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PubMedDate not supplied

Classification of macrolide-lincosamide-streptogramin-B-type antibiotic resistance determinants.

We have examined the relationship between the genes specifying resistance towards macrolid-lincosamide-streptogramin-B-type (MLS) antibiotics from group D and H streptococci, Staphylococcus aureus, Bacillus licheniformis, and Bacteroides fragilis by DNA annealing. We detected homology between the MLS resistance determinants from the Gram-positive cocci (streptococci and staphylococci) but not between these and the genes from B. licheniformis and B. fragilis. Based on these DNA-DNA hybridizations and on data obtained from the literature, at least four distinct classes of MLS R determinants could be defined: classes A and B for the Gram-positive cocci, class C for B. licheniformis and class D and B. fragilis. These genetic classes did not correlate with differences in phenotypic expression or in regulation (inducibility or constitutivity) of resistance towards MLS antibiotics. These findings are in favor of a recent common origin of R determinants in streptococci and staphylococci but do not suggest that gene transfer may occur between Gram-positive cocci and anaerobes (B. fragilis) despite the fact that these pathogenic bacterial genera share common human eco-systems.

Anti-Bacterial Agents↗
PubMed2006

Differentiation of selected Salmonella enterica serovars by Fourier transform mid-infrared spectroscopy.

Salmonella enterica serovars include pathogens responsible for high numbers of foodborne salmonellosis. Fourier transform infrared (FT-IR) spectroscopy can be used to rapidly and accurately identify microorganisms based on unique spectra of bacterial cell components. The objectives of this study were to discriminate closely related Salmonella enterica serovars by using FT-IR spectroscopy and multivariate analysis and to compare the performance of three techniques for differentiating among Salmonella serovars. Selected serovars of S. enterica were streaked onto plate count agar and incubated (37 degrees C, 24 h). Isolated colonies were suspended in phosphate buffer or 50% ethanol (10 microL). Suspensions were placed on (1) ZnSe crystals for transmission, (2) disposable polyethylene membranes (DPM) for transmission, and (3) diamond crystal plate for attenuated total reflectance (ATR) analyses; all samples were dried under vacuum. Classification models, soft independent modeling of class analogy (SIMCA), from derivatized infrared spectra (1300-900 cm(-1)), discriminated among Salmonella serovars presumably attributed to cell's lipopolysaccharides (1000-980 cm(-1)). Samples on DPM required high cell density for reliable spectra. High-quality spectra were obtained when a single colony was suspended in ethanol or buffer and mounted on ZnSe crystals for transmission or diamond plate for ATR analysis. Prediction of unknowns, representative of serovars used to construct classification models, showed that all techniques were suitable for the rapid and accurate differentiation of Salmonella serovars.

Algorithms↗
PubMed2002

Differential rates of frameshift alterations in four repeat sequences of hereditary nonpolyposis colorectal cancer tumors.

DNA sequences of mono-, di-, and trinucleotide repeats are prone to replication errors and thus constitute mutational hot spots. This is well illustrated by the occurrence of DNA microsatellite instability in tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) resulting from a defect in a gene that participates in postreplicative DNA mismatch repair (MMR). We selected repeat sequences present within coding regions of four genes involved in either cell proliferation or promotion of apoptosis. These repeats consisted of (A)10 in the TGF beta RII, (G)8 in the BAX, (A)8 in the CASP1, and (CCA)7 in the APP genes. These repeats were analyzed in ten tumors from HNPCC patients carrying a germline pathogenic mutation in the MMR gene MLH1. For each tumor the rate of somatic replication errors was measured by sequencing 20-50 cloned PCR-amplified fragments. Substantial intertumor variations were observed in the pattern of repeat alterations, with error rates varying between 12% and 80% for TGF beta RII, 2% and 84% for BAX, 0% and 30% for CASP1, and 0% to 18% for APP. The BAX repeat error rate did not exceed 20% in nine of the ten tumors, in contrast to results from previous studies. High error rates in more than one gene in a same tumor suggested additive selective effects from inactivation of different pathways influencing tumorigenesis. Our methodology can contribute to define tumor characteristics and may, if applied to genes strongly involved in tumorigenesis, improve tumor classification and outcome prediction.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Enterococci at the crossroads of food safety?

