Increased incidence and recurrence rates of acute diverticulitis in patients with irritable bowel syndrome.

AIM: Acute diverticulitis (AD) is commonly diagnosed in outpatient and emergency departments and is associated with severe complications such as perforation and fistula. Symptoms of irritable bowel syndrome (IBS), such as abdominal pain, constipation and diarrhoea, are also common with AD. This study aimed to evaluate the strength of a possible association between IBS and AD. METHOD: This retrospective study analysed records from Taiwan's National Health Insurance Research Database and involved a total of 25 810 patients, including 12 905 IBS patients diagnosed between 2000 and 2012. The IBS and non-IBS cohorts were matched by propensity score for age, gender, comorbidities and medication, then compared for confounding variables by the chi-square test or Student's t-test. The association between AD and IBS was determined using Cox proportional hazards models. Kaplan-Meier curves assessed the cumulative incidence of AD in IBS patients. RESULTS: The overall incidence of AD was 3.95-fold higher in the IBS cohort than in the non-IBS cohort (63.34 vs 16.02 per 100 000 person-years, respectively) and IBS was an independent risk factor for subsequent diagnosis of AD in multivariate Cox proportional hazards regression model adjusted hazards ratio (aHR = 3.84, 95% CI = 2.29-6.44, P < 0.001) and Kaplan-Meier (log-rank test, P < 0.001) analysis. IBS was also associated with a high recurrence rate of AD (aHR = 8.30, 95% CI = 1.07-64.30, P = 0.04). CONCLUSION: The epidemiological evidence in this study demonstrates that patients with IBS are associated with a higher incidence of AD and also its recurrence.

Mitochondrial DNA variants as genetic risk factors for Parkinson disease.

BACKGROUND AND PURPOSE: Investigation of the relationship between mitochondrial DNA (mtDNA) variants and Parkinson disease (PD) remains an issue awaiting more supportive evidence. Moreover, an affirming cellular model study is also lacking. METHODS: The index mtDNA variants and their defining mitochondrial haplogroup were determined in 725 PD patients and 744 non-PD controls. Full-length mtDNA sequences were also conducted in 110 cases harboring various haplogroups. Cybrid cellular models, composed by fusion of mitochondria-depleted rho-zero cells and donor mitochondria, were used for a rotenone-induced PD simulation study. RESULTS: Multivariate logistic regression analysis revealed that subjects harboring the mitochondrial haplogroup B5 have resistance against PD (odds ratio 0.50, 95% confidence interval 0.32-0.78; P = 0.002). Furthermore, a composite mtDNA variant group consisting of A10398G and G8584A at the coding region was found to have resistance against PD (odds ratio 0.50, 95% confidence interval 0.33-0.78; P = 0.001). In cellular studies, B4 and B5 cybrids were selected according to their higher resistance to rotenone, in comparison with cybrids harboring other haplogroups. The B5 cybrid, containing G8584A/A10398G variants, showed more resistance to rotenone than the B4 cybrid not harboring these variants. This is supported by findings of low reactive oxygen species generation and a low apoptosis rate in the B5 cybrid, whereas a higher expression of autophagy was observed in the B4 cybrid particularly under medium dosage and longer treatment time with rotenone. CONCLUSIONS: Our studies, offering positive results from clinical investigations and cybrid experiments, provide data supporting the role of variant mtDNA in the risk of PD.

Increased risk of cardiovascular events in end-stage renal disease patients with osteoporosis: a nationwide population-based cohort study.

