Discrepancies between clinical and pathological findings seen at renal biopsy in rheumatological diseases.

OBJECTIVE: Renal biopsy contributes to the diagnosis, follow-up, and treatment of many rheumatic conditions. This study assessed the diagnostic role and safety of renal biopsies in a tertiary rheumatology clinic. METHODS: Renal biopsies performed between June 2020 and December 2022 were screened, and demographic, clinical, histopathological, and safety data were collected from patient records. RESULTS: In this study, 33 males and 38 females were included. Except for 1 patient who received acetylsalicylic acid, antiaggregant, and/or anticoagulant drugs were stopped before the biopsy. Complications included a decrease of hemoglobin in 8 patients (11.3%) and microscopic hematuria in 40 patients (56.3%). Control ultrasonography was performed in 16 patients (22.5%), and a self-limiting hematoma was found in 4 of them (5.6%) without additional complications. While less than 10 glomeruli were obtained in 9 patients (9.9%), diagnosis success was 94.4%. Histopathological data were consistent with one of the pre-biopsy diagnoses in 54 of 67 cases (80.6%) but showed discrepancies in 19.4% (n=13) of patients. A repeat biopsy was performed in 7 patients for re-staging or insufficient biopsy. CONCLUSIONS: Renal biopsy significantly contributes to rheumatology practice, especially in patients with complex clinical and laboratory findings or in whom different treatments can be given according to the presence, severity, and type of renal involvement. Although the possibility of obtaining insufficient tissue and the need for re-staging and repeat biopsy in the follow-up might be expected, complication risk does not seem to be a big concern. Renal biopsy often evidenced discrepancies between pre-biopsy diagnosis and histopathological findings.

Rumen bacteria at work: bioaugmentation strategies to enhance biogas production from cow manure.

AIMS: To investigate the effects of different bioaugmentation strategies for enhancing the biogas production from cow manure and evaluate microbial community patterns. METHODS AND RESULTS: Co-inoculation with cow rumen fluid and cow rumen-derived enriched microbial consortia was evaluated in anaerobic batch tests at 36°C and 41°C. Singular addition of both rumen fluid and enriched bioaugmentation culture had a promising enhancement on methane yields; however, the highest methane yield (311 ml CH4 per gram VS at 41°C) was achieved when the anaerobic seed sludge was co-inoculated together with rumen fluid and enriched bioaugmentation culture. Bacterial community profiles were investigated by Ion PGM Platform, and specific lignocellulolytic bacteria dynamics in batch tests were assessed by qPCR. The temperature had minor effects on the abundance of bacterial community; in which Bacteroidetes and Firmicutes were the most abundant phyla in all digesters. Furthermore, Rikenellaceae, Clostridiaceae, Porphyromonadaceae, Bacteroidaceae and Ruminococcaceae played a crucial role during the anaerobic degradation of cow manure. There was an important impact of Firmicutes flavefaciens and Ruminococcus albus at 41°C, which in turn positively affected the methane production. CONCLUSION: The degree of enhancement in biogas production can be upgraded by the co-inoculation of rumen-derived bioaugmentation culture with anaerobic seed sludge with high methanogenic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: A close look at the biotic interactions and their associations with abiotic factors might be valuable for evaluating rumen-related bioaugmentation applications.

Does Internet-based guided-self-help for depression cause harm? An individual participant data meta-analysis on deterioration rates and its moderators in randomized controlled trials.

BACKGROUND: Almost nothing is known about the potential negative effects of Internet-based psychological treatments for depression. This study aims at investigating deterioration and its moderators within randomized trials on Internet-based guided self-help for adult depression, using an individual patient data meta-analyses (IPDMA) approach. METHOD: Studies were identified through systematic searches (PubMed, PsycINFO, EMBASE, Cochrane Library). Deterioration in participants was defined as a significant symptom increase according to the reliable change index (i.e. 7.68 points in the CES-D; 7.63 points in the BDI). Two-step IPDMA procedures, with a random-effects model were used to pool data. RESULTS: A total of 18 studies (21 comparisons, 2079 participants) contributed data to the analysis. The risk for a reliable deterioration from baseline to post-treatment was significantly lower in the intervention v. control conditions (3.36 v. 7.60; relative risk 0.47, 95% confidence interval 0.29-0.75). Education moderated effects on deterioration, with patients with low education displaying a higher risk for deterioration than patients with higher education. Deterioration rates for patients with low education did not differ statistically significantly between intervention and control groups. The benefit-risk ratio for patients with low education indicated that 9.38 patients achieve a treatment response for each patient experiencing a symptom deterioration. CONCLUSIONS: Internet-based guided self-help is associated with a mean reduced risk for a symptom deterioration compared to controls. Treatment and symptom progress of patients with low education should be closely monitored, as some patients might face an increased risk for symptom deterioration. Future studies should examine predictors of deterioration in patients with low education.

