Septicaemia is associated with increased disease activity and mortality in systemic lupus erythematosus: a retrospective analysis from Taiwan.

OBJECTIVE: This study aimed to investigate how septicaemia, non-septicaemia infection and the disease itself are associated with disease activity and mortality in inpatients with systemic lupus erythematosus (SLE) in Taiwan. METHODS: We retrospectively reviewed 1115 patients and enrolled 427 with SLE admitted for lupus flare-ups and co-morbidities. Disease activity and infection type/site were recorded and categorized according to the causes of admission and mortality into three categories, of which two were specified as follows: (a) septicaemia admissions, non-septicaemia admissions; and (b) septicaemia mortality, non-septicaemia infection mortality and non-infection mortality. The relationships between lupus flare-ups and mortality in different groups were analysed using an unpaired t-test, Mann-Whitney U-test and logistic regression. RESULTS: Septicaemia was the major cause of mortality in SLE inpatients. There were 98 (22.95%) mortality patients among all 427 SLE patients. The septicaemia admissions had higher disease activity (SLE Disease Activity Index 2000 = 13.00 ± 7.98) than the non-septicaemia admissions (9.77 ± 5.72; p < 0.01). The mean current SLEDAI score of the septicaemia mortality group (14.91 ± 8.01) was higher than that of the non-septicaemia infection mortality group (10.05 ± 5.75; p = 0.02), in spite of the similar mean earlier SLEDAI score. The risk of mortality in the septicaemia mortality group due to previous septicaemia admissions was 13.2 times (odds ratio) higher than in the non-septicaemia infection mortality group and 15.6 times higher than in the non-infection mortality group. CONCLUSION: Septicaemia relates to increased lupus disease activity and is associated with a greater risk of mortality in the SLE patients than other causes of admission. Fewer previous septicaemia admissions decrease the risk of septicaemia mortality.

Comparison of elastic scattering spectroscopy with histology in ex vivo prostate glands: potential application for optically guided biopsy and directed treatment.

The false-negative rate of ultrasound-guided sextant prostate biopsy has been estimated to be as high as 35 %. A significant percentage (10-35 %) of these prostate cancers diagnosed at a second or later attempt are high grade and, therefore, potentially lethal. We discuss the feasibility for performing optically guided biopsy using elastic scattering spectroscopy (ESS) to reduce sampling errors and improve sensitivity. ESS measurements were performed on 42 prostate glands ex vivo and correlated with standard histopathological assessment. Sliced glands were examined with wavelength ranges of 330-760 nm. The ESS portable system used a new fiber-optic probe with integrated cutting tool, designed specifically for ex vivo pathology applications. ESS spectra were grouped by diagnosis from standard histopathological procedure and then classified using linear support vector machine. Preliminary data are encouraging. ESS data showed strong spectral trends correlating with the histopathological assignments. The classification results showed a sensitivity of 0.83 and specificity of 0.87 for distinguishing dysplastic prostatic tissue from benign prostatic tissue. Similar results were obtained for distinguishing dysplastic prostatic tissue from prostatitis with a sensitivity and specificity of 0.80 and 0.88, respectively. The negative predictive values obtained with ESS are better than those obtained with transrectal ultrasound (TRUS)-guided core-needle biopsy.

Cytomegalovirus infection causes morbidity and mortality in patients with autoimmune diseases, particularly systemic lupus: in a Chinese population in Taiwan.