SUMMARY: We investigated the cardiovascular disease risk and mortality in end-stage renal disease (ESRD) patients. A total of 12,535 patients with ESRD undergoing incident dialysis were enrolled, 4,153 (33.13 %) of whom had osteoporosis. The osteoporosis group was associated with a significantly higher risk of coronary artery disease, congestive heart failure, stroke, and mortality. INTRODUCTION: In this study, we aimed to investigate the risk of cardiovascular disease and mortality in a sample of end-stage renal disease patients with osteoporosis. METHODS: We conducted this retrospective cohort study of incident dialysis patients with and without osteoporosis to evaluate the risk of overall mortality and cardiovascular complications including stroke, coronary heart disease, and congestive heart failure between the two groups. A total of 12,535 patients with ESRD undergoing incident dialysis were enrolled, 4,153 (33.13 %) of whom had osteoporosis, from the National Health Insurance Research Database of Taiwan for the years 1998 through 2011. The osteoporosis group had more comorbidities than the group without osteoporosis including hypertension, hyperlipidemia, mental disorders, and hepatitis C infection. RESULTS: After adjusting for age, gender, and related comorbidities, the osteoporosis group was associated with a significantly higher risk of coronary artery disease (hazard ratio (HR)=1.32, 95 % confidence interval (CI)=1.20-1.45) which was significant in both genders (women, HR=1.35, 95% CI=1.20-1.50; men HR=1.27, 95% CI=1.06-1.52) and all age groups (≤49 years HR=1.41, 95% CI=1.16-1.70; >49 years HR=1.30, 95% CI=1.16-1.45). Similar results were observed for the outcomes of congestive heart failure, stroke, and mortality. CONCLUSIONS: The results showed that osteoporosis was significantly associated with the subsequent risk of cardiovascular events in patients with ESRD. When encountering patients with ESRD and osteoporosis, physicians should be alert to the subsequent cardiovascular risk in incident dialysis patients to prevent the subsequent occurrence of these adverse events.

Association of NLRP3 and CARD8 genetic polymorphisms with juvenile idiopathic arthritis in a Taiwanese population.

OBJECTIVES: An elevated interleukin (IL)-1ß response in peripheral blood mononuclear cells (PBMCs) has been observed in systemic juvenile idiopathic arthritis (sJIA), suggesting a role for inflammasomes in the pathogenesis of JIA. We aimed to determine whether genetic polymorphisms of the NLRP3 inflammasome components confer risk for oligoarticular and polyarticular JIA in a Taiwanese population. METHOD: A total of 118 JIA patients and 103 healthy controls were genotyped for rs4353135 OR2B11/NLRP3 and rs2043211 CARD8 polymorphisms. Clinical laboratory data and serum IL-1ß of JIA patients were evaluated by medical chart review and enzyme-linked immunosorbent assay (ELISA), respectively. The production of IL-17 in lymphocytes of different genotype carriers was measured using flow cytometry. RESULTS: The variant rs4353135 G allele carrier conferred increased risk for oligoarticular and polyarticular JIA. The G allele was also found to be associated with higher levels of clinical inflammatory markers. Moreover, G variant carriers enhanced the lymphocyte IL-17 response. The G/G genotype further increased the need for treatment with the tumour necrosis factor (TNF) inhibitor etanercept. CONCLUSIONS: Our data indicate that the rs4353135 OR2B11/NLRP3 polymorphism might be functional in, and could contribute to, the pathophysiology of oligoarticular and polyarticular JIA in a Taiwanese population.

Dose-Responsive Impacts of Social Frailty on Intrinsic Capacity and Healthy Aging among Community-Dwelling Middle-aged and Older Adults: Stronger Roles of Social Determinants over Biomarkers.

OBJECTIVE: The intricate relationship between social determinants, e.g., social frailty, biomarkers and healthy aging remains largely unexplored, despite the potential for social frailty to impact both intrinsic capacity (IC) and functional ability in the aging process. DESIGN: Retrospective longitudinal cohort study. SETTING AND PARTICIPANTS: Participants aged 50+ years from the Social Environment and Biomarkers of Aging Study (SEBAS) in Taiwan, stratified into three age groups: 50-64, 65-74 and 75+. MEASUREMENTS: Social frailty was defined based on a score derived from four domains: exclusion from general resources, social resources, social activity, and fulfillment of basic social needs. The scores were categorized as score=0 (no social frailty), 1 (social pre-frailty), and 2+ (social frailty). Multivariable logistic regression and Cox proportional hazard models were employed to examine the dose-responsive relationship between social frailty, low IC, functional and psychological health, and mortality. RESULTS: Of 1015 study participants, 24.9% and 7.9% were classified as social pre-frailty and social frailty, respectively. No significant differences were observed in most biomarkers between those with social frailty and those without. A dose-responsive relationship was found between social frailty and increased risk of low IC (social pre-frailty: aOR 2.20 [95% CI 1.59-3.04]; social frailty: 5.73 [3.39-9.69]). Similar results were found for functional and psychological health. However, no significant association between social frailty and all-cause mortality was found at the 4-year follow-up (social pre-frailty: aHR 1.52 [95% CI 0.94-2.43]; social frailty: 1.59 [0.81-3.09]). CONCLUSIONS: The significant association between social frailty and low IC, functional limitations, cognitive declines, and depressive symptoms underscores the pressing need for research on intervention strategies to enhance healthy aging in the lifespan course.