Negative pressure wound therapy in the early period after hand and forearm replantation, is it safe?

OBJECTIVE: In this study, effectiveness and reliability of negative pressure wound therapy (NPWT) in the early period after replantation will be examined retrospectively in a series of patients. METHOD: Patients who underwent replantation between 2007 and 2014, and had tissue defect or partial necrosis in the absence of a major circulation problem were included in this retrospective study. Following debridement of necrotic tissues on the postoperative 7-10 days, NPWT was applied to all patients one day later and adjusted as intermittent 75 mmHg pressure. Intermittent phase adjustment was arranged as 5 minutes suction and 2 minutes resting, and resting pressure was adjusted as 35 mmHg. NPWT was applied for six days and dressings were changed in every three days in the first six day period. Open wounds was debrided again and grafted with split-thickness skin graft and NPWT was continued over the graft for 4 days more. RESULTS: There were 11 patients included of which nine amputations were complete and two were nearly total amputations of forearm. Granulation tissue was observed following 6 days of NPWT application in all patients. Graft survival was observed to be almost complete. Wound infection did not occur and tissue cultures obtained in the course of debridement were all negative. Partial oxygen saturations were between 96-99% during the NPWT. CONCLUSION: NPWT (75 mmHg) can be used in the intermittent mode in order to improve wound healing and shorten the period to start physical therapy in the early period after replantation and revascularisation.

Performance of anaerobic sequencing batch reactor in the treatment of pharmaceutical wastewater containing erythromycin and sulfamethoxazole mixture.

This study evaluates the joint effects of erythromycin-sulfamethoxazole (ES) combinations on anaerobic treatment efficiency and the potential for antibiotic degradation during anaerobic sequencing batch reactor operation. The experiments involved two identical anaerobic sequencing batch reactors. One reactor, as control unit, was fed with synthetic wastewater while the other reactor (ES) was fed with a synthetic substrate mixture including ES antibiotic combinations. The influence of ES antibiotic mixtures on chemical oxygen demand (COD) removal, volatile fatty acid production, antibiotic degradation, biogas production, and composition were investigated. The influent antibiotic concentration was gradually increased over 10 stages, until the metabolic collapse of the reactors, which occurred at 360 days for the ES reactor. The results suggest that substrate/COD utilization and biogas/methane generation affect performance of the anaerobic reactors at higher concentration. In addition, an average of 40% erythromycin and 37% sulfamethoxazole reduction was achieved in the ES reactor. These results indicated that these antibiotics were partly biodegradable in the anaerobic reactor system.

Malnutrition risk in hospitalized patients measured with Nutrition Risk Screening 2002 tool and its association with in-hospital mortality.

