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Rheumatoid arthritis (RA) is a disease with a strong association to collagen antibodies. These associations have also been made with other joint and inflammatory diseases. Previous research has revealed that a response to type II collagen may contribute to the pathogenesis of RA. Histocompatibility antigens and HLA-typed patients were studied to extend previous work on this association and to determine if there is a specific gene involved in the pathogenesis of RA. The possible immunogenetic association of RA was studied by examining the antibodies to collagen. The association between RA and collagen antibodies is believed to be disease specific; however the importance of these antibodies needs to be clarified. There were no significant associations between HLA antigens and high antibody titers; however, in previous studies, antibody titers to collagen in patients who were DR4 positive were higher than those who were DR4 negative. There were significant associations made between HLA antigens and high antibody titers to collagen in the 105 patients studied. An association between RA and HLA-DR4 is well established and investigators believe that the gene DR4 may be susceptible to, or closely linked to RA. Clinical subsets of patients with RA may be associated with different combinations of HLA antigens and further research is needed to determine the gene that is activated in rheumatoid arthritis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Basal cell carcinoma, a form of skin cancer, is especially common in Australia. This cancer has an especially high likelihood of occurring more than once in the same individual. About one third of all patients will develop another basal cell carcinoma within five years. Each year, about 650 new cases of basal cell carcinoma and other skin cancers will occur within a population of 100,000 Australians. As is the case with many cancers, although the majority of cases are sporadic and not inherited, there does seem to be a genetic predisposition among some people. That is, although the cancer itself is not inherited, some people inherit a characteristic, or characteristics, which give them a special susceptibility to skin cancer. Among the most widely studied of inherited characteristics in people is the system of human leukocyte antigens (HLA), which are most important medically because they determine the rejection of transplanted tissues. However, since these antigens seem to be involved with many subtle aspects of immune system function, it is thought they may play a role in the defense against cancer as well. A study was conducted of 34 unrelated patients (30 men and four women) who had developed at least five skin cancers. If HLA antigens are in some way involved in the development of skin cancer, then the frequency of different HLA antigens within the patient group might be expected to be different from the general population. No difference was observed in the Class I antigens, which were the first studied by the transplantation immunologists. However, the risk of skin cancer was found to be related to two of the Class II antigens, also known as the ''DR'' antigens. In confirmation of other research, it was found that the HLA DR1 antigen tended to be preferentially found among patients with basal cell carcinoma. However, the study also found that a second Class II antigen, HLA DR7, was preferentially associated with both basal cell carcinoma and squamous cell carcinoma, another major type of skin cancer. (Consumer Summary produced by Reliance Medical Information, Inc.)

Allogeneic solid organ transplantation often occurs across multiple donor-recipient HLA mismatches with consequent risk of allograft rejection. However, there is growing evidence that not all HLA mismatches are equivalent in their stimulation of allogeneic T cells making it important to determine which of these might be more significant as predictors of allograft rejection. To this end, we used defined antigen-presenting cell (APC) transfectants expressing single MHC-I allotypes as target cells that could discriminate the relative contribution of individual mismatched MHC-I allotypes to direct T-cell alloreactivity. We demonstrate remarkably reproducible patterns of immunodominance in reactivity across mismatched MHC-I allotypes. These patterns are HLA context-dependent, partly reflecting alloantigenic competition in responder cell responses. In strong alloresponses, we also observed an increased percentage of alloreactive TCD8cells in female responders, regardless of the stimulator gender, highlighting HLA-independent factors in the potency of the alloresponse. This approach provides a potential measure of specific alloreactive T cells that could be used in clinical practice for selection of donors, assessment of posttransplant outcomes, modulation of immunosuppression and detection of rejection episodes.

Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.

On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S3‘ pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S3‘ pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.

Because few HLA-DR-positive cells are present in the fetal spleen and liver, full HLA typing cannot be performed. However, B lymphocyte precursors can be transformed with Epstein-Barr virus to produce lymphoblas-toid cells which express HLA-A, B, and DR antigens. Successful transformation was achieved, usually with spleen and liver, in nine fetuses aged from 15 to 18 weeks, mostly within 7 to 14 days of initiation of the cultures. Spleen-derived lymphoblasts were more suitable for typing because of their greater homogeneity and higher viability. Tissues from two 13-week fetuses from prostaglandin-induced abortions and from a spontaneously aborted 22-week fetus could not be transformed. This is probably attributable to prolonged ischemia before the tissues were obtained but, in the 13-week fetuses, absence of B lymphocyte precursors was not excluded. HLA-DR typing may be useful in obtaining well matched donor-recipient pairs in fetal pancreatic islet transplantation.

A prospective randomized trial was performed comparing survival of cadaveric grafts allocated by HLA-AB matching and HLA-DR matching. The two allocation methods resulted in very similar graft survivals. HLA-A matching had no significant effect on graft survival. HLA-B and HLA-DR matching were shown to have approximately equal, significant, independent, and additive effects on graft survival. Other factors that were demonstrated to have significant effects were blood transfusion, preformed antibodies, graft number, and recipient sex.

