product is required for objective diagnosis of APL. This can be accomplished by conventional cytogenetic methods, fluorescence in situ hybridization or RT-PCR. Such techniques are time consuming and not universally available. The intracellular distribution of the PML protein in promyelocytes is characteristically altered in APL and this can be detected by immunocytochemistry. We have assessed two immunocytochemical methods, immunofluorescence and alkaline phosphatase-anti-alkaline phosphatase staining (APAAP), with regard to sensitivity, specificity and rapidity of diagnosis. 85 patients with AML including 15 cases of APL were studied. Immunofluorescence PML detection was concordant with RT-PCR for t(15:17) in 14/15 (93.3%) cases with no false positives. The negative APL case in our series was a patient with a 5' PML breakpoint who did not express the reciprocal t(17;15) fusion product. APAAP was concordant in only 6/13 (46%) APL cases with one false positive. In conclusion, immunofluorescent localization of PML using 5E10 monoclonal antibody is a rapid, sensitive and specific diagnostic tool for APL.

Antibodies, Monoclonal↗
PubMed1996

Mutational analysis of human papillomavirus type 16 E6 demonstrates that p53 degradation is necessary for immortalization of mammary epithelial cells.

We have previously demonstrated that normal human mammary epithelial cells (MECs) are efficiently immortalized by human papillomavirus type 16 (HPV16) E6. HPV16 E6 binds to and induces p53 degradation in vitro and induces a marked reduction of p53 protein in MECs. Low-risk HPV6 E6 is defective for p53 binding and degradation in vitro but immortalized MECs at low efficiency. The HPV6 E6-immortalized MECs had markedly reduced levels of p53. To directly investigate whether the ability of HPV16 E6 to stimulate p53 degradation is required for E6-induced immortalization, a series of HPV16 E6 mutants were analyzed for the ability to bind and degrade p53 in vitro, induce a reduction in p53 levels in vivo, and immortalize MECs. We observed that one set of mutants efficiently immortalized MECs, caused a reduction in p53 levels in vivo, and degraded p53 in vitro. Other mutants immortalized MECs with low efficiency and either induced p53 degradation at low levels or were unable to induce p53 degradation in vitro; however, all of the immortal clones displayed low levels of p53. A third class of mutants did not immortalize MECs and failed to induce a reduction in p53 levels in vivo or degrade p53 in vitro. These results demonstrate that a reduction in p53 protein levels due to enhanced degradation is essential for MEC immortalization by HPV16 E6.

Base Sequence↗