On the syntheses of triacylglycerols from branched saturated fatty acids.

A number of triacylglycerols with branched acyl groups were prepared via 1,2-isopropylidene glycerol for the purpose of studying three different physical properties: gel point, refractive index, and density. The monoacid triacylglycerols were prepared either via the corresponding acids or the acyl chlorides.

The relationship between the structure of monoalkyl branched saturated triacylglycerols and some physical properties.

Three different physical properties, the gel point ("solidification point"), the refractive index and the density, were determined and related to the structure of the branched triacylglycerols. A four-factor central composite face-centered design was constructed where the four variables were the length of the main chain, the branching position, the length of the side chain, and the number of branched fatty acyl groups attached to the glycerol backbone. Second-order models were calculated in which the three physical properties were related to the structure. Four additional branched triacylglycerols were analyzed in order to confirm the validity of each model. Contour plots are shown in order to visualize the prediction equations which were obtained.

Deoxythymidine kinase in the staging of prostatic adenocarcinoma.

The role of prostate-specific antigen in the management of prostatic adenocarcinoma is still not fully ascertained. Its place in the monitoring of patients who have undergone radical treatment is without question but its role in the primary assessment of a lesion is a point of continuous discussion. This study reports the analysis of prostate-specific antigen (PSA) in 92 patients with different stages of prostatic adenocarcinoma prior to treatment; in the case of the localized lesions, this was based to a great extent on the findings at lymphadenectomy. Apart from PSA analysis, deoxythymidine kinase (dTK) analyses were also performed in an attempt to discover whether the latter could provide additional information about the tumor load in the different patient categories, viz. those with lymph node involvement (group 1), those with lymph node involvement but without distant metastases (group 2), and those with disseminated disease (group 3). The median PSA and dTK values in groups 1-3 were 6.5 micrograms/L and 2.7 U/microliter, 16 micrograms/L and 2.6 U/microL, and 90 micrograms/L and 7.8 U/microL, respectively. If the two analyses were used concomitantly, they could differentiate true localized disease from metastatic in approximately 92% of cases. The combination should prove of value in the primary assessment of a patient with a newly diagnosed prostatic adenocarcinoma.

Synthesis and antiviral effects of 2-heteroaryl substituted adenosine and 8-heteroaryl substituted guanosine derivatives.

2-(2"- and 3"-Thienyl)adenosine and the corresponding furyl derivatives were prepared though Pd(0)-catalyzed coupling of 2',3',5'-tri-O-(t-butyldimethylsilyl)-2-iodoadenosine with the appropriate tributyltin derivatives followed by deprotection. Preparation of the 8-(2"- and 3"-thienyl)guanosines and 8-(2"- and 3"-furyl)guanosines followed a similar route. Antiviral properties of these compounds and the related 2,6-diaminopurine ribofuranosides were of no pharmacological interest.

Serum levels of interleukin-2 receptor (CD 25) in patients with Hodgkin's disease, with special reference to age and prognosis.

BACKGROUND: The serum levels of soluble interleukin-2 receptor (S-sIL-2R) have been shown to be related to clinical outcome in Hodgkin's disease (HD). sIL-2R may be involved in or aggravate the immunodeficiency seen in HD patients. This immunodeficiency is most pronounced in elderly patients. PATIENTS AND METHODS: S-sIL-2R was determined in 127 untreated patients with HD, diagnosed between 1979 and 1991, in order to evaluate its prognostic value in relation to other known prognostic variables with special emphasis on the elderly. RESULTS: S-sIL-2R levels were significantly higher in patients with stages III-IV and with B-symptoms (p < 0.001) but not in patients over 60 years of age. In multivariate analyses, S-sIL-2R, stage and S-orosomucoid were the most important prognostic factors in all patients and S-sIL-2R was the only prognostic factor in patients over the age of 60. CONCLUSIONS: The results indicate a future role for estimation of S-sIL-2R in the management of patients with HD.

No evidence for spumavirus or oncovirus infection in relapsing-remitting multiple sclerosis.