Analysis of the proteome of intracellular Shigella flexneri reveals pathways important for intracellular growth.

Global proteomic analysis was performed with Shigella flexneri strain 2457T in association with three distinct growth environments: S. flexneri growing in broth (in vitro), S. flexneri growing within epithelial cell cytoplasm (intracellular), and S. flexneri that were cultured with, but did not invade, Henle cells (extracellular). Compared to in vitro and extracellular bacteria, intracellular bacteria had increased levels of proteins required for invasion and cell-to-cell spread, including Ipa, Mxi, and Ics proteins. Changes in metabolic pathways in response to the intracellular environment also were evident. There was an increase in glycogen biosynthesis enzymes, altered expression of sugar transporters, and a reduced amount of the carbon storage regulator CsrA. Mixed acid fermentation enzymes were highly expressed intracellularly, while tricarboxylic acid (TCA) cycle oxidoreductive enzymes and most electron transport chain proteins, except CydAB, were markedly decreased. This suggested that fermentation and the CydAB system primarily sustain energy generation intracellularly. Elevated levels of PntAB, which is responsible for NADPH regeneration, suggested a shortage of reducing factors for ATP synthesis. These metabolic changes likely reflect changes in available carbon sources, oxygen levels, and iron availability. Intracellular bacteria showed strong evidence of iron starvation. Iron acquisition systems (Iut, Sit, FhuA, and Feo) and the iron starvation, stress-associated Fe-S cluster assembly (Suf) protein were markedly increased in abundance. Mutational analysis confirmed that the mixed-acid fermentation pathway was required for wild-type intracellular growth and spread of S. flexneri. Thus, iron stress and changes in carbon metabolism may be key factors in the S. flexneri transition from the extra- to the intracellular milieu.

Intrinsic Capacity Impairment Patterns and their Associations with Unfavorable Medication Utilization: A Nationwide Population-Based Study of 37,993 Community-Dwelling Older Adults.

OBJECTIVES: Our aim was to explore the patterns of intrinsic capacity (IC) impairments among community-dwelling older adults and the associations of these different patterns with excessive polypharmacy, potentially inappropriate medications, and adverse drug reactions in a nationwide population-based study. DESIGN: A cross-sectional study included older adults from the Taiwan Integrated Care for Older People (ICOPE) program in 2020. SETTING AND PARTICIPANTS: The study subjects comprised 38,308 adults aged 65 years and older who participated in the ICOPE Step 1 screening and assessed six domains of IC following the World Health Organization (WHO) ICOPE approach. METHODS: Latent class analysis was adopted to identify distinct subgroups with different IC impairments patterns. The associations between different IC impairments patterns and unfavorable medication utilization, including excess polypharmacy (EPP), potentially inappropriate medications (PIMs), and adverse drug reactions (ADRs), were assessed by multivariate logistic regression models. RESULTS: Latent class analysis identified five distinct subgroups with different IC impairment patterns: robust (latent class prevalence: 59.4%), visual impairment (17.7%), physio-cognitive decline (PCD) with sensory impairment (12.3%), depression with cognitive impairment (7.7%), and impairments in all domains (2.9%). Compared to the robust group, all other groups were at higher odds for unfavorable medication utilization. The "depression with cognitive impairment" group (EPP: aOR=4.35, 95% CI 3.52-5.39, p<0.01; PIMs: aOR=2.73, 95% CI 2.46-3.02, p<0.01) and the "impairment in all domains" group (EPP: aOR=9.02, 95% CI 7.16-11.37, p<0.01; PIMs: aOR=3.75, 95% CI 3.24-4.34, p<0.01) remained at higher odds for EPP and PIMs after adjustment. CONCLUSIONS: We identified five distinct impairment patterns of IC, and each impairment pattern, particularly the "depression with cognitive impairment" and "impairment in all domains", was associated with higher odds of EPP and PIMs. Further longitudinal and intervention studies are needed to explore long-term outcomes of different impairment pattern and their reversibility.

