Changing trends of services used as first contact by patients with mental health problems.

BACKGROUND: In the past, traditional faith healers and practitioners of alternative medicine have often been reported to be the first source of contact for Indian patients with mental health problems. However, over the past few decades, this trend seems to be changing. METHOD: Using a semi-structured questionnaire, we assessed 200 new patients at a psychiatric outpatient service in a general hospital for the first service contact used by them for their mental health problems. RESULTS: Psychiatrists, non-psychiatric physicians, traditional faith healers and practitioners of alternative medicine were the first service contact for 91 (45.5%), 88 (44%), 16 (8%) and 5 (2.5%) patients, respectively. Patients suffering from severe mental illnesses were more likely to choose a psychiatrist as the first contact, whereas those with neurotic, stress-related and organic mental disorders contacted a non-psychiatric physician. CONCLUSION: In the current scenario, psychiatrists and nonpsychiatric physicians serve as the first service contact for most patients with mental health problems in India, though traditional faith healers and practitioners of alternative medicine are contacted by a minority.

Global analysis of nuclear receptor expression and dysregulation in human osteoarthritic articular cartilage: reduced LXR signaling contributes to catabolic metabolism typical of osteoarthritis.

OBJECTIVE: Compare the expression and regulation of nuclear receptors (NRs) in osteoarthritic and normal human articular cartilage. METHOD: The transcriptional levels of 48 NRs and additional related proteins were measured in mRNA from human articular cartilage from subjects with osteoarthritis (OA) and compared to samples from subjects without OA, using microarrays, individual quantitative reverse transcriptase polymerase chain reaction assays, and a custom human NR TaqMan Low Density Array (TLDA). The functional effect of liver X receptor (LXR) activity in cartilage was studied by measuring proteoglycan (PG) synthesis and degradation in articular cartilage explant cultures following treatment with the synthetic LXR agonist T0901317. RESULTS: Thirty-one of 48 NRs analyzed by TLDA were found to be measurably expressed in human articular cartilage; 23 of these 31 NRs showed significantly altered expression in OA vs unaffected cartilage. Among these, LXRalpha and LXRbeta, and their heterodimeric partners retinoid X receptor (RXR)alpha and RXRbeta were all expressed at significantly lower levels in OA cartilage, as were LXR target genes ABCG1 and apolipoproteins D and E. Addition of LXR agonist to human OA articular chondrocytes and to cartilage explant cultures resulted in activation of LXR-mediated transcription and significant reduction of both basal and interleukin (IL)-1-mediated PG degradation. CONCLUSIONS: Articular cartilage expresses a substantial number of NRs, and a large proportion of the expressed NRs are dysregulated in OA. In particular, LXR signaling in OA articular cartilage is impaired, and stimulation of LXR transcriptional activity can counteract the catabolic effects of IL-1. We conclude that LXR agonism may be a possible therapeutic option for OA.

The carboxy-terminal hydrophobic domain of TIG3, a class II tumor suppressor protein, is required for appropriate cellular localization and optimal biological activity.

TIG3 is a recently discovered class II tumor suppressor protein, originally isolated from retinoid-treated cultured epidermal keratinocytes, that suppresses the proliferation of a variety of epithelial cell types. In the present study, we examine the ability of this protein to reduce CHO, T47D and HaCaT cell proliferation, and the role of the carboxy-terminal hydrophobic domain in this regulation. Vector-mediated expression of the full length TIG3 protein, TIG31-164, results in a 50-70% reduction colony formation efficiency. Expression of a truncated mutant, TIG31-134, that lacks the putative carboxy-terminal membrane-anchoring domain, results in a partial loss of ability to suppress colony formation. The fact that the truncated protein remains partially active suggests that both the amino- and carboxy-terminal regions of TIG3 are required for optimal growth suppression. The full-length protein is distributed in a perinuclear location, and is not present in the nucleus. TIG31-134, in contrast, is distributed in the cytoplasm. Thus, a change in location is associated with the partial loss of activity. We also monitored the distribution of green fluorescent protein (GFP)-TIG3 fusion proteins. GFP-TIG31-164 was localized in a pattern similar to that observed for TIG31-164, while GFP-TIG31-134 displayed a distribution pattern similar to GFP. This suggests that the c-terminal hydrophobic domain has an important role in determining the intracellular localization of TIG3. In addition, GFP-TIG31-164 retains the ability to inhibit cell function, while GFP-TIG31-134 is inactive.