Polymerase chain reaction analysis was used to investigate the possible role of human spumaretrovirus and oncoretroviruses (human T-cell lymphotropic virus types I [HTLV-I] and II [HTLV-II]) in multiple sclerosis. Eleven patients with relapsing-remitting multiple sclerosis in exacerbation and 11 normal blood donors were included in the study. Cerebrospinal fluid cells, peripheral blood mononuclear cells, and plasma were cocultured with allogeneic mononuclear cells for 6 weeks. Cultured cells were subjected to polymerase chain reaction analysis with primers selected for the pol and gag (human spumaretrovirus), pol and env (HTLV-I), and pol (HTLV-II) genes. Polymerase chain reaction was negative in all patient and blood donor control samples, whereas positive controls were consistently reactive with high sensitivity. No culture exhibited cytopathic effects and supernatants were negative for reverse transcriptase activity. Thus, our results do not support a role for these retroviruses in the pathogenesis of multiple sclerosis.

Pyridine-substituted hydroxythiophenes. I. Preparation of o-(2-, 3- and 4-pyridyl)-3-hydroxythiophenes.

2-(2-, 3- and 4-pyridyl)-3-hydroxythiophenes and 4-(2-, 3- and 4-pyridyl)- 3-hydroxythiophenes have been prepared by hydrogen peroxide oxidation of the corresponding boronic esters. In the former case the boronic esters were obtained in three steps from 2,3-dibromothiophene via the corresponding 3-bromo-2-pyridylthiophenes synthesized by Pd(0)-catalyzed coupling between 3-bromo-2-trimethylstannylthiophene and the corresponding bromopyridines. In the latter case the known isomeric pyridylthiophenes were converted into the corresponding boronic esters in three steps via tribromo- and 3-bromo-4-pyridylthiophenes successively. 4-(3- and 4-pyridyl) thiophen-2(5H)-ones were also obtained in the syntheses of 4-(3- and 4-pyridyl)-3-hydroxythiophene. They are suggested to arise from rearrangement during the halogen-metal exchange. Spectroscopic investigations by 1H NMR and IR show that these hydroxythiophene systems exist exclusively as enol forms.

Triester glycerothiophosphates of cholecalciferol (vitamin D3).

Tris(N,N-dimethyl)amide of phosphorous acid activated by addition of iodine at an optimal molar ratio of 1.05:0.05 was used as a phosphorylating reagent to synthesize cholecalciferyl-3-O-(1-2-isopropylidene-rac-glycero-3-O-)-thiophos phate and cholecalciferyl-3-O-(1,2-dipalmitoyl-rac-glycero-3-O-)thiophosphat e of methyl alcohol, 2-dimethylaminoethanol, 3-dimethylamino-1-propanol and 1,2-isopropylidene-rac-glycerol in a "one-pot procedure" in overall yields of 60-80%. Activation of the reaction with an equimolar mixture of imidazole and carbon disulfide at the triester formation step permits selective phosphorylation at room temperature. The compounds synthesized represent new triester phospholipid model compounds in which (in addition to glycerol and another requisite alcohol) a steroid and an element other than oxygen are bond to phosphorus.

Thymidine kinase in extracts of human brain tumours.

Deoxythymidine kinase (TK) is an enzyme involved in DNA synthesis. It can be used as a marker of cell proliferation. TK was measured in extracts of human brain tumours and non-neoplastic brain tissue. In astrocytomas the mean TK activity increased with increasing grade of malignancy. Oligodendrogliomas showed higher TK activity than astrocytomas. The highest activities were noted in menigiomas, of which the recurrent ones exceeded the primary in TK activity. In non-neoplastic brain tissue lower TK activity was found. It is concluded that TK can be measured in human brain tumour extracts, and is potentially of use for studies on tumour cell proliferation.

Serum thymidine kinase as a prognostic marker in Hodgkin's disease.

In 72 of 81 consecutively diagnosed patients with Hodgkin's disease pretreatment sera were available for analysis of serum thymidine kinase (S-TK) levels. In relation to clinical parameters, such as stage, histopathology and general symptoms, significant correlations were found with higher (S-TK) levels in advanced disease as well as in patients with B-symptoms. When the prognostic ability was examined, patients in stages IA and IIA could be divided according to S-TK levels into two different groups in relation to disease-free survival. This latter finding makes this serum test interesting as an additional tool in the clinical evaluation and in the therapeutic decision concerning patients with Hodgkin's disease.