To investigate the clinical outcome of cytomegalovirus (CMV) infection in febrile hospitalized patients with autoimmune diseases, mostly systemic lupus erythematosus (SLE). Fifty-four febrile patients were analyzed retrospectively. Half were diagnosed as CMV infection, by positive CMV pp65 antigenemia assay. Clinical and laboratory data between two groups were compared. Correlation between laboratory data and SELENA-SLEDAI scores/mortality were analyzed in the CMV infection group. Receiver operating characteristic analysis was performed to determine the cutoff points of different parameters for predicting mortality or morbidity. The CMV infection group received a higher corticosteroid dosage (mean 26.3 mg/day) and a higher percentage of azathioprine use before admission than the non-CMV infection group. In the former, the deceased subgroup had a significantly higher number of infected leukocytes for CMV (shortened as CMV counts, P = 0.013), more cases of bacterial infection (P = 0.090), and a higher SLE disease activity index score (P = 0.072) than the alive subgroup. The CMV infection group had lower lymphocyte count and more positive bacterial infection than the non-CMV infection group did (P = 0.013 and P = 0.027, respectively). A level of 25 CMV particles/5 × 10(5) polymorphonuclear neutrophils (PMN) was the best cutoff point for predicting CMV-associated mortality, with a sensitivity of 75.0% and specificity of 72.2%. Moderate dose (30 mg/day) of prednisolone or azathioprine use predisposes patients with autoimmune diseases to CMV infection with concurrent bacterial infection. In particular, peak CMV counts at 25/5 × 10(5) PMN or low lymphocyte counts predict mortality or morbidity, respectively.

Macrophages and abnormal BCL-6 or c-MYC gene expression affect the resistance of peritoneal B cells to induction of hyporesponsiveness.

Our earlier results indicate that peritoneal B cells (PEB cells) were not hyporesponsive to in vitro crosslinking of the immunoglobulin (Ig) with a secondary anti-IgG reagent. In this study, the response of PEB cells was reduced by the same treatment given i.p. PEB cells were only sensitive to anti-IgM hyper-crosslinking in the presence of peritoneal macrophages. This sensitivity was partially reversed by anti-interferon-beta antibody. Elevated BCL-6 with c-MYC gene expression in NZB/W F1 splenic B cells after anti-IgM treatment correlated well with reduction of IgM secretion. On the contrary, PEB cells not sensitive to induction of hyporesponsiveness cause abnormal BCL-6/c-MYC gene expression after challenges. A bigger change of increased BCL-6 gene expression after anti-IgM treatment was seen in PEB cells than in splenic B cells. Higher BCL-2 gene expression in NZB/W splenic B cells than those in NZB/W PEB cells do not prevent hyporesponsiveness in the former. In conclusion, the relationship between BCL-6/c-MYC gene expression and IgM secretion in NZB/W F1 splenic B cells is similar to that of conventional B2 cells. Although PEB cells from wild type strain can be rendered hyporesponsive in vivo in the presence of macrophages, the resistance to hyporesponsiveness of challenged autoimmune NZB/W PEB cells in vivo is probably related to abnormal BCL-6/c-MYC gene expression. These combined findings suggest that autoimmune B1 cells violate the accepted paradigm for expression of differentiation-associated transcription factors in B2 cells.

The dark side of dioxygen biochemistry.

The cellular biochemistry of dioxygen is Janus-faced. The good side includes numerous enzyme-catalyzed reactions of dioxygen that occur in respiration and normal metabolism, while the dark side encompasses deleterious reactions of species derived from dioxygen that lead to damage of cellular components. These reactive oxygen species have historically been perceived almost exclusively as agents of the dark side, but it has recently become clear that they play beneficial roles as well.

Bovine conglutinin (BC) mRNA expressed in liver: cloning and characterization of the BC cDNA reveals strong homology to surfactant protein-D.

Bovine conglutinin (BC) is a C-type lectin isolated from bovine serum that appears to play a role in first-line host defense. The BC cDNA was cloned from a bovine liver library and the nucleotide (nt) sequence of 1519 bp was determined. The longest open reading frame encoded a 20-amino-acid (aa) signal sequence and a mature protein of 351 aa. Analysis of the nt and deduced aa sequences revealed 87 and 78% identity, respectively, with the sequences of another vertebrate lectin: bovine surfactant protein-D (SP-D). Of interest, the expression of the BC mRNA, as determined by RNase protection assay, is restricted to liver, unlike bovine SP-D, a lung-surfactant protein.