Regions of association between the alpha and the beta subunit of the gastric H,K-ATPase.

A binding and a yeast two-hybrid analysis were carried out on the gastric H,K-ATPase to determine interactive regions of the extracytoplasmic domains of the alpha and beta subunits of this P type ATPase. Wheat germ agglutinin fractionation of fluorescein 5-maleimide-labeled tryptic fragments of detergent-solubilized H, K-ATPase showed that a fragment Leu855 to Arg922 of the alpha subunit was bound to the beta subunit. The yeast two-hybrid system showed that the region containing only a part of the seventh transmembrane segment, the loop, and part of the eighth transmembrane segment was capable of giving positive interaction signals with the ectodomain of the beta subunit. The sequence in the extracytoplasmic loop close to the eighth transmembrane segment, namely Arg898 to Thr928, was identified as being the site of interaction using this method. We deduced that the sequence Arg898 to Arg922 in the alpha subunit has strong interaction with the extracytoplasmic domain of the beta subunit. Again, using yeast two-hybrid analysis, two different sequences in the beta subunit Gln64 to Asn130 and Ala156 to Arg188 were identified as association domains in the extracytoplasmic sequence of the beta subunit. These data enable identification of major associative regions of the alpha-beta subunits of the H,K-ATPase.

Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin.

Retinoids exert their biologic effects through two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which belong to the superfamily of steroid/thyroid hormone nuclear receptors. By using a subtraction hybridization approach, we have identified a cDNA sequence TIG2 (Tazarotene-induced gene 2), whose expression is up-regulated by the treatment of skin raft cultures by an RAR beta/gamma-selective anti-psoriatic synthetic retinoid tazarotene [AGN 190168/ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl] nicotinate]. The retinoid-mediated up-regulation in the expression of TIG2 was confirmed by Northern blot analysis. Upon sequencing, TIG2 was found to be a cDNA whose complete sequence was not in the GenBank and EMBL data bases. The TIG2 cDNA is 830 bp long and encodes a putative protein product of 164 amino acids. TIG2 is neither expressed nor induced by tazarotene in primary keratinocyte and fibroblast cultures. Thus, TIG2 is expressed and induced by tazarotene only when keratinocytes and fibroblasts form a tissue-like 3-dimensional structure. We further demonstrate that RAR-specific retinoids increase TIG2 mRNA levels. In contrast, neither RXR-specific retinoids nor 1,25-dihydroxyvitamin D3 increased TIG2 levels. Finally, we demonstrate that TIG2 is expressed at high levels in nonlesional psoriatic skin but at lower levels in the psoriatic lesion and that its expression is up-regulated in psoriatic lesions after topical application of tazarotene.

Negative regulation of two hyperproliferative keratinocyte differentiation markers by a retinoic acid receptor-specific retinoid: insight into the mechanism of retinoid action in psoriasis.

Retinoids down-regulate the expression of metalloproteinases, cytokines, and other genes involved in cell proliferation and inflammation. Tazarotene (AGN 190168), a retinoic acid receptor (RAR)-specific retinoid, is effective in the treatment of psoriasis, a hyperproliferative and inflammatory skin disease. Because negative regulation of genes appears to be important in the antiproliferative and antiinflammatory action of retinoids, we studied the down-regulation of genes in skin raft cultures by this antipsoriatic retinoid. By subtraction hybridization, we found that migration inhibitory factor-related protein (MRP-8) and skin-derived anti-leukoproteinase (SKALP) are down-regulated by AGN 190168. MRP-8 and SKALP are overexpressed in psoriatic lesions as compared to the normal epidermis, and they are markers of hyperproliferative keratinocyte differentiation. We also show that MRP-8 expression is retinoid inhibitable in cultured keratinocytes induced to differentiate with 10% serum or IFN-gamma, and that MRP-8 is inhibited by RAR but not by retinoid X receptor-specific retinoids in a dose-dependent manner. Finally, MRP-8, SKALP, and the previously characterized differentiation marker, transglutaminase I, are all down-regulated in vivo in psoriatic lesions after treatment with AGN 190168 in comparison to placebo. Taken together, these data suggest that these markers may be down-regulated by tazarotene in psoriasis through direct action on keratinocyte gene expression rather than by an overall tazarotene effect on lesional therapeutic status.

