In vivo pharmacological profile of substituted (3-pyridyl)-2-phenylisoxazolidine analogues of nicotine as novel antinociceptives.

Nicotinic ligands have been studied as novel therapeutic interventions in pain therapeutics since a long time. Several nicotinic agonists have been withdrawn from later stages of clinical trials due to lack of efficacy or narrow therapeutic window. These have been documented to act in the central nervous system and produce a wide range of pharmacological effects, including memory enhancing and analgesic actions, antianxiety, antidepressant and muscle coordination. Taking cognizance of the wide pharmacological profile of nicotine and its ligands, it was decided to evaluate some novel isoxazolidine analogues of nicotine for their potential as analgesics, using animal models like Eddy's hot plate and Tail immersion method. The compounds showed marked decrease in hyperalgesic response as compared to pentazocine at a wide range of doses. They were well tolerated as none of the compounds was found to have any seizure potential or mortality even at the highest doses. Thus, these compounds can be developed as potent antinociceptives with better safety profile than nicotine and other currently available pain therapeutics.

Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases--the UK experience.

BACKGROUND: The global lapatinib expanded access programme provided access to lapatinib combined with capecitabine for women with HER2-positive metastatic breast cancer (MBC) who previously received anthracycline, taxane and trastuzumab. METHODS: Progression-free survival (PFS) and safety data for 356 patients recruited from the United Kingdom are reported. Efficacy was assessed in 162 patients from the five lead centres, including objective tumour response rate (ORR), time to disease progression (TTP) and efficacy in those with central nervous system (CNS) metastases. Correlation of PFS and ORR with previous capecitabine treatment was also documented. RESULTS: Overall, PFS for the 356 UK patients was 21 weeks (95% CI: 17.6-24.7). In the 162 assessable patients, ORR was 21% (95% CI: 15-27%) and median TTP was 22 weeks (95% CI: 17-27). Efficacy was greater in capecitabine-naive patients (ORR 23 vs 16.3%, P=0.008). For 34 patients with CNS metastases, ORR was 21% (95% CI: 9-39%), with evidence of improvement in neurological symptoms, and median TTP was 22 weeks (95% CI: 15-28). CONCLUSIONS: Lapatinib combined with capecitabine is an active treatment option for women with refractory HER2-positive MBC, including those with progressive CNS disease.

Sharp dissection of the Weiss ring to induce a posterior vitreous detachment.

Removal of the posterior hyaloid is an important aspect of pars plana vitrectomy surgery in cases including but not limited to macular holes. A surgical technique is described in which the Weiss ring can be easily detached from the optic nerve with little to no trauma.

Inter-pregnancy folate and iron status of women in an inner-city population.

The purpose of the present study was to evaluate whether micronutrient supplementation improved the nutritional status of women with poor diets during the inter-pregnancy interval. Fifty-five women who had given birth to a low birth weight baby (<2.5 kg), and who planned to have a further pregnancy, were recruited to a prospective randomised study in East London, UK. Of the fifty-five mothers recruited, forty-four (78 %) met fewer than four of sixteen dietary reference values according to the information provided in a 7 d diet diary, and were categorised as having an 'inadequate' diet. Half of the mothers in the 'inadequate'-diet group were randomly assigned to receive a micronutrient and a single cell oil supplement containing docosahexaenoic acid. All participants received dietary advice based on analysis of their diet diaries, and general lifestyle advice on preparing for pregnancy. Mothers had a blood sample taken at 3 and 9 months post-partum to measure their folate, Fe stores and fatty acid status. Mean serum and erythrocyte folate levels increased significantly between 3 and 9 months post-partum in both the adequate-diet group and the supplemented group. At 9 months post-partum, over half of the unsupplemented, inadequate-diet group remained severely deficient in folate (serum folate <230 nmol/l) and had low serum ferritin levels (<15 microg/l). The high prevalence of inadequate diets in this inner-city population and the low motivation of women to participate in a nutrition programme suggests that consideration should be given to the provision of free folate and Fe supplements to all women in this and similar populations, or at least to women who have delivered a low birth weight baby, who plan further pregnancies.