OBJECTIVE: Malnutrition is related to increased morbidity, mortality, and costs. NRS-2002 is a practical malnutrition risk (MR) screening tool approved by the European Society for Clinical Nutrition and Metabolism (ESPEN) for inpatients. We aimed to reveal the inpatient MR using NRS-2002, and to examine the relationship between MR and in-hospital mortality. PATIENTS AND METHODS: The results of inpatient nutritional screening in a tertiary referral center university hospital were retrospectively analyzed. The NRS-2002 test was used for defining MR. Comorbidities, initial and follow-up anthropometric data, NRS-2002 score, food intake, weight status, and laboratory analysis were examined. In-hospital mortality was noted. RESULTS: Data from 5,999 patients were evaluated. On admission, 49.8% of the patients had MR, and 17.3% had severe MR (sMR). MR-sMR was higher in geriatric patients (62.0-28.5%). Those with dementia had the highest MR (71%), followed by stroke (66%) and malignancy (62%). Age and serum C-reactive protein (CRP) were higher, and body weight, BMI, serum albumin, and creatinine were lower in patients with MR. Multivariate analysis showed that age, albumin, CRP, congestive heart failure (CHF), malignancy, dementia, and stroke were independently associated with MR. The overall mortality rate during hospitalization was 7.9%. MR was associated with mortality regardless of serum CRP, albumin, body mass index (BMI), and age. Half of the patients received nutritional treatment (NT). NT resulted in preserved or increased body weight and albumin levels among patients and the geriatric group with MR. CONCLUSIONS: AMR revealed that NRS-2002 is positive in approximately half of the hospitalized patients, which is associated with in-hospital mortality independent of the underlying diseases. NT is related to weight gain and increased serum albumin.

Can exposure to manganese and extremely low frequency magnetic fields affect some important elements in the rat teeth?

BACKGROUND: Length and level of exposure to electromagnetic fields (EMFs) is increasing in association with the widespread use of electrical and electronic devices and technological progress. The undesirable effects of extremely low frequency magnetic fields (ELF-MFs) on health have attracted considerable interest. MATERIALS AND METHODS: Sixty-four four-month-old male Wistar rats divided into eight groups of eight rats each were used. Seven groups were exposed to varying dosages of manganese (Mn) and a 50 Hz magnetic field (MF) of approximately 1 mT, while the last group was set aside as the cage control group and not subjected to any procedure. This study was intended to investigate the interactions between the application of MF and Mn and the elements Ca, Zn, Mg, and P thought to be involved in caries, in rat teeth. RESULTS: Levels of Ca, Mg, Zn, and P in the experimental group rats were different to those in the control group. CONCLUSIONS: The results demonstrate that ELF-MF and Mn can have significant effects on levels of elements in rat teeth. Further experimental and epidemiological studies of ELF-MF and Mn are needed in order to evaluate their dental effects.

Effect of seed sludge microbial community and activity on the performance of anaerobic reactors during the start-up period.

In this study, two laboratory-scale anaerobic batch reactors started up with different inoculum sludges and fed with the same synthetic wastewater were monitored in terms of performance and microbial community shift by denaturant gradient gel electrophoresis fingerprinting and subsequent cloning, sequencing analysis in order to reveal importance of initial quality of inoculum sludge for operation of anaerobic reactors. For this purpose, two different seed sludge were evaluated. In Reactor1 seeded with a sludge having less diverse microbial community (19 operational taxonomic unit (OTU's) for Bacterial and 8 OTU's for Archaeal community, respectively) and a methanogenic activity of 150 ml CH(4) g TVS(-1) day(-1), a chemical oxygen demand (COD) removal efficiency of 78.8 ± 4.17% was obtained at a substrate to microorganism (S/X) ratio of 0.38. On the other hand, Reactor2, seeded with a sludge having a much more diverse microbial community (24 OTU's for Bacterial and 9 OTU's for Archaeal communities, respectively) and a methanogenic activity, 450 ml CH(4) g TVS(-1) day(-1), operated in the same conditions showed a better start-up performance; a COD removal efficiency of over 98% at a S/X ratio of 0.53. Sequence analysis of Seed2 revealed the presence of diverse fermentative and syntrophic bacteria, whereas excised bands of Seed1 related to fermentative and sulfate/metal-reducing bacteria. This study revealed that a higher degree of bacterial diversity, especially the presence of syntrophic bacteria besides the abundance of key species such as methanogenic Archaea may play an important role in the performance of anaerobic reactors during the start-up period.

Management of mole gun injuries: Review of 19 cases with proposed treatment algorithm.