Abstract: The influence of the preioniser and main discharge circuit parameters on the performance of a high pressure UV preionised KrF laser using NF3 as the fluorine donor has been investigated. Output laser energy densities of 1.7J1−1 based on the mode volume have been obtained under optimised conditions.

A novel series of nonpeptidic compounds that contain a biphenyl carboxylic acid group have been shown to inhibit HIV-1 protease. The active compounds, most of which are highly soluble, have IC50values in the range of 3.4-74 μM. The structure-inhibitory activity relationship demonstrates the necessity of the biphenyl carboxylic acid group for inhibition, which is enhanced by the presence of a sulfone group and by halogenation of an adjacent phenyl group. A double reciprocal plot of inhibition data on two of the compounds clearly shows that the inhibition occurs in a competitive manner, with Kivalues of 1.1 and 3.4 μM. Inhibition by several of the compounds was found to be reversible and fast-binding, while one of the biphenyl carboxylic acids inhibits in a reversible slow-binding manner. Time-dependent inhibition studies were conducted on this compound, and it was determined to have the kinetic values of kon= 0.18 μM−1min−1, koff= 9.7 × 10−2min−1, and Ki= 0.14 μM. Thus, the slow-binding inhibitor is the most potent in the series. Molecular modeling has provided information on a possible binding mode for two different biphenyl carboxylic acid inhibitors of HIV-1 protease.

The potential of the chelate extraction mode displayed by diamine extractants is illustrated by using two tertiary diamine extractants to extract palladium(II) and platinum(IV) from a base metal solution containing copper(II), nickel(IT), cobalml) and iron(III) in 1 mol/dm3lithium chloride. The extraction behaviour of the diamine extractants is compared with that of the commercially-available extractants Alamine 336 (a tertiary monoamine extractant) and Aliquat 336 (a quaternary monoammonium chloride salt). By exploiting the chelate extraction mode, specific to diamine extractants, separation of palladium(IT) from platinum(lv) can be achieved. The only base metal ion that is extracted is iron(III). Iron(III) can be stripped with 1 mol/dm3sulphuric acid or the extraction can be performed under mildly acidic conditions, e.g. pH 4.7. Under the latter conditions ironflll) precipitates quantitatively as a hydroxide complex and can be removed by filtration. The selective back-extraction of palladium(II) and platinum(lV) by thiourea in hydrochloric acid and sodium thiocyanate respectively is demonstrated.

The extraction of cobalt(II) from a chloride medium (pH 1 to 5) by N,N,N1,N1-tetra-n-octylethylenediamine, N,N-di-n-octyl-2-(aminomethyl)pyridine, Alamine 336 and Aliguat 336 dissolved in 5% isodecanol - benzene was investigated. The protonation constants of the tertiary amine extractants are reported. They were obtained using the program SUPERQUAD in conjunction with the electrode calibration program MAGEC.The nature of the extracted complexes was elucidated using spectrophotometric methods, including the program TRIANG. Extraction equilibria are proposed based on these results.Gaussian analysis was employed to resolve the spectra of the extracted complexes in order to obtain estimates of the concentrations of the individual extracted complexes. These estimates were utilized in a non-linear least squares curve-fitting procedure to obtain extraction constants for the proposed extraction equilibria.

The 4-hydroxy-5,6-dihydropyrone template was utilized as a flexible scaffolding from which to build potent active site inhibitors of HIV protease. Dihydropyrone 1c (5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one) was modeled in the active site of HIV protease utilizing a similar binding mode found for the previously reported 4-hydroxybenzopyran-2-ones. Our model led us to pursue the synthesis of 6,6-disubstituted dihydropyrones with the aim of filling S1 and S2 and thereby increasing the potency of the parent dihydropyrone 1c which did not fill S2. Toward this end we attached various hydrophobic and hydrophilic side chains at the 6-position of the dihydropyrone to mimic the natural and unnatural amino acids known to be effective substrates at P2 and P2‘. Parent dihydropyrone 1c (IC50 = 2100 nM) was elaborated into compounds with greater than a 100-fold increase in potency [18c, IC50 = 5 nM, 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic acid and 12c, IC50 = 51 nM, 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one]. Optimization of the 3-position fragment to fill S1‘ and S2‘ afforded potent HIV protease inhibitor 49 [IC50 = 10 nM, 3-[(2-tert-butyl-5-methylphenyl)sulfanyl]-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one]. The resulting low molecular weight compounds (<475) have one or no chiral centers and are readily synthesized.