Aneusomy of chromosomes 7, 8, and 17 and amplification of HER-2/neu and epidermal growth factor receptor in Gleason score 7 prostate carcinoma: a differential fluorescent in situ hybridization study of Gleason pattern 3 and 4 using tissue microarray.

Recent evidence shows that the proportion of poorly differentiated prostate carcinoma (Gleason pattern [GP] 4/5) is a surrogate factor for biochemical failure after radical prostatectomy (RP). However, little is known about specific molecular and cytogenetic changes in this aggressive component of localized prostate cancer. We constructed a tissue microarray containing areas of GP 3 and 4 from formalin-fixed radical prostatectomy specimens of 39 patients with Gleason score 7 carcinoma (>or=50% GP 4), known pathologic staging parameters (stage < T3b), and biochemical failure data (mean follow-up, 30 months; range, 5 to 74 months). Interphase fluorescent in situ hybridization (FISH) was performed on 5-microm microarray sections using pericentromeric probes to chromosomes 7, 8, and 17 and probes for the HER-2/neu and epidermal growth factor receptor (EGFR) genes. Low-level amplification of HER-2/neu was found in 26% of cases (3 to 5 signals per nucleus, corrected for chromosome 17 aneusomy). Aneusomy of chromosomes 7, 8, and 17 was identified in 21%, 15%, and 5% of cases, respectively. All aberrations occurred almost exclusively in GP 4 carcinoma (8 of 8 aneusomies 7, 2 of 2 trisomies 17, 9 of 10 HER-2/neu amplifications, and 5 of 6 aneusomies 8; P < .001). The presence of HER-2/neu amplification was associated with high tumor volume (>2.0 cm(3), P = 0.004). Among patients with negative surgical margins, gain of chromosome 7 was associated with biochemical failure after RP (P =.004, log-rank). Amplification of the EGFR gene occurred in only 1 case (3%). Significant differences in HER-2/neu amplification and gain of chromosomes 7, 8, and 17 were detected between GP 4 prostate carcinoma and GP 3. The frequency of aberrations increased with tumor volume. Chromosome 7 abnormalities may play an important role in cancer progression in margin-negative patients. EGFR amplification was rare, suggesting that this oncogene is not altered at the gene copy number level.

Adrenocortical carcinoma in children. Review and recent innovations.

Adrenocortical carcinoma in childhood is a rare potentially fatal disease. Despite its often dramatic presentation, there typically has been a distressingly long delay between the onset of symptoms and the time of diagnosis. This delay undoubtedly has contributed to the historically poor prognosis in these children by permitting the disease to reach an advanced stage before treatment is started. It is imperative that the physician recognizes the endocrine manifestations of these tumors early and has a high index of suspicion. Although biochemical and histologic evaluations are helpful, they often cannot differentiate benign lesions from malignant neoplasms and should not unduly delay intervention. Aggressive complete surgical resection continues to be the mainstay of treatment and is the best prognosticator of overall survival. The role of adjuvant therapy and chemotherapy continues to evolve. Molecular studies have increased understanding of cancer biology and may provide possible novel therapeutic approaches in the future. It is hoped that increased familiarity with this unusual tumor will result in earlier detection, prompt intervention, and improved survival for children with adrenocortical carcinoma.

Different monocyte reaction patterns in newly diagnosed, untreated rheumatoid arthritis and lupus patients probably confer disparate C-reactive protein levels.