Injuries caused by mole guns are mostly localized in the hands and characterized by contaminated and necrotic tissues due to the blast effect and a large number of residual foreign bodies in the wound. This study analyzed the medical records of patients' who had hand injuries caused by mole guns and presents our approach through a reconstruction algorithm. Data from 19 consecutive patients who sustained mole gun injuries between March 2015 and May 2019 were reviewed in this retrospective study. Demographics, affected tissues at the injury site, surgical treatment, presence of foreign bodies, and postoperative complications were recorded. A treatment algorithm was created based on the results of this study. Six patients underwent one operation, while the remaining 13 underwent more than one operation. A bone defect was found in four patients, skin and soft tissue defects in six patients, and a neurovascular defect in six patients. Two or less foreign bodies were seen in seven patients. Foreign body removal and debridement procedures are important in the first surgical session. The repair of defectless structures during the same session is also essential. Preparation of the structures with defects that will be repaired 5-7 days later simplifies the secondary surgery.

Methanogenic and sulphate reducing bacterial population levels in a full-scale anaerobic reactor treating pulp and paper industry wastewater using fluorescence in situ hybridisation.

In this study, specific methanogenic activity (SMA) test and fluorescence in situ hybridisation (FISH) were respectively used to determine acetoclastic methanogenic capacity, and composition and number of methanogenic and sulphate reducing bacterial (SRB) populations within a full scale anaerobic contact reactor treating a pulp and paper industry effluent. The sludge samples were collected from three different heights along the anaerobic reactor having a difficulty of completely stirring. Performance of the anaerobic reactor in terms of COD removal efficiency varied between 47 and 55% at organic loading rates in a range of 1.6-1.8 kg COD m(-3) d(-1) and methane yield varied between 0.18 and 0.20 m3CH4kg CODrem(-1). The anaerobic reactor was not operated for 2 weeks during the monitoring period. According to SMA test results, potential methane production rate was 276 mLCH4 gVSS(-1) d(-1) before the off period of the reactor, however it decreased to 159 mL CH4 gVSS(-1) d(-1) after this period. SMA test and FISH results along the reactor height showed that the acetoclastic methanogenic activity of the sludge samples, the relative abundance of acetoclastic methanogens, hydrogenotrophic methanogens and acetate oxidising SRB decreased as the reactor height increased, however the relative abundance of non-acetate oxidising SRB increased.

Anaerobic sulfamethoxazole degradation is driven by homoacetogenesis coupled with hydrogenotrophic methanogenesis.

In this study, microbial community dynamics were assessed in two lab-scale anaerobic sequencing batch reactors (ASBRs). One of the reactors was fed by synthetic pharmaceutical industry wastewater with sulfamethoxazole (SMX) as the test reactor and the other without sulfamethoxazole as the control reactor. DNA based DGGE results indicated that Clostiridum sp. became dominant in the SMX reactor while the inoculum was dominated with Firmicutes (61%) and Methanomicrobiales (28%). However their abundances in active community decreased through the last phase. Also the abundance of hydrogenotrophs was high in each phase, while acetoclastic methanogens disappeared in the last phase. Q-PCR analysis revealed that there is a significant reduction in the bacterial community approximately 84%, while methanogens increased to 97% through the operation. Additionally an increase in the expression level of bacterial and methanogenic 16S rRNA (60% and 20%, respectively) was detected. Significant correlation between microbial community and the reactor operation data was found. The study demonstrated that the microbial community maintains the system stability under high antibiotic concentration and long-term operation by homoacetogenesis coupled with hydrogenotrophic methanogenesis.

Activation of transcriptionally inactive human estrogen receptors by cyclic adenosine 3',5'-monophosphate and ligands including antiestrogens.

We show that some transcriptionally inactive human estrogen receptor (ER) mutants can be activated by 17 beta-estradiol (E2), and sometimes by antiestrogens, in the presence of elevated levels of intracellular cAMP. ER-deficient Chinese hamster ovary or 3T3 mouse fibroblast cells were transfected with mutant ERs (the point mutant L540Q, the frameshift mutant S554fs, or the carboxy-terminal truncated receptor ER1-530) and various estrogen response element-containing reporter genes. Individual treatments with E2, the antiestrogens trans-hydroxytamoxifen and ICI 164,384, or with 3-isobutyl-1-methyl-xanthine plus cholera toxin (IBMX plus CT) which raise intracellular cAMP, generally do not activate the mutant receptors. However, cotreatment with IBMX/CT and one of the three ligands (E2, trans-hydroxytamoxifen, or ICI164,384) results in the unexpected recovery of strong activation of the L540Q or S554fs receptors, the magnitude of which is dependent upon promoter- and cell-contexts. Unlike L540Q and S554fs, the transcriptionally inactive ER1-530 is not activated by any combination of ligands and IBMX/CT. These data demonstrate that some ER mutants that form transcriptionally nonproductive ER-E2 complexes can be successfully activated by the combination of an agonist or antagonist ligand and an agent thought to act via phosphorylation pathways. Also highlighted is the promoter- and cell-specific nature of the transcriptional response to different ligand-ER complexes. Lastly, the enhanced transcriptional activity of wild type ER and some ER mutants in the presence of antiestrogens and elevated intracellular cAMP may provide a partial explanation of the ability of some estrogen-dependent human breast tumors to resist antiestrogen therapies currently employed.