Characterization of the substrate specificity of alpha1,3galactosyltransferase utilizing modified N-acetyllactosamine disaccharides.

alpha1,3galactosyltransferase (alpha1,3GalT) catalyzes the synthesis of a range of glycoconjugates containing the Galalpha1,3Gal epitope which is recognized by the naturally occurring human antibody, anti-Gal. This enzyme may be a useful synthetic tool to produce a range of compounds to further investigate the binding site of anti-Gal and other proteins with a Galalpha1,3Gal binding site. Thus, the enzyme has been probed with a series of type 2 disaccharide-C8(Galbeta1-4GlcNAc-C8) analogs. The enzyme tolerated acceptors with modifications at C2 and C3 of the N-acetylglucosamine residue, producing a family of compounds with a nonreducing alpha1,3 linked galactose. Compounds that did not serve as acceptors were evaluated as inhibitors. Interestingly, the type 1 disaccharide-C8, Galbeta1-3GlcNAc-C8, was a good inhibitor of the enzyme (Ki = 270 microM vs. Km = 190 microM for Galbeta1-4GlcNAc-C8). A potential photoprobe, based on a modified type 2 disaccharide (octyl 3-amino-3-deoxy-3-N-(2-diazo-3, 3, 3-trifluoropropionyl-beta-D-galactopyranosyl-(1, 4)-2-acetamindo-2-deoxy-beta-D-glycopyranoside, (DTFP-LacNAc-C8)), was evaluated as an inhibitor of alpha1,3GalT. alpha1,3GalT bound DTFP-LacNAc-C8 with an affinity (Ki = 300 microM) similar to that displayed by the enzyme for LacNAc-C8. Additional studies were done to determine the enzyme's ability to transfer a range of sugars from UDP-sugar donors. The results of these experiments demonstrated that alpha1,3GalT has a strict specificity for UDP-Gal. Finally, inactivation studies with various amino acid modifiers were done to obtain information on the importance of different types of amino acids for alpha1,3GalT activity.

The projection of the cervical disc and uncinate process on the posterior aspect of the cervical spine.

BACKGROUND: Surgical techniques of foraminotomy for decompression of the cervical nerve have been well described in the literature. Excessive resection of the facet joint and laminae may decrease segmental stability and increase scar formation. How much bony resection is adequate to remove a soft or hard disc herniation is not known. No studies regarding this subject are available. METHODS: Thirty-nine adult dry bone spines from C3 to C7 were used and four measurements on each vertebra were taken in this study. The first three measurements included the vertical distances between the superior borders of the lamina and the vertebral body measured at the midline of the laminae, the middle of the lamina, and the lamina-facet junction, respectively. The fourth was the horizontal distance between the medial most border of the superior facet and the tip of the uncinate process. RESULTS: No significant differences between male and female specimens were found in any measurements in this study. The mean vertical distances from the superior border of the lamina inferior to the superior border of the vertebral body measured at the three points for all levels were approximately 1-3 mm, although the standard deviations for those were relatively high. The tip of the uncinate process was located from 2 mm at C3 to 1 mm at C6 medial to the medial most border of the superior facet, and then changed to be located 1 mm lateral to the medial most border of the superior facet. CONCLUSIONS: This study suggests that a semicircular laminotomy placed on the inferior aspect of the lamina above may be adequate for a lateral soft disc herniation because the inferior border of the disc is higher than the superior border of the inferior lamina, whereas a traditional foraminotomy is needed for a hard disc pathology.

Inhibitory effect of amiloride on the urokinase plasminogen activators in prostatic cancer.