Evolution of microbiological trends and treatment outcomes in peritoneal dialysis-related peritonitis.

BACKGROUND AND AIM: Peritoneal dialysis (PD)-related peritonitis is a major risk factor of technique failure and contributes to significant mortality in patients undergoing PD. The aim of this study was to examine the evolution of microbiological trends and treatment outcomes of PD-related peritonitis in our hospital over the past 26 years. METHODS: A total of 630 patients entered our CAPD program from February 1984 to June 2010. Among them, 119 patients (18.9%) experienced 599 episodes of peritonitis. Microbiological trends, treatment responses, techniques and patient survival were analyzed. RESULTS: The incidence rate of total peritonitis showed a steady decline from 1.08 episodes/patient-year in 1984 to 0.25 episode/ patient-year in 2009 (p < 0.001). A similar trend was found in gram-positive (p < 0.001) and gram-negative peritonitis (p = 0.015). In contrast, there was a trend toward an increased proportion of gram-negative peritonitis. This increase was not due to an increased rate of gram-negative peritonitis but to the more dramatic fall in gram-positive peritonitis. Treatment of peritonitis resulted in a complete cure in 78.0% of patients, while 16.7% of patients required catheter removal and 5.3% died. Gram-positive organisms were associated with a more favorable outcome compared to gram-negative pathogens as manifested by a higher cure rate (p = 0.023). The patient survival and technique survival were much improved after 2000 compared to that before 2000 (p < 0.0001). CONCLUSION: A remarkable improvement in the outcome of PD-related peritonitis has been achieved in the past 26 years in our hospital. To further decrease peritonitis rates, attention needs to be directed at reducing gram-negative peritonitis.

Outcome of peritoneal dialysis in cirrhotic patients with end-stage renal disease: a 24-years' experience in Taiwan.

BACKGROUND: Use of peritoneal dialysis (PD) in liver cirrhosis patients with end-stage renal disease remains controversial. Moreover, the long-term outcome in cirrhotic patients is unclear. The aim of the present study was to analyze the outcome of cirrhotic patients treated with PD in our center during the past 24 years. METHODS: We retrospectively reviewed the data of cirrhotic patients who received PD between 1984 and 2009. A group of noncirrhotic patients who were age- and sex-matched during the same period were selected as controls. Peritonitis rates, complications and outcomes were compared. RESULTS: A total of 30 cirrhotic patients and 60 control patients were included in the analysis. Peritonitis-free survival did not differ between groups. Gram-positive organisms, especially coagulase-negative staphylococcus and streptococcus sp., were the major causes of peritonitis in the cirrhotic patients. Also in the cirrhotic patients, complications such as umbilical hernia, chronic hypotension and erythropoietin resistance were more common as compared with controls. An initially higher solute and water transport capacity was observed in the cirrhotic patients, which became comparable to controls by the end of the 2nd year of treatment. Serum albumin concentrations were lower in cirrhotic patients (p = 0.01), and the decline of renal Kt/V was slower in cirrhotic patients as compared to that of controls (p < 0.0001). There was no significant difference in patient and technique survival between the two groups. CONCLUSION: Our study suggests that PD is an effective therapy with a comparable risk of peritonitis and solute clearance in liver cirrhosis patients with end-stage renal failure.

Predicting Performances on Processing and Memorizing East Asian Faces from Brain Activities in Face-Selective Regions: A Neurocomputational Approach.

