Thrombelastographic measures of clot propagation: a comparison of alpha with the maximum rate of thrombus generation.

The alpha angle alpha (degrees) is a thrombelastographic measure of clot propagation. A parametric measurement of clot propagation [maximum rate of thrombus generation (MRTG), dynes/cm2 per s], however, has recently been utilized. Thus, the relationship of changes in alpha with changes in MRTG were determined. alpha and MRTG values obtained from 859 thrombelastograms was collected from nine studies. Data were analyzed and the relationship between alpha and MRTG defined with commercially available software. Additional comparisons were made retrospectively from whole-blood and plasma data obtained from 33 normal individuals. Data from the nine studies demonstrated that MRTG increased in an exponential fashion compared with increases in alpha (R2 = 0.88, P < 0.001). Whole-blood alpha values were in the range 66.7-74.7 whereas MRTG values were 5.5-10.8, and plasma alpha values were 65.1-77.9 with corresponding MRTG values of 3.5-12.0. Assessment of clot propagation utilizing MRTG provides a more parametric evaluation than the determination of alpha. While normal alpha values may vary by only 12-20%, MRTG values vary by approximately 200-300%. The MRTG should be progressively utilized to a greater extent in both laboratory and clinical settings to parametrically quantify clot growth kinetics with thrombelastography.     

Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study.

The aim of this study was to study the influence of hormone replacement therapy (HRT) on weight changes, body composition, and bone mass in early postmenopausal women in a partly randomized comprehensive cohort study design. A total of 2016 women ages 45-58 years from 3 months to 2 years past last menstrual bleeding were included. One thousand were randomly assigned to HRT or no HRT in an open trial, whereas the others were allocated according to their preferences. All were followed for 5 years for body weight, bone mass, and body composition measurements. Body weight increased less over the 5 years in women randomized to HRT (1.94 +/- 4.86 kg) than in women randomized to no HRT (2.57 +/- 4.63, p = 0.046). A similar pattern was seen in the group receiving HRT or not by their own choice. The smaller weight gain in women on HRT was almost entirely caused by a lesser gain in fat. The main determinant of the weight gain was a decline in physical fitness. Women opting for HRT had a significantly lower body weight at inclusion than the other participants, but the results in the self-selected part of the study followed the pattern found in the randomized part. The change in fat mass was the strongest predictor of bone changes in untreated women, whereas the change in lean body mass was the strongest predictor when HRT was given. Body weight increases after the menopause. The gain in weight is related to a decrease in working capacity. HRT is associated with a smaller increase in fat mass after menopause. Fat gain protects against bone loss in untreated women but not in HRT-treated women. The data suggest that women's attitudes to HRT are more positive if they have low body weight, but there is no evidence that the conclusions in this study are skewed by selection bias.     

Distribution of spermatogenesis in the testicles of azoospermic men: the presence or absence of spermatids in the testes of men with germinal failure [published erratum appears in Hum Reprod 1998 Mar;13(3):780]

The aim of the study was to determine whether a prior diagnostic testicle biopsy can predict success or failure of testicular sperm extraction (TESE) with intracytoplasmic sperm injection (ICSI) in patients with non-obstructive azoospermia caused by testicular failure, and what is the minimum threshold of sperm production in the testis which must be surpassed for spermatozoa to reach the ejaculate. Forty- five patients with non-obstructive azoospermia caused by testicular failure underwent diagnostic testicle biopsy prior to a planned future TESE-ICSI procedure. The diagnostic testicle biopsy was analysed quantitatively, and correlated with the quantitative findings of spermatogenesis in patients with normal spermatogenesis, as well as with the results of subsequent attempts at TESE-ICSI. Men with non- obstructive azoospermia caused by germinal failure had a mean of 0-6 mature spermatids/seminiferous tubule seen on a diagnostic testicle biopsy, compared to 17-35 mature spermatids/tubule in men with normal spermatogenesis and obstructive azoospermia. These findings were the same for all types of testicular failure whether Sertoli cell only, maturation arrest, cryptorchidism, or post-chemotherapy azoospermia. Twenty-two of 26 men with mature spermatids found in the prior testis biopsy had successful retrieval of spermatozoa for ICSI, 12 of their partners became pregnant, and are either ongoing or delivered. The study suggests that 4-6 mature spermatids/tubule must be present in the testis biopsy for any spermatozoa to reach the ejaculate. More than half of azoospermic patients with germinal failure have minute foci of spermatogenesis which are insufficient to produce spermatozoa in the ejaculate. Prior diagnostic testicle biopsy analysed quantitatively (for the presence of mature spermatids) can predict subsequent success or failure with TESE-ICSI. Incomplete testicular failure may involve a sparse multi-focal distribution of spermatogenesis throughout the entire testicle, rather than a regional distribution. Therefore, it is possible that massive testicular sampling from many different regions of the testes may not be necessary for successful TESE-ICSI.      

Adhesion inhibitory activity of β-lactoglobulin isolated from infant formulae

β-Lactoglobulin was isolated from infant formulae that were ultra high temperature (UHT) -treated, sterilized or spray-dried. The effect of the isolated β-lactoglobulin on SfaII-fimbriae-mediated adhesion of Escherichia coli to human ileostomy glycoproteins was studied in vitro. β-Lactoglobulin isolated from sterilized formulae was found to perform significantly less well than preparations from spray-dried formulae (p = 0:05). Great heterogeneity was observed in the adhesion inhibitory capacity of β-lactoglobulin isolated from UHT-treated formulae. Therefore, no significant difference was observed between UHT-treated and sterilized formulae or spray-dried formulae (p < 0:10). It can be hypothesized that β-lactoglobulin from spray-dried and some UHT-treated infant formulae may affect the colonization of mucous membranes by E. coli strains causing neonatal septicaemia and meningitis.     