The diuretic drug amiloride (AMLD), which competitively inhibits the catalytic activity of urokinase plasminogen activators (UPA), was used to study its effects on the proteolytic enzymes implicated in the invasiveness and metastases in a prostatic tumor model carrying two different sublines of adenocarcinoma of the prostate. Our data showed that UPA activity was significantly higher, both in the cytosol and pellet of R3327-AT3, a fast-growing highly metastatic and androgen-insensitive tumor, as compared to the G3327-G subline, a slow-growing nonmetastatic tumor of the prostate. The UPA activity in AT3 tumor dropped when the rats were treated with AMLD for 3 weeks. The UPA activity in the sera and tumor effusions from rats with AT3 tumor was significantly higher as compared to those with G subline tumor. The number of pulmonary metastatic foci was the same in untreated rats as compared to those treated with AMLD. The lymph node inspection after 3 weeks revealed no secondary tumor in the AMLD-treated group. The role of UPA in the metastases of prostate cancer is discussed.

Metastatic behavior of prostatic tumor as influenced by the hematopoietic and hematogenous factors.

Metastasis represents a hallmark of the tumor cell's escape from normal cellular behavior to acquired invasive and migratory style. Metastasis of prostate cancer (Pca) depends upon the interplay of a series of hematogenous and hematopoietic factors. We investigated the role of some of those factors implicated in the dissemination process in two separate sublines of adenocarcinoma of the prostate. Our data revealed that (1) the urokinase plasminogen activator activity was significantly higher in R3327-AT3, an aggressive metastatic tumor, as compared to R3327-G, a nonmetastatic tumor of the prostate, (2) the concentration of platelets decreased, and the platelet-aggregating activity increased significantly when the platelets were reacted with exogenous aggregating agents and tumor effusions to suggest that activation of the hemostatic system could protect tumor cells from immunosurveillance and facilitate the process of hematogenous dissemination, and (3) transferrin, which has been reported to have a growth-promoting effect on Pca, did not show any appreciable effect on tumor growth but did alter the level of in vitro adherence which possibly could lead to better attachment and increased invasive behavior of tumor cells.

Potential role of platelets and coagulation factors in the metastasis of prostatic cancer.

One of the common surgical procedures used in the management of prostate cancer is transurethral resection of the prostate in which the possibility of the escape of tumor cells and their encounter with the hemostatic system is reported to contribute to the threat of hematogenous dissemination. We are reporting about the role of the hemostatic system involving the platelets and coagulation factors in the dissemination process in a tumor model carrying Dunning's R3327 AT3 adenocarcinoma of the prostate whose metastatic behavior is similar to that of human prostatic cancer. Our data revealed that the number of circulating platelets dropped and their aggregation activity increased in tumor-bearing rats as compared to controls. Normal platelets when treated with tumor effusions and reacted with the exogenous aggregating agent collagen exhibited a significant increase in the aggregating activity suggesting that the tumor and its microenvironment were capable of activating the hemostatic system. Out of eight coagulation factors measured only factors XI and XII were significantly decreased in tumor-bearing rats. The role of platelets in the metastatic process is discussed.

Body shape perception and dieting in preadolescent British Asian girls: links with eating disorders.

Body shape dissatisfaction and dieting have previously been reported in 9-year-old Caucasian girls. As British adolescents of Asian origin appear at least as vulnerable to eating disorders, the present study investigated these issues in preadolescent British Asian girls. Fifty-five Asian and 42 Caucasian 9-year-olds completed assessments of dietary restraint, body esteem, body satisfaction, and body figure preferences. The study revealed a high priority for thinness in both the Asian and Caucasian girls. Their desire for thinness was present even though the Asian girls had a significantly lower body weight than their Caucasian peers. Both groups of high restraint girls expressed body shape discontent and lower body esteem. In addition, an association was found in the Asian sample between reported dieting and the cultural orientation of their family. These results demonstrate the wide appeal of thinness, which in combination with intercultural and intrafamilial conflict, may strongly influence eating and contribute to the development of eating disorders.

Family pathology and anorexia in the Indian context.