For more than two decades, a network of face-selective brain regions has been identified as the core system for face processing, including occipital face area (OFA), fusiform face area (FFA), and posterior region of superior temporal sulcus (pSTS). Moreover, recent studies have suggested that the ventral route of face processing and memory should end at the anterior temporal lobes (i.e., vATLs), which may play an important role bridging face perception and face memory. It is not entirely clear, however, the extent to which neural activities in these face-selective regions can effectively predict behavioral performance on tasks that are frequently used to investigate face processing and face memory test that requires recognition beyond variation in pose and lighting, especially when non-Caucasian East Asian faces are involved. To address these questions, we first identified during a functional scan the core face network by asking participants to perform a one-back task, while viewing either static images or dynamic videos. Dynamic localizers were effective in identifying regions of interest (ROIs) in the core face-processing system. We then correlated the brain activities of core ROIs with performances on face-processing tasks (component, configural, and composite) and face memory test (Taiwanese Face Memory Test, TFMT) and found evidence for limited predictability. We next adopted an multi-voxel pattern analysis (MVPA) approach to further explore the predictability of face-selective brain regions on TFMT performance and found evidence suggesting that a basic visual processing area such as calcarine and an area for structural face processing such as OFA may play an even greater role in memorizing faces. Implications regarding how differences in processing demands between behavioral and neuroimaging tasks and cultural specificity in face-processing and memory strategies among participants may have contributed to the findings reported here are discussed.

Prophylactic mirtazapine reduces intrathecal morphine-induced pruritus.

BACKGROUND: Activation of the serotonergic system is an important factor in the pathogenesis of intrathecal morphine-induced pruritus. Mirtazapine is a new antidepressant that selectively blocks 5-HT(2) and 5-HT(3) receptors. We therefore tested the hypothesis that preoperative mirtazapine would reduce the incidence of intrathecal morphine-induced pruritus. METHODS: One hundred and ten ASA I patients undergoing lower limb surgery under spinal anaesthesia were randomly allocated into two equal groups and received either mirtazapine 30 mg or an orally disintegrating placebo tablet 1 h before operation in a prospective, double-blinded trial. All patients received an intrathecal injection of 15 mg of 0.5% isobaric bupivacaine and 0.2 mg preservative-free morphine. The occurrence and the severity of pruritus were assessed at 3, 6, 9, 12, and 24 h after intrathecal morphine. RESULTS: Pruritus was significantly more frequent in the placebo group compared with the mirtazapine group (75% vs 52%, respectively; P=0.0245). The time to onset of pruritus in the two groups was also significantly different. The patients who experienced pruritus in the placebo group had a faster onset time than that in the mirtazapine group [mean (sd): 3.2 (0.8) vs 7.2 (4.1) h, P<0.0001]. CONCLUSIONS: Mirtazapine premedication prevents pruritus induced by intrathecal morphine in patients undergoing lower limb surgery with spinal anaesthesia.

Thrombin and interleukin-1beta regulate HOXA10 expression in human term decidual cells: implications for preterm labor.

CONTEXT: Preterm delivery is commonly caused by intraamniotic infection with expression of proinflammatory cytokines (IL-1beta) or by abruption resulting in generation of decidual thrombin. Although human parturition is not preceded by overt progesterone withdrawal, progesterone resistance likely leads to labor. The uteri of Hoxa10(-/-) mice demonstrate progesterone resistance; several genes, including prostaglandin receptors, are inappropriately regulated in response to progesterone. OBJECTIVE: We hypothesized that IL-1beta or thrombin would decrease HOXA10 expression, contributing to the progestin-resistant environment. We analyzed expression of HOX genes and their regulation by IL-1beta or thrombin in decidual cells. DESIGN AND SETTING: We conducted an in vitro experiment at an academic medical center. INTERVENTION: Term decidual cells were treated with estradiol (E(2)) or E(2) plus medroxyprogesterone acetate followed by addition of thrombin or IL-1beta. MAIN OUTCOME MEASURE: HOX mRNA was evaluated by microarray and confirmed by quantitative RT-PCR. Protein expression was detected using immunohistochemistry and Western analysis. RESULTS: HOXA9, HOXA10, and HOXA11 were expressed in decidual cells and regulated by IL-1beta and thrombin. HOXA10 was further analyzed because of its association with progesterone responsiveness. After E(2) treatment, IL-1beta and thrombin decreased HOXA10 mRNA by 94 and 81%, respectively. After E(2) plus medroxyprogesterone acetate treatment, IL-1beta and thrombin resulted in an 86 and 72% decrease in HOXA10 mRNA, respectively. A similar decrease was noted in HOXA10 protein expression. CONCLUSION: The expression of HOXA10 protein at term indicates that it may have a role in maintaining decidual cell phenotype and pregnancy. The dramatic decrease of HOXA10 in response to IL-1beta or thrombin may contribute to progestin resistance in preterm labor, mimicking progesterone resistance seen in Hoxa10(-/-) mice.