OBJECTIVES: To investigate the different capacities of monocytes to produce cytokines in newly diagnosed, untreated patients with rheumatoid arthritis (RA) or systemic lupus and to examine the possible correlation among serum C-reactive protein (CRP), cytokines, swollen joint counts, and erythrocyte sedimentation rates (ESR) in untreated RA patients. METHODS: Monocytes from untreated RA or lupus patients were cultured in vitro with lipopolysaccharide (LPS, as bacterial infection) or immune complexes (as endogenous immune deviation) and supernatants were collected for cytokine determination. Sera from RA patients were assayed for interleukin-6 (IL-6), IL-1 beta, IL-10, tumor necrosis factor-alpha (TNF-alpha) and IL-1 receptor antagonist (IL-1ra). These cytokines were related to serum CRP, swollen joint counts, and ESR. RESULTS: RA monocytes uniformly produced IL-6, IL-1 beta, TNF-alpha, or IL-10 in vitro. In contrast, lupus monocytes could be divided into two subsets: (i) monocytes which produce cytokines on LPS stimulation but not on challenging with immune complexes; and (ii) monocytes which, interestingly, generate cytokines on stimulation by immune complexes but not LPS. These cytokines in turn stimulate the liver to synthesize CRP differently in the SLE subsets and RA patients. Moreover, serum IL-1ra levels correlated significantly with serum IL-6, IL-1 beta, and TNF-alpha concentrations (p = 0.005, 0.008, or 0.040, respectively), but not with IL-10 (p = 0.582) in RA patients. CONCLUSIONS: Two lupus subsets exist that react either to LPS or immune complexes to produce CRP-inducing cytokines, in contrast to homogeneous RA monocytes. This is the first report that different reaction patterns of CRP-inducing cytokine production in RA and lupus monocytes probably underlie the high CRP levels in RA versus low heterogeneity in lupus. The correlation of serum IL-1ra levels with serum IL-6, IL-1 beta, or TNF-alpha concentrations, and the borderline correlation of the former with CRP levels, demonstrate that IL-1ra is an acute phase reactant in RA as well as in SLE patients.

Serum and in vitro production of IL-1 receptor antagonist correlate with C-reactive protein levels in newly diagnosed, untreated lupus patients.

OBJECTIVE: To examine the correlation between C-reactive protein (CRP) and CRP-inducing cytokines (IL-1 beta, IL-6, TNF-alpha) and IL-1 receptor antagonist (IL-1ra), as well as to study their relationship with systemic lupus erythematosus disease activity (SLEDAI) in newly diagnosed, untreated lupus patients. METHODS: Sera from newly diagnosed untreated lupus and rheumatoid arthritis (RA) patients were examined for CRP and cytokines. Data were compared among patient groups and correlated individually among the lupus group. Lupus monocytes and neutrophils were cultured in vitro to produce IL-1ra and experimental results were related to CRP levels and SLEDAI. RESULTS: Within lupus, serum CRP, IL-6, IL-1 beta and TNF-alpha levels were significantly lower than those of RA (all p values were < 0.005) and generally higher than those in the controls (p = 0.002, < 0.001, > 0.2, and < 0.001, respectively). Except IL-1ra, which was correlated with CRP (p = 0.045), no substantial correlation was discovered between CRP and IL-6, IL-1 beta or TNF-alpha individually. Moreover, excluding IL-1ra (p = 0.024), there was no association between cytokines and SLEDAI. In vitro IL-1ra as secreted by monocytes correlated with serum CRP and SLEDAI. CONCLUSION: In lupus patients, serum IL-1 beta, IL-6 or TNF-alpha levels failed to correlate with low CRP levels. This indicates a complicated CRP production process, which can not be explained solely by single cytokines as reported previously. Both serum and in vitro produced IL-1ra may be applied clinically as a surrogate CRP marker in untreated lupus patients as they are both correlated with serum CRP.

Matrix metalloproteinase-8 in sera and from polymorphonuclear leucocytes in rheumatoid arthritis: in vitro characterization and correlation with disease activity.