Persistence of systemic mastocytosis after allogeneic bone marrow transplantation in spite of complete remission of the associated myelodysplastic syndrome.

A myelodysplastic syndrome (MDS), type 5 (RAEB-t), and systemic mastocytosis affecting the spleen, the splenic lymph nodes, the bone marrow and the liver were diagnosed in a 38-year-old woman. The clinical course was complicated by splenic vein thromboses and iliac artery embolism. The thrombotic episodes might be secondary to mast cell mediator release. A complete remission of the MDS was obtained by allogeneic bone marrow transplantation, but the mastocytosis persisted. Thus, the possibility that the mast cell originates from a common myeloid precursor cell may be questioned.     

SARS CTL Vaccine Candidates — HLA Supertype, Genome-Wide Scanning and Biochemical Validation

An effective SARS vaccine is likely to include components that can induce specific cytotoxic T-cell (CTL) responses. The specificities of such responses are governed by HLA-restricted presentation of SARS-derived peptide epitopes. Exact knowledge of how the immune system handles protein antigens would allow for the identification of such linear sequences directly from genomic/proteomic sequence information. The latter was recently established when a causative coronavirus (SARS CoV) was isolated and full-length sequenced. Here, we have combined advanced bioinformatics and high-throughput immunology to perform an HLA supertype, genome-wide scan for SARS-specific cytotoxic T cell epitopes. The scan includes all nine human HLA supertypes in total covering >99% of all major human populations. For each HLA supertype, we have selected the 15 top candidates for test in biochemical-binding assays. At this time (approximately 6 months after the genome was established), we have tested the majority of the HLA supertypes and identified almost 100 potential vaccine candidates. These should be further validated in SARS survivors and used for vaccine formulation. We suggest that immunobioinformatics may become a fast and valuable tool in rational vaccine design.     

No correlation between number of MRI-evident lesions in cerebrum and the soleus stretch reflex in multiple sclerosis patients

The aim of the study was to investigate if the stretch reflex of the soleus muscle was useful in quantifying upper motor neuron lesions. The soleus stretch reflex was recorded in 10 healthy subjects and 20 patients with active relapsing-remitting multiple sclerosis and correlated to the number of MRI lesions in cerebrum and clinical scores (expanded disability status scale and regional functional scoring system). The short latency stretch reflex was elicited by rotating the left ankle joint 4 degrees with a rise time in the interval of 40-640 ms. The amplitude of the stretch was larger in multiple sclerosis patients being 88.5 microV in patients and 12.8 microV in controls, P = 0.007. The sensitivity of the stretch reflex expressed as the slope of the best linear fit was increased in MS patients to 2.6 microVs/degree compared with 0.6 microVs/degree (0.1-2.2) in controls, P = 0.009. There was no correlation between amplitude of the stretch reflex and number of MRI lesions (r = -0.03). In conclusion, the soleus stretch reflex might be useful to quantify spasticity but is not useful in detecting dysfunction of upper motor neurons in MS.     

Evidence for an association between hairy cell leukemia and renal cell and colorectal carcinoma.

BACKGROUND. Hairy cell leukemia (HCL) has been associated with several disease states. In this study, a possible association is reported between HCL and renal cell carcinoma (RCC) and colorectal carcinoma (CRC). METHODS. A retrospective study of the case records of 50 patients with HCL in a study of alpha-interferon (alpha-IFN) treatment of HCL. RESULTS. Three of 50 patients with HCL studied had RCC, and 2 of these also had CRC. In addition, two other patients had CRC. The other malignant lesions developed either before or after the diagnosis of HCL. In all patients, the HCL responded to alpha-interferon (alpha-IFN), but in four patients, the second lesion was diagnosed during IFN treatment. CONCLUSIONS. These findings could indicate that IFN does not correct a possible common basic etiologic defect and shows that even early CRC and RCC do not respond to the IFN doses administered. These findings should be considered in future trials of IFN treatment of these diseases. The authors also recommend a reevaluation of the frequency of second malignant lesions in HCL; this may be important particularly with the increased survival in patients with HCL who receive alpha-IFN treatment.     

Excitatory amino acid agonists. Enzymic resolution, X-ray structure, and enantioselective activities of (R)- and (S)-bromohomoibotenic acid

The enantiomers of alpha-amino-4-bromo-3-hydroxy-5-isoxazolepropionic acid (4-bromohomoibotenic acid, Br-HIBO, 1) a selective and potent agonist at one class of the central (S)-glutamic acid receptors, were prepared with an enantiomeric excess higher than 98.8% via stereoselective enzymic hydrolysis of (RS)-alpha-(acetylamino)-4-bromo-3-methoxy-5-isoxazolepropionic acid (4) using immobilized aminoacylase. The absolute configuration of the enantiomers of Br-HIBO was established by X-ray crystallographic analysis, which confirmed the expected preference of the enzyme for the S form of the substrate 4. (S)- and (RS)-Br-HIBO were potent neuroexcitants on cat spinal neurones in vivo, while (R)-Br-HIBO was a very weak excitant. Correspondingly, the S enantiomer of Br-HIBO (IC50 = 0.34 microM) was considerably more potent than the R form (IC50 = 32 microM) as an inhibitor of [3H]-(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([ 3H]AMPA) binding to rat brain synaptic membranes in vitro. In contrast, (S)- and (R)-Br-HIBO were approximately equipotent (IC50 values of 0.22 and 0.15 microM, respectively) as inhibitors of [3H]-(S)-glutamic acid binding in the presence of CaCl2. The enantiomers of Br-HIBO showed no significant affinity for those binding sites on rat brain membranes which are labeled by [3H]kainic acid or [3H]-(R)-aspartic acid.