Induction of anti-DNA IgG and IgE antibodies in BALB/c mice.

Immunization of BALB/c mice with denatured DNA (dnDNA)-methylated bovine serum albumin (MBSA) complex along with aluminium hydroxide gel as adjuvant, resulted in the induction of anti-DNA antibodies of both IgG and IgE isotypes demonstrable by avidin-biotin micro enzyme-linked immunosorbent assay (ELISA) and solid phase radioimmunoassay (SPRIA), respectively. In contrast to the high levels of IgG2a and IgG2b anti-DNA antibodies observed in SLE-prone autoimmune mice, more than 90% of the anti-DNA antibodies of IgG isotype were found to be of IgG1 subclass. Specificity of both IgG and IgE antibodies which recognized activated DNA, dnDNA and double-stranded DNA but not RNA was established by competitive ELISA and SPRIA inhibition assays. These antibodies cross-reacted with cibacron blue and chondroitin sulfate but not with various other proteoglycans, nucleosides and nucleotides. Passive cutaneous anaphylaxis reaction in rats showed that these antibodies are capable of inducing in vivo degranulation of mast cells in a dose-dependent manner. These studies lend support to the concept that IgE antibodies directed against DNA may mediate mast cell degranulation and thus contribute to immediate-type hypersensitivity phenomena including hives seen in patients with systemic lupus erythematosus and to the localization of IgE-nucleic acid complexes.

Immediate hypersensitivity to Parthenium hysterophorus. II. Clinical studies on the prevalence of Parthenium rhinitis.

The airborne pollen of the South American weed, Parthenium hysterophorus (American feverfew), accidentally introduced into India was found to be responsible for severe allergic rhinitis. A random clinical survey conducted on 2035 residents of Bangalore city with the aid of questionnaires and skin tests revealed that 7.1% of the study population was suffering from allergic rhinitis due to exposure to Parthenium pollen. Skin-prick tests performed on 1294 clinic patients suffering from nasobronchial allergy during the past 4 years have also shown that 42.5% were sensitive to Parthenium pollen. IgE and IgG antibodies specific for Parthenium pollen allergens were demonstrable in the sera of Parthenium-sensitive rhinitis patients. The specificity of these antibodies to Parthenium allergens was established by ELISA. A 7- to 11-fold higher stimulation was observed when lymphocytes from two Parthenium-sensitive rhinitis patients were treated in vitro with Parthenium pollen extract. To our knowledge, nowhere in the world has such a high incidence of allergic rhinitis due to a single pollen ever been reported.

Surgical treatment for ductal adenocarcinoma of the pancreas.

A ten year community hospital experience of 124 patients with ductal adenocarcinoma of the pancreas proved at biopsy is reported. All patients underwent a celiotomy, and 94 per cent were observed until death. All of the patients were stratified by stage (I, 9 per cent; II, 30 per cent; III, 18 per cent, and IV, 43 per cent). Nine of the patients with Stage I disease underwent resection with a high postoperative mortality rate of 44 per cent and only one five year survivor. Fifty-nine patients with Stages II and III disease underwent biliary bypass with a low postoperative mortality rate of 2 per cent. Bypass of the common bile duct (N = 24) provided more permanent palliation against recurrent jaundice or cholangitis (p less than 0.05), but did not improve the survival time when compared with bypass of the gallbladder (N = 20). This was not true for those with Stage IV disease in whom recurrent jaundice did not develop in those with either bypass of the gallbladder or common duct. Adding prophylactic gastroenterostomy (GE) to biliary bypass (N = 25) conferred no survival benefit, but did protect against subsequent duodenal obstruction (p less than 0.05). Thirty-seven per cent of the 38 patients in whom a GE was not performed had duodenal obstruction develop. Adjuvant radiation and chemotherapy in 22 patients with unresectable Stages II and III disease resulted in a significant prolongation of survival time compared with 15 untreated patients in the control group (p less than 0.05). Fifty-one patients with Stage IV disease underwent biliary bypass or biopsy of the tumor resulting in a 14 per cent postoperative mortality rate and a median survival time of four months. Nine per cent of the 44 survivors with Stage IV disease lived at least one year. The implications of these findings to clinical practice are discussed.