Progestin suppresses thrombin- and interleukin-1beta-induced interleukin-11 production in term decidual cells: implications for preterm delivery.

CONTEXT: Decidual inflammation and hemorrhage are major contributors to the pathogenesis of preterm delivery (PTD). IL-11 is a cytokine with pleiotropic biological effects, including induction of T helper cell type 2 and inhibition of T helper cell type 1 cytokine responses. Paradoxically, it enhances the synthesis of prostaglandins, which induce labor. OBJECTIVE: The objectives of this study were to evaluate in vivo IL-11 expression in decidua after term and preterm deliveries and evaluate the effects of the primary mediators of inflammation, IL-1beta and TNF-alpha, as well as the primary regulator of hemostasis, thrombin, on IL-11 expression in cultured term decidual cells (DCs). INTERVENTIONS AND MAIN OUTCOME MEASURES: Human decidua from uncomplicated term deliveries and chorioamnionitis- or placental abruption-related PTDs were immunostained for IL-11. Cultures of DCs were primed with estradiol (E2) or with E2 and medroxyprogesterone acetate (MPA), then incubated in a defined medium with corresponding steroid(s) with or without IL-1beta, TNF-alpha, or thrombin. IL-11 levels in DC-defined media were assessed by ELISA and Western blotting; IL-11 mRNA levels were measured by quantitative RT-PCR. RESULTS: IL-11 immunostaining was significantly higher in DCs after PTD compared with those after term delivery (P < 0.05). In the absence of cytokines or thrombin, IL-11 levels in the defined medium were 47% lower in incubations with E2 plus MPA vs. E2 alone (P = 0.001). IL-1beta and thrombin elevated IL-11 output during incubations with E2 [24-fold (P < 0.05) and 120-fold (P < 0.05), respectively]. These increases were blunted by the addition of MPA [13-fold (P < 0.05) and 36-fold (P < 0.05), respectively]. Western blot analysis confirmed the ELISA results, and RT-PCR demonstrated corresponding effects on IL-11 mRNA levels. Unexpectedly, TNF-alpha did not affect IL-11 levels. CONCLUSION: Because excess IL-1beta and thrombin generation are associated with chorioamnionitis- and abruption-related PTD, respectively, these findings add to our understanding of the genesis of inflammation- and abruption-associated prematurity.

Ligand binding to wild-type and E-B13Q mutant insulins: a three-state allosteric model system showing half-site reactivity.

By using ultra-violet and visible absorbance in conjunction with high field 1H-nuclear magnetic resonance spectroscopy, the insulin hexamer has been shown to undergo two allosteric transitions in solution involving three allosteric states (T6<-->T3 R3<-->R6). A simple mathematical model consisting of four variables has been derived that quantitatively describes the complex homotropic and heterotropic interactions that modulate these allosteric transitions. The mutation of one residue, Glu-B13 to Gln, results in an unexpected change in the T3R3 to R6 equilibrium by a factor of 10(7).

Developmental response to hypoxia.