OBJECTIVES: To determine matrix metalloproteinase-8 (MMP-8) secretion from rheumatoid arthritis (RA) peripheral blood polymorphonuclear leucocytes (PMNs), in response to immune complexes (IC), cytokines and their combinations, and to study correlation of serum MMP-8 with disease activity. METHODS: PMNs from RA patients and controls were stimulated in vitro with interleukin-15 (IL-15), IL-18, adherent immune complexes, rabbit anti-human immunoglobulin G (anti-HIgG), human immunoglobulin G (HIgG), and their F (ab') 2 prongs, phorbol myristate acetate (PMA) or combinations of above. Supernatants from these experiments and sera from both groups were assayed for MMP-8 using ELISA and correlated with disease activity measures in patients. RESULTS: MMP-8 secretion from stimulated PMNs was compared to unstimulated PMNs. Immune complexes elicited significant MMP-8 secretion (p = 0.006 and 0.001, control and RA respectively). Unlike HIgG and its F (ab')2 fragment, very high secretion was elicited by anti-HIgG (242.37 +/- 10.85 ng/ml) and its F (ab')2 prong (195.85 +/- 28.67 ng/ml). IL-15 did not elicit any secretion. IL-18 with PMA increased secretion significantly only from RA PMNs (p = 0.003). Serum MMP-8 correlated positively with serum CRP (p = 0.017) and not with disease activity score (p = 0.199). CONCLUSIONS: We for the first time demonstrate that immune complexes elicit MMP-8 secretion from PMNs. Except for higher secretion from RA PMNs in response to combination of IL-18 and PMA, both control and RA PMNs respond similarly to various stimuli. Secretion by anti-HIgG occurs by a mechanism independent of Fc receptor. Correlation with CRP suggest that serum MMP-8 may be an indicator of acute inflammatory activity.

[Hypothyroid myopathy: a case report].

Though proximal muscle weakness is characteristic of polymyositis, other agents may also lead to proximal muscle weakness, such as drugs, endocrine diseases, or infections. Here, we report a thirty year-old female suffering from proximal weakness which initially was thought to be a case of polymyositis with high serum creatine phosphokinase level. Very low thyroid hormone levels were found as the history inquiry revealed constipation, hoarseness and cold intolerance. The muscle biopsy showed no obvious inflammation. After thyroxine therapy, her muscle weakness recovered. Up to now, hypothyroid myopathy with muscle mitochondrial abnormalities shown by electron microscopic examination has not been reported in the medical literature in Taiwan. Hypothyroid myopathy, though it is rare, may be misdiagnosed as polymyositis clinically. Therefore, it is recommended that hypothyroid myopathy should be considered in the differential diagnosis of proximal muscle weakness.

Lymphadenopathy in an oriental with ankylosing spondylitis.

We report a case of a patient suffering from enlargement of multiple lymph nodes and low back pain for one year. The diagnosis of ankylosing spondylitis was made by bilateral sacroilitis and HLA-B27 positivity. Lymph nodes biopsy revealed lymphoid hyperplasia. No other cause for the lymphadenopathy was found after a thorough study. Furthermore, high serum IgA and C-reactive protein which were most likely related to active ankylosing spondylitis existed together with lymph node enlargement. Therefore, it was a case of ankylosing spondylitis associated with generalised lymphadenopathy which was the first reported in an oriental person. Several other possible cases also existed. We suggested that ankylosing spondylitis should be considered for young adult patients with lymphadenopathy.

Motion-based grouping of optical flow fields: the extrapolation and subtraction technique.

The goal of three-dimensional (3-D) motion segmentation is to identify the image areas projected by different moving objects in 3-D space. However, many prevailing methods merely detected the discontinuity of optical flow field and usually considered these boundaries as that produced by different 3-D motions. In fact, the flow discontinuity can be generated either by two different 3-D motions or by the structural discontinuity on the same moving object. The wrong identification causes several problems in 3-D motion estimation. A simple method called the extrapolation and subtraction (ES) technique is proposed to solve these problems. The input image flow field is first partitioned into several functionally analytic regions. Each analytic region is assumed to be projected by a roughly planar patch moving in 3-D space. Based on the parameterization of these analytic flow fields, the ES technique provides a very simple and fast method to test the 3-D motion compatibility between two interested analytic flow fields.