A transcriptionally active estrogen receptor mutant is a novel type of dominant negative inhibitor of estrogen action.

We have characterized a human estrogen receptor (ER) mutant, V364E, which has a single amino acid substitution in its hormone-binding domain. This ER mutant is fully active or even superactive at saturating levels of estradiol (10(-8) M E2) yet has the capacity to act as a strong dominant negative inhibitor of the wild type ER. In transient transfection assays using ER-negative Chinese hamster ovary (CHO) cells and two different estrogen response element (ERE)-containing promoter reporter genes, V364E treated with 10(-8) M E2 exhibited approximately 250% and 100% of the activity of the wild type ER with these two promoter contexts, respectively. Despite the high activity of V364E when present alone in cells, coexpression of both V364E and wild type ER causes a significant decrease in overall ER-mediated transcriptional activity. On the TATA promoter, where V364E was more inhibitory, estrogen-stimulated activity was reduced by approximately 50% at a 1:1 ratio of mutant to wild type ER expression vector, and at a 10:1 ratio, 75% of ER activity was inhibited. V364E was expressed at lower levels than wild type ER and has a approximately 40-fold lower affinity for E2 compared with wild type ER. In promoter interference assays, V364E exhibited a strict dependence upon E2 for binding to an ERE. Surprisingly, even when V364E was unable to bind to ERE DNA (i.e. either at low E2 concentration or by mutation of its DNA-binding domain), this mutant retained full dominant negative activity. This highly active ER mutant is, thus, able to repress ER-mediated transcription when the mutant and wild type ER are present together in cells, even without DNA binding. Since competition for ERE binding and the formation of inactive heterodimers cannot fully account for the dominant negative activity of V364E, it is probable that altered interactions with proteins important in ER-mediated transcription play a key role in the repression of transcription by V364E. The properties and probable mechanism of action of V364E distinguish it from other previously described dominant negative inhibitors, in which competition for cis-acting DNA elements by transcriptionally inactive receptors played a large role in the resultant dominant negative phenotype.

Monitoring the abundance and the activity of ammonia-oxidizing bacteria in a full-scale nitrifying activated sludge reactor.

Cell-specific ammonia oxidation rate (AOR) has been suggested to be an indicator of the performance of nitrification reactors and to be used as an operational parameter previously. However, published AOR values change by orders of magnitude and studies investigating full-scale nitrification reactors are limited. Therefore, this study aimed at quantifying ammonia-oxidizing bacteria (AOB) and estimating their in situ cell-specific AOR in a full-scale activated sludge reactor treating combined domestic and industrial wastewaters. Results showed that cell-specific AOR changed between 5.30 and 9.89 fmol cell(-1) h(-1), although no significant variation in AOB cell numbers were obtained (1.54E + 08 ± 0.22 cell/ml). However, ammonia-removal efficiency varied largely (52-79 %) and was proportional to the cell-specific AOR in the reactor. This suggested that the cell-specific AOR might be the factor affecting the biological ammonia-removal efficiency of nitrification reactors independent of the AOB number. Further investigation is needed to establish an empirical relationship to use cell-specific AOR as a parameter to operate full-scale nitrification systems more effectively.

Acute effect of erythromycin on metabolic transformations of volatile fatty acid mixture under anaerobic conditions.