Molecular mechanisms underlying fetal growth restriction due to placental insufficiency and in utero hypoxia are not well understood. In the current study, time-dependent (3 h-11 days) changes in fetal tissue gene expression in a rat model of in utero hypoxia compared with normoxic controls were investigated as an initial approach to understand molecular events underlying fetal development in response to hypoxia. Under hypoxic conditions, litter size was reduced and IGFBP-1 was up-regulated in maternal serum and in fetal liver and heart. Tissue-specific, distinct regulatory patterns of gene expression were observed under acute vs. chronic hypoxic conditions. Induction of glycolytic enzymes was an early event in response to hypoxia during organ development; consistently, tissue-specific induction of calcium homeostasis-related genes and suppression of growth-related genes were observed, suggesting mechanisms underlying hypoxia-related fetal growth restriction. Furthermore, induction of inflammation-related genes in placentas exposed to long-term hypoxia (11 days) suggests a mechanism for placental dysfunction and impaired pregnancy outcome accompanying in utero hypoxia.

Interferon-related and other immune genes are downregulated in peripheral blood leukocytes in the luteal phase of the menstrual cycle.

Interaction between the endocrine and the immune systems has been suggested by observations of sexual dimorphism of the immune response, differential susceptibility to autoimmunity between the sexes, changes in autoimmune disease activity during the menstrual cycle and in pregnancy and in vitro studies of hormonal influence on cytokine production.We hypothesized that if there is hormonal regulation of the immune response, this would be manifest in peripheral blood leukocytes (PBLs) at different phases of the menstrual cycle. In this study, we describe gene profiling of PBLs from the follicular and luteal phases of the menstrual cycle. We observe important differences in immune gene expression, with significant down-regulation of the Th1 immune response in the luteal phase. A significant number of interferon (IFN)-related genes are amongst the downregulated genes. These results support significant hormonal regulation of the immune system and may have therapeutic implications in diseases of autoimmunity in women.

Hemorrhagic disorder due to an isoniazid-associated acquired factor XIII inhibitor in a patient with Waldenström's macroglobulinemia.

A case is described of a 75-year-old woman with a history of pulmonary tuberculosis and Waldenström's macroglobulinemia who developed an inhibitor of coagulation factor XIII while taking isoniazid. The patient presented with a subcutaneous hematoma of the abdominal wall that extended from the xiphoid process to the symphysis pubis and measured 20 cm in diameter. Results of routine coagulation studies were normal with the exception of an increased solubility of the patient's plasma clot in 5M urea consistent with a deficiency of factor XIII activity. Persistence of the deficiency following a 1:2 dilution of the patient's plasma in normal plasma indicated the presence of an inhibitor. A sample of the patient's plasma was depleted of IgG by streptococcal protein G adsorption. The IgG-depleted plasma did not inhibit factor XIII activity, indicating that the inhibitory activity was not attributable to the underlying IgM paraprotein. The patient's purified IgG, on the other hand, inhibited factor XIII activity and the inhibitory activity could be neutralized by anti-IgG antibody. The patient's IgG also inhibited factor XIII-mediated incorporation of fluorescent monodansylcadaverine into casein. Binding of the patient's IgG to factor XIII concentrate was demonstrated by enzyme-linked immunosorbent assay and the IgG that bound to the factor XIII was demonstrated to be polyclonal. Isoniazid was discontinued after the patient was admitted to the hospital. Cryoprecipitate infusion controlled bleeding and reduced the inhibitor titer by 50%. Treatment with cyclophosphamide and prednisone, followed by extracorporeal immunoadsorption over a staphylococcal protein A column, did not reduce the inhibitor titer further. Plasma exchange therapy reduced the inhibitor titer to undetectable levels but failed to restore factor XIII activity. Infusions of factor XIII concentrate reproducibly restored factor XIII activity and were not associated with an anamnestic rise in the inhibitor titer. This represents the seventh reported case of an acquired inhibitor to factor XIII associated with the ingestion of isoniazid.

Agglutination of blood cardioplegia by cold-reacting autoantibodies.

Cold-reacting autoantibodies occasionally occur in patients requiring cardiac operations. This report describes the clinical course of 1 patient with cold-reacting autoantibodies and intracoronary agglutination of the blood cardioplegia solution. Observations made in vivo and in vitro are considered in discussing recommendations for the management of extracorporeal circulation and cardioplegic arrest in patients with clinically silent cold-reacting autoantibodies.