Frequent associations have been found between family interaction and anorectic behaviour. Family theorists have viewed anorexia as a manifestation of a dysfunctional family system. We report three families of cases of anorexia (one male and two female) where the symptom was a reflection of family pathology and was being maintained by it. The cases emphasize the need to assess families of anorectics in detail and view them in the cultural context of eating.

Immunomodulatory effect of cyclophosphamide on host humoral immunity in Dunning's R-3327 adenocarcinoma of the prostate.

The object of the present investigations was delineation of the exclusive effects of cyclophosphamide (Cytoxan) on host humoral response to tumor, as evaluated by the level of circulating antigen/antibody complexes (AACs), which may reflect the chemo-responsiveness of hosts and provide a rationale for new therapeutic strategies. Our data, recorded in Copenhagen X Fischer rats bearing Dunning's R-3327 Mat Ly-Lu adenocarcinoma of the prostate, show no modulatory effect of cyclophosphamide at 10 mg/kg, a nonspecific immunosuppressive effect at 30 mg/kg, and a definite immunostimulatory effect on host humoral immunity at 100 mg/kg. Sequential determination of AAC levels at different stages of tumor growth, i.e. from the primary to the metastatic stage, performed with the original purpose of demonstrating that any disturbance in the immunoregulatory mechanism of the host was due to cyclophosphamide rather than to changes in tumor load, revealed that levels of AACs parallel disease progression in the initial stages of primary tumor growth but rapidly decrease to near-normal levels in the presence of heavy tumor burden.

Suppression of canine antral gastrin secretion by urine.

Distention of the gastric antrum with an alkaline fluid normally results in the secretion of gastrin. Following gastrocystoplasty in humans, however, hypergastrinemia has not been observed. We explored the possibility that a component of urine may suppress antral gastrin activity in the dog. Partial cystectomy and antral transposition to the bladder (ATB) was performed in five animals and antral transposition to the colon (ATC) was performed in five other dogs to serve as a hypergastrinemic controls. At four and eight weeks after surgery the mean serum gastrin levels in the ATC dogs were significantly greater than the mean preoperative levels (p less than 0.05). In contrast, at four and eight weeks after surgery the mean serum gastrin levels in the ATB animals were significantly less than the mean preoperative levels (p less than 0.05). The antral G-cell density as determined by immunohistochemical study at eight weeks after surgery was greater than normal in the ATC dogs but less than normal in the ATB dogs; but the differences did not achieve statistical significance. In another series of experiments using four other dogs a 4% aqueous peptone solution and a 4% peptone solution in concentrated dog urine were instilled into exteriorized antral pouches. The mean serum gastrin levels at 60 and 90 minutes after instillation of the former were significantly increased (p less than 0.05), but there was little or no change after instillation of the latter. Urine, or a component of urine, appears to suppress canine antral gastrin secretion and may explain the absence of hypergastrinemia following gastrocystoplasty in humans.

Transient post-partum thyroid dysfunction and postnatal depression.

In the course of a population study of thyroid dysfunction in pregnancy and the post-partum period, 65 women, considered to be antibody-positive (microsomal and thyroglobulin), and 82 antibody-negative women were assessed for postnatal depression at 6-8 weeks post partum. The women were also assessed for the development of post-partum thyroid dysfunction. Of the 147 women, 22 met DSM-III criteria for major depression. The presence of autoantibodies showed little association with depressed mood but there was a minor association of postnatal depression with actual thyroid dysfunction in that incidence of the latter condition was higher in depressed women (Raskin scale P less than 0.01; Edinburgh scale P less than 0.05; Montgomery-Asberg scale P less than 0.1). Three of eight mothers with thyroid dysfunction had major depression and were depressed on all three scales.

Role of transurethral resection of the prostate in hematogenously disseminated metastasis.

Dissemination of tumor cells by vascular channels seems to be enhanced by certain surgical procedures, e.g. transurethral resection of the prostate, an operative procedure commonly used in the diagnosis and management of prostatic cancer, the third biggest killer of men in the United States. Circulating tumor cells have been the subject of great controversy as they are considered to be the connecting link between the primary tumor and the hematogenously disseminated metastatic growths. Isolation and identification of tumor cells which get released into the vascular channels is somewhat complicated. We report our experience with a technique for isolating and identifying prostatic tumor cells in the circulation and briefly discuss the role of transurethral resection of the prostate in the management of prostatic cancer.