The study explored the acute inhibitory impact of erythromycin on the methanogenic activity of acclimated biomass fed with a volatile fatty acid mixture and acetate alone. Parallel batch reactors were operated for six days, with increasing erythromycin dosing in the range of 1-1000 mg L(-1). Substrate removal was monitored by means of soluble COD and volatile fatty acid (VFA) measurements together with parallel observations on biogas and methane generation. The inhibitory impact was variable with the initial erythromycin dose: At lower doses, the VFA mixture was completely removed but partially utilized, leading to reduced biogas and methane generation, suggesting the analogy of uncompetitive inhibition. At higher doses, propionate utilization was totally impaired and butyrate removal was reduced, but acetate was still fully removed. Remaining VFAs were partly converted to new VFA compound through isomerization and polymerization reactions. High erythromycin doses induced total inactivation of microbial metabolism with negligible methane generation.

Repression of endogenous estrogen receptor activity in MCF-7 human breast cancer cells by dominant negative estrogen receptors.

We have investigated the ability of several transcriptionally inactive estrogen receptor (ER) mutants to block endogenous ER-mediated transcription in MCF-7 human breast cancer cells. In transient transfections of MCF-7 cells, two of the mutants, a frame-shifted ER (S554fs) and a point-mutated ER (L540Q), strongly inhibit the ability of endogenous wild-type ER to activate transcription of estrogen-regulated reporter plasmids. A third mutant, ER1-530, which is missing 65 residues from its carboxy-terminus, is a weaker repressor of estradiol-stimulated transcription. When an estrogen response element (ERE)-thymidine kinase-chloramphenicol acetyltransferase reporter gene is used, S554fs, L540Q, and ER1-530 suppress the transcriptional activity of endogenous MCF-7 ER by 87%, 97%, and 62%, respectively. The magnitude of dominant negative repression is promoter specific; when an ERE-pS2-chloramphenicol acetyltransferase reporter is employed, inhibition of endogenous ER activity by equivalent amounts of S554fs, L540Q, and ER1-530 ranges from 85-97%. Dose-response studies show the S554fs mutant to be the most potent of the three ER mutants as a repressor of estrogen action in these cells. In addition, elevated levels of intracellular cAMP, achieved by the addition of 3-isobutyl-1-methylxanthine plus cholera toxin to cells, fail to compromise the effectiveness of these mutants as dominant negative ERs despite the cAMP-enhanced transcriptional activity of ER. The mutants are also powerful repressors of the agonist activity of trans-hydroxytamoxifen-stimulated ER transcription. The dominant negative activity of the three mutants is lost when the A/B domain of these receptors is deleted, implying an important role for this N-terminal region of the ER in the ability of these mutants to inhibit endogenous wild-type ER activity. All in all, the data suggest that S554fs in particular is a reasonable candidate for studies designed to use a dominant negative ER to inhibit the estrogen- and tamoxifen-stimulated growth of human breast cancer cells.

Lowering dietary protein to U.S. Recommended dietary allowance levels reduces urinary calcium excretion and bone resorption in young women.

High-protein diets increase calciuria. No previous studies have examined the ad libitum U.S. diet's effect on calciuria or bone resorption.Thirty-nine healthy, premenopausal women consuming ad libitum diets [mean, 1.1 g/kg protein, 819 mg (20.5 mmol) Ca, 1152 mg (37 mmol) P, 129 mmol Na] were switched to isocaloric diets containing the U.S. recommended dietary allowance (RDA) of protein (0.8 g/kg) and similar amounts of calcium, phosphorus, and sodium. Bone resorption and related endpoints were assessed before and 1 wk after the switch. As dietary protein changed from ad libitum to RDA levels, mean urine nitrogen decreased 26% (2.4 g/d; P < 0.001) and mean blood urea nitrogen decreased 15% (1.9 mg/dl; P < 0.001). Mean urine pH increased from 6.3 to 6.8 (P < 0.001), and net renal acid excretion (NRAE = urine ammonium plus titratable acids minus bicarbonate) decreased 68% (21.4 mEq/d; P < 0.001). Mean urinary calcium decreased 32% [42 mg (1 mmol)/d; P < 0.001], and bone resorption urine N-telopeptides) decreased 17% (74 micromol bovine collagen equivalents/d; P < 0.001). Mean serum calcium, PTH, and 1,25 dihydroxy vitamin D remained unchanged. In this 2-wk study, decreasing dietary protein from ad libitum to RDA levels decreased NRAE, calciuria and estimates of bone resorption, suggesting that decreased U.S. protein consumption might reduce bone loss. Inasmuch as other dietary modifications, such as increasing vegetable and fruit intake, can result in sustained reductions in NRAE without reducing protein intake, the advisability of reducing protein intake for skeletal protection from acid attack requires further investigation.