Auditory effect of kanamycin given to newborn guinea pigs whose mothers received kanamycin during pregnancy.

Clinical and experimental data indicate that aminoglycoside ototoxicity occurs more frequently in individuals previously exposed to ototoxic drugs. This study investigated the auditory effect of repetitive administration of kanamycin on newborn guinea pigs that had previously been exposed, in utero, to kanamycin administered to their mothers. Sixteen pregnant guinea pigs in the late stages of gestation were divided into two groups, one receiving kanamycin 500 mg/kg per day intramuscularly for 8 days, and the other acting as a control. After birth, the mothers and their newborns in both groups were examined for auditory brain stem response (ABR) and then treated with kanamycin 500mg/kg per day for 4 days. The results from the second examination demonstrated that the group receiving prior treatment with kanamycin, despite their good ABR responses during the first measurement, showed significantly elevated auditory thresholds compared to the control group. Therefore, any ototoxic drugs should be used with extreme caution in newborns having had prior exposure to the drugs in utero, even if they have a "normal" auditory response after birth.

Early-stage development of auditory center: an experimental study of auditory evoked electrophysiologic recordings from fetal and newborn guinea pigs.

Five guinea pig fetuses at 8 weeks' gestation (term is 9 weeks) were tested for auditory brain stem response (ABR) generated by earphones placed outside the maternal abdomen. The results obtained from these fetuses were compared with the ABRs in 10 term newborn guinea pigs on the 1st and 20th day after delivery. The ABRs indicated a decreasing peak latency over wave III with increasing age. The interpeak latency to wave III-V decreased markedly, with very little change in wave I-III. The results suggested rapid maturation of the upper brain stem and midbrain during late gestation and in newborns. They also exhibited an increasing peak latency of ABRs from both fetuses and newborns with decreasing stimulus intensity.

A proposed new paracentesis electrode for the measurement of foetal auditory brain stem response: a preliminary report.

A proposed new electrode for measurement of foetal auditory brain stem response (ABR) is presented, the structure of which resembles a syringe needle. It can be placed subdermally in the head of the guinea pig foetus through the wall of the maternal abdomen. In the anterior end of the electrode a special device similar to a hook is situated. The device may be controlled from outside the maternal abdomen. In comparison with the placement of electrodes through the surgical incision, its placement is simple and injury to tissue is relatively small. It is not only firmly fixed in the subcutaneous tissue of the foetus to satisfy the need for the measurement of foetal ABR, but is easily removed from the foetus. To our knowledge no other similar electrode has been reported.

Domain-specific suppression of auditory mismatch negativity with transcranial direct current stimulation.

OBJECTIVE: To evaluate the influence of frontal transcranial direct current stimulation (tDCS) on auditory mismatch negativity (MMN). METHODS: MMN is an event related potential calculated by subtracting the amplitude of the evoked potentials in response to a "standard" stimulus from the evoked potentials produced by a rare "oddball" stimulus. Here we assessed the influence of anodal tDCS, cathodal tDCS or sham stimulation delivered over the right inferior frontal cortex on MMN in response to duration and frequency auditory deviants in 10 healthy subjects. RESULTS: MMN to frequency deviants was significantly reduced after anodal tDCS compared with sham or cathodal stimulation which did not change MMN to frequency deviants. Neither anodal nor cathodal tDCS had any effect on MMN to duration deviants. CONCLUSIONS: Non-invasive brain stimulation with tDCS can influence MMN. The differing networks known to be activated by duration and frequency deviants could account for the differential effect of tDCS on duration and frequency MMN. SIGNIFICANCE: Non-invasive brain stimulation could be a useful method to manipulate MMN for experimental purposes.