The study was designed to examine the effect on clinical expression of rheumatoid arthritis (RA) of HLA alleles, particularly DR4 and DR1 that contain susceptibility sequences for RA in the third hypervariable region (HVR3) of HLA-DRB1. We studied 114 consecutive Australian patients with RA attending a hospital outpatient clinic. The effects on indices of disease severity and activity of HLA DR4 and DR1, the DRB1*04 subtypes, and the polymorphism in the RA susceptibility sequence (QRRAA or QKRAA) were examined. The patients were initially divided into 6 groups, DR4,4; DR4,1; DR1.1; DR4/X; DR1,X, and DRX/X, and then further subdivided according to the actual HVR3 susceptibility sequence. The high risk conferred by the HVR3 susceptibility sequence, present in 76%, was confirmed, but 24% of the patients with long-standing seropositive erosive RA lacked this sequence. Among these those with DR2 had early-onset severe disease, and those with DR3 had late-onset milder disease. Differences in expression correlated with polymorphisms in the susceptibility sequence, in that active RA was associated more with QRRAA than QKRAA. There was no correlation of any HLA allele with disease severity. Our finding that the presence of the HVR3 sequence confers susceptibility and also influences the clinical expression and tempo of progression of RA suggests a role in pathogenesis for antigen presentation, whether of an autoantigenic molecule or a persisting infection.

The effect of a commonly used modifier, isodecanol, on the cobalt(II) -chloride system with the tertiary diamine extractants N,N,N' N'-tetra-n-octylethylenediamine (tetocen) and N,N-di-n-ocryl-2-(aminomethyl)pyridine (pyridioc) was studied. The diamine extractants behave as stronger bases, the extraction of cobalt(II) decreases and chelate extraction mode is enhanced as the alcohol concentration in benzene is increased. The observations have been discussed in terms of changes in the solubility parameter and dielectric constant of the diluent and the solvation energy and solubility of the solute.

The tertiary amine extractants N,N,N',N'-tetra-n-octylethylenediamine, N,N-di-n-octyl-2-(aminomethyl)pyridine and Alamine 336 were used to extract cobalt(II) from a thiocyanate medium. The extraction equilibria were identified and the extraction constants for these equilibria are presented.Thiocyanic and sulphuric acid extraction was investigated. The protonation constants of the tertiary amines with these acids are reported.The potential of the chelate mode, displayed by tertiary diamine extractants, was evaluated. The extraction properties of tertiary diamine extractants were demonstrated to be superior to a tertiary monoamine extractant, Alamine 336.

The observation that promethazine hydrochloride inhibited red cell agglutination in the ABO blood group system led to the screening of a series of drugs structurally related to promethazine in an attempt to establish a structure activity relation. Standard group O serum agglutinated group A and group B cells. The serum in each test was pretreated with drug and the degree of agglutination on the slide was assessed by both direct and microscopic means. All phenothiazines tested possessed this property except thiopropazate and the cyclic compound MO967C. Several tricyclic antidepressants and antihistamines tested possessed inhibitory activity, the tricyclic compounds were generally as active as the phenothiazines but the antihistamines varied in activity. The structure associated with maximum activity appeared to be a mono- or di-methyl substituted ethylamine or propylamine chain. However, the presence of the phenothiazine nucleus seems to strengthen activity suggesting that the overall shape of the molecule is important. Within the phenothiazine group there appeared to be a relation between basicity and inhibitory activity. It is suggested that the positively charged drug molecules in solution are attracted to the negative acidic groups on the red cell membrane thus inhibiting the formation of antibody-antigen complexes. The cyclization of the phenothiazine and the tricyclic compounds’ side-chain appears to abolish the inhibitory action. These findings may be of clinical importance with respect to ABO incompatibilities between mother and foetus and also in laboratory serum antibody studies.

A statistically significant association of clinical rheumatoid vasculitis (excluding nodules or nail-fold infarcts only) with the HLA B8 DR3 phenotype was found when comparing 30 patients with vasculitis with 84 classic or definite rheumatoid patients without clinical vasculitis. The previously reported association on HLA DR4 with rheumatoid disease was also confirmed.

Antibody activity against collagen was measured in 53 samples of serum from 48 patients with active signs of epidemic polyarthritis (EPA) following infection with Ross River virus. Activity was higher against denatured collagen than against native collagen, but was within the normal range for each. Determination of HLA phenotypes permitted a search for any relationship between HLA type and differences in collagen antibody levels within the normal range. No relationship was detected with HLA antigens predominating in EPA or with HLA antigens that are associated with high collagen-antibody levels in rheumatoid arthritis (RA), which suggests that the latter associations may represent failure to control collagen antibody levels after the onset of RA. The findings also provide evidence against a role for nonspecific enhancement of humoral immune responses in the pathogenesis of EPA, and constitute a further point of distinction between EPA and RA.

The authors address themselves to a method of boron determination by curcumin in samples of more than moderate CaCO3hardness.

Electronegative substitution at C‐3 of cyclohexanones, e.g. in (I), and of methylenecyclohexanes, e.g. in (II), is found to increase the relative proportion of axial attack in a number of reactions widely differing from the points of view of the transition‐state polarization, geometry, and electron deficiency.

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Addition of the reagent (II) to the enolizable carbonyl compounds (I) gives the products (III) in the presence of cerium chloride with yields superior to those obtained with other reagents.

In addition to the reaction shown in the scheme, the oxidation of (I) with m‐chloroperoxybenzoic acid followed by reduction and the catalytic osmylation of (I) with subsequent methylation of the resulting diols lead to the methyl carbinols (II) and (III).