Dolichoectasia of the intracranial arteries in patients with first ischemic stroke: a population-based study.

OBJECTIVE: The objective of this study was to estimate the frequency of intracranial arterial dolichoectasia among patients with first ischemic stroke and to compare clinical characteristics, survival, and recurrence in those with and without the abnormality. BACKGROUND: Dolichoectasia may cause cerebral infarction by thrombosis, embolism, stenosis, or occlusion of deep penetrating arteries. METHODS: The chi-square, Fisher's exact, and logrank tests were used to compare clinical characteristics, survival, and recurrence for patients with and without dolichoectasia among the 387 residents of Rochester, MN, who had brain CT or MRI for first cerebral infarction from 1985 through 1989. RESULTS: Twelve patients (3.1%) had dolichoectasia. Patients with dolichoectasia were more likely to have had stroke fitting a clinical and radiographic pattern of lacunar infarction than those without (42% and 17% respectively; p=0.04). Dolichoectasia was detected in the vertebrobasilar system in eight patients (66.7%), in the carotid system in two patients (16.7%), and in both circulatory systems in two patients (16.7%). There were no significant differences in the following characteristics among those with and without dolichoectasia: age, sex, hypertension, diabetes, smoking, and preceding transient ischemic attack. Patients with dolichoectasia had better survival (relative risk [RR] for death, 0.26; p=0.04) after first cerebral infarction but higher rates of stroke recurrence (RR, 2.4; p=0.02). CONCLUSIONS: Dolichoectasia is detected in 38 of patients with first cerebral infarction and is associated with better survival but higher rates of stroke recurrence.

Hormone binding and transcription activation by estrogen receptors: analyses using mammalian and yeast systems.

We have used affinity labeling, site-directed mutagenesis and regional chemical mutagenesis in order to determine regions of the human estrogen receptor (ER) important in hormone binding, ligand discrimination between estrogens and antiestrogens, and transcriptional activation. Affinity labeling studies with the antiestrogen, tamoxifen aziridine and the estrogen, ketononestrol aziridine have identified cysteine 530 in the ER hormone binding domain as the primary site of labeling. In the absence of a cysteine at 530 (i.e. C530 mutant), C381 becomes the site of estrogen-compatible tamoxifen aziridine labeling. Hence these two residues, although far apart in the primary linear sequence of the ER protein, must be close in the three-dimensional structure of the protein, in the ER ligand binding pocket, so that the ligand can reach either site. Site-directed mutagenesis of selected residues in the ER and region-specific chemical mutagenesis of the ER hormone binding domain with initial phenotypic screening in yeast have enabled the identification of a region near C530 important in discrimination between estrogens and antiestrogens and of other residues important in hormone-dependent transcriptional activation. Some ER mutants with alterations in the carboxy-terminal portion of the hormone binding domain are transcriptionally inactive yet bind hormone and also function as potent dominant negative ERs, suppressing the activity of wild-type ER at low concentrations. These studies reveal a separation of the hormone binding and transcription activation functions of the ER. They are also beginning to provide a more detailed picture of the ER hormone binding domain and amino acids important in ligand binding and discrimination between different categories of agonist and antagonist ligands. Such information will be important in the design of maximally effective antiestrogens. In addition, since there is now substantial evidence for a mixture of wild-type and variant ERs in breast cancers, our studies should provide insight about the bioactivities of these variant receptors and their roles in modulating the activity of wild type ER, and should lead to a better understanding of the possible role of variant receptors in altered response or resistance to antiestrogen and endocrine therapy in breast cancer. In addition, some dominant negative receptors may prove useful in examining ER mechanisms of action and in suppressing the estrogen-dependent growth of breast cancer cells.