Biochemical markers in non-Hodgkin's lymphoma stages III and IV and prognosis: a multivariate analysis.

The prognostic value of different pretreatment laboratory and clinical findings at diagnosis was assessed in a series of 141 patients with generalized non-Hodgkin's lymphoma. Univariate and multivariate survival analysis (Cox's regression model) was performed, using serum analysis of deoxythymidine kinase (S-TK), beta 2-microglobulin, lactic dehydrogenase, alpha 1-acid glycoprotein = orosomucoid (S-alpha 1 AGP), haptoglobin and ferritin. In addition, Hb and the erythrocyte sedimentation rate (ESR) were measured. The clinical variables were age, presence or absence of B-symptoms, histopathology ('low-grade'; 'intermediate grade' and 'high-grade' malignancy) and bone marrow involvement. Of the 8 biochemical markers, all except Hb and the ESR showed a significant relationship to survival. Among the clinical variables, this finding was made for B-symptoms and histopathology. Using a multivariate analysis on all variables, S-TK was found to be the best factor for predicting duration of survival. The only significant additional information was provided by S-alpha 1 AGP. When only the clinical variables were taken into account, it was found that histopathology added significant information to that yielded by B-symptoms in the prediction of the survival time. When the biochemical variables were added to this model, only S-TK was of significant additional prognostic value.

Serum thymidine kinase in vitamin B12 deficiency.

In DNA synthesis deoxythymidine kinase (TK) catalyses the conversion of deoxythymidine to deoxythymidine monophosphate (dTMP) via the 'salvage pathway'. Serum deoxythymidine kinase (S-TK) was measured in this study in 75 patients with vitamin B12 deficiency by a new, very sensitive method, using 125I-deoxyuridine as substrate. Elevated S-TK levels were found in those patients who had developed haemolysis and anaemia and the more advanced the disease the higher the S-TK value. Thus there was a highly significant correlation between S-TK, haemoglobin level and lactic dehydrogenase activity. These findings are consistent with the theory that elevated levels of S-TK are due to release from unstable proliferating tissue.

Digestion and absorption of trioleoyl-thioglycerol in the rat.

A triacylglycerol analogue, rac-1,2-di-O-oleoyl-3-S-oleoyl-3-thioglycerol, was fed to rats and chyle acylglycerols were analyzed. Triacylglycerol was the dominating chyle lipid but X-triacyl-1-thioglycerol constituted approx. 6% of total chyle lipids. Its identity was verified by ultraviolet and mass spectra and its stereochemical structure by ORD and CD. The proportions of triacyl-1-thio-sn-glycerol/triacyl-3-thio-sn-glycerol were 63/37 and 78/22 in two experiments. Possible reasons for this stereospecificity are discussed. The study shows that the stereochemical configuration of lipids isolated from biological material can be assessed by ORD and CD.

Absorption of synthetic, stereochemically defined acylglycerols in the rat.

The stereochemistry of fat digestion and absorption was investigated in rats with thoracic duct fistulas, after feeding synthetic triacylglycerol or alkyldiacylglycerol. After feeding 1,2-dilauroyl-3-oleoyl-sn-glycerol, dilauroyloleoylglycerol and lauroyldioleoylglycerol were the most abundant chyle triacylglycerols. Positional analysis of the fatty acid distribution and the absence of optical activity indicated that the following structures dominated: rac-1,2-dilauroyl-3-oleoylglycerol and rac-1,3-dioleoyl-2-lauroylglycerol. Therefore, the triacylglycerol resynthesized from 2-lauroylglycerol (pre-cursor to 60% of chyle triacylglycerol) and other precursors was essentially racemic. Chyle phospholipids contained largely endogenous fatty acids, and the proportion of lauric acid was very low. A racemic mixture of 1,2-di[3H] oleoyl-3-tetradecyl-sn-glycerol and 1-tetradecyl-2,3-di[12C] oleoyl-sn-glycerol was absorbed to a lower degree than triacylglycerol. The appearace of oleic acid with different labels in chyle and intestinal lipids did not differ, indicating the absence of stereospecificity in fat digestion. Possible explanations for the low absorption are discussed.