Social support system and family burden due to chronic schizophrenia in rural and urban background.

The present study discusses the possible relationship between the Family Burden as experienced by the family members of chronic schizophrenic patients and Social Support System as perceived by the patients and compares these two between rural and urban backgrounds. Thirty patients each from rural and urban areas were selected. Subjects were administered the Alan Vax et al (1986) Social Support Appraisal and Pai et al (1981) Interview Schedule for assessing Burden on the family of psychiatric patient. The rural and urban families were found to have experienced equal burden and also perceived equal Social Support System. The study finds no relationship between Family Burden and Social Support System. After discussion suggestions for future studies are offered.

Inhibition of sensitized leukocyte's in vitro reactivity by circulating immune complexes in prostate cancer.

Circulating immune complexes in the sera of patients with confirmed histological diagnosis of carcinoma of the prostate, were found to interfere in the sensitized leukocyte's in vitro reactivity to prostate cancer associated antigen as evaluated by tube leukocyte adherence inhibition assay, thereby suggesting an inhibitory role of such serum factors in host's anti tumor cell mediated immune responses.

An evaluation of prostate specific antigen in prostatic cancer.

Prostate specific antigen levels were measured in 118 patients with prostatic cancer and 138 control individuals. Prostate specific antigen was sensitive in detecting prostatic cancer. The levels of prostate specific antigen were elevated in 10 per cent of the patients with stage A, 24 per cent with stage B, 53 per cent with stage C and 92 per cent with stage D disease. However, prostate specific antigen levels also were elevated in 9 per cent of the patients with benign prostatic hypertrophy. This lack of specificity in the presence of benign prostatic hypertrophy probably precludes prostate specific antigen from being recommended as a screening test for prostatic cancer. The ultimate role of prostate specific antigen might be as the marker of choice to monitor therapy for prostatic carcinoma.

An evaluation of five tests to diagnose prostate cancer.

In an effort to determine which of five tests was the most efficient in the diagnosis of prostate cancer, 280 male patients were screened employing aspiration cytology, transrectal ultrasound, acid phosphatase, prostate specific antigen, and the digital rectal examination. The digital rectal examination was the most efficient (75%) and in order of decreasing accuracy were prostate specific antigen (74%), prostatic ultrasound (71%), acid phosphatase (66%), and finally aspiration cytology (63%). In an era when what are more expensive and more technology are assumed to be better, what is simple and traditional is ignored. From an evaluation of these patients it appears that the digital rectal examination still retains its diagnostic efficiency. Finally, in this age of escalating medical costs and physician accountability for these expenses, you can't beat the cost - benefit ratio for the old fashioned rectal exam.

Leukocytic subset distributions of spleen cells obtained from rats bearing variants of the Dunning prostatic adenocarcinoma.

Employing monoclonal antibodies, the relative frequencies of mononuclear cell types found in spleen cell populations were compared between rats bearing variants of the Dunning prostate adenocarcinoma and a series of non-tumor bearing control animals. The identification and quantitation of such subsets greatly expands our knowledge of immune status and function. The results indicate that the spleen cell populations from animals bearing either the Dunning R3327-H, G or MAT-LyLu sublines have significant decreases in their helper T cell/suppressor T cell ratios when comparisons are made to cells obtained from non-tumor bearing animals. In addition decreases in total T cell content and increases in splenic monocytes were noted. It appears that most of these deviations are the result of general Dunning tumor presence, rather than due to any particular subline characteristic. These changes may be analogous to similar alterations reported in the peripheral blood of humans bearing Stage D prostatic cancer, suggesting that the Dunning tumor may provide an appropriate model for evaluating interactions between the immune response, the tumor and therapy.