Enterococci are gram-positive bacteria and fit within the general definition of lactic acid bacteria. Modern classification techniques resulted in the transfer of some members of the genus Streptococcus, notably some of the Lancefield's group D streptococci, to the new genus Enterococcus. Enterococci can be used as indicators of faecal contamination. They have been implicated in outbreaks of foodborne illness, and they have been ascribed a beneficial or detrimental role in foods. In processed meats, enterococci may survive heat processing and cause spoilage, though in certain cheeses the growth of enterococci contributes to ripening and development of product flavour. Some enterococci of food origin produce bacteriocins that exert anti-Listeria activity. Enterococci are used as probiotics to improve the microbial balance of the intestine, or as a treatment for gastroenteritis in humans and animals. On the other hand, enterococci have become recognised as serious nosocomial pathogens causing bacteraemia, endocarditis, urinary tract and other infections. This is in part explained by the resistance of some of these bacteria to most antibiotics that are currently in use. Resistance is acquired by gene transfer systems, such as conjugative or nonconjugative plasmids or transposons. Virulence of enterococci is not well understood but adhesins, haemolysin, hyaluronidase, aggregation substance and gelatinase are putative virulence factors. It appears that foods could be a source of vancomycin-resistant enterococci. This review addresses the issue of the health risk of foods containing enterococci.

Animals↗
PubMed2003

The epidemiology of sepsis in the United States from 1979 through 2000.

BACKGROUND: Sepsis represents a substantial health care burden, and there is limited epidemiologic information about the demography of sepsis or about the temporal changes in its incidence and outcome. We investigated the epidemiology of sepsis in the United States, with specific examination of race and sex, causative organisms, the disposition of patients, and the incidence and outcome. METHODS: We analyzed the occurrence of sepsis from 1979 through 2000 using a nationally representative sample of all nonfederal acute care hospitals in the United States. Data on new cases were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification. RESULTS: Review of discharge data on approximately 750 million hospitalizations in the United States over the 22-year period identified 10,319,418 cases of sepsis. Sepsis was more common among men than among women (mean annual relative risk, 1.28 [95 percent confidence interval, 1.24 to 1.32]) and among nonwhite persons than among white persons (mean annual relative risk, 1.90 [95 percent confidence interval, 1.81 to 2.00]). Between 1979 and 2000, there was an annualized increase in the incidence of sepsis of 8.7 percent, from about 164,000 cases (82.7 per 100,000 population) to nearly 660,000 cases (240.4 per 100,000 population). The rate of sepsis due to fungal organisms increased by 207 percent, with gram-positive bacteria becoming the predominant pathogens after 1987. The total in-hospital mortality rate fell from 27.8 percent during the period from 1979 through 1984 to 17.9 percent during the period from 1995 through 2000, yet the total number of deaths continued to increase. Mortality was highest among black men. Organ failure contributed cumulatively to mortality, with temporal improvements in survival among patients with fewer than three failing organs. The average length of the hospital stay decreased, and the rate of discharge to nonacute care medical facilities increased. CONCLUSIONS: The incidence of sepsis and the number of sepsis-related deaths are increasing, although the overall mortality rate among patients with sepsis is declining. There are also disparities among races and between men and women in the incidence of sepsis. Gram-positive bacteria and fungal organisms are increasingly common causes of sepsis.

Female↗
PubMed2005

Intestinal parasite isolates in AIDS patients with chronic diarrhea in Gondar Teaching Hospital, North west Ethiopia.

Chronic diarrhea is one of the major AIDS-defining illnesses in WHO Classification and occurs in 60-90% of HIV-infected patients in Africa. We did a case series study on parasite isolation in stool samples of AIDS patients with chronic diarrhea using wet-mount, Formol-Ether concentration technique and Modified Acid-Fast staining method in Gondar Teaching Hospital between January and September 2000. Seventy AIDS patients with chronic diarrhea were included in the study. Wasting syndrome was the clinical presentation in (97%) almost all AIDS patients who had chronic diarrhea. Intestinal parasites were detected in 41 out of 70 diarrheal specimens in AIDS patients. Multiple parasitic injections were detected in three diarrheal specimens. Intracellular parasite, (29%) Cryptosporidium parvum, and mucosal parasite, (17%) Strongyloides stercoralis were the frequently isolated parasites in diarrheal specimens of AIDS patients, accounting for 80% diarrhaegen pathogens among positive specimens. Cryptosporidium parvum, under-estimated cause of chronic diarrhea in immunocompetent adults, was found to be the prominent diarrheagen in AIDS patients in this study, similar with other studies in different African countries.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

[Left aortic arch without a circumflex segment and a right descending aorta: a hypothetical case and a real example].

We studied a case of a patent left ductus arteriosus, with a left aortic arch connected to a right descending aorta without an aortic circumflex (retroesophageal) segment. We believe this is the first world-published example of this--so far--hypothetical anomaly, included in Kirkling and Edwards classification of vascular rings. The case was a 27-year-old deaf-mute female patient with a patent left ductus arteriosus, with important left to right shunt and moderate pulmonary arterial hypertension who underwent a successful closing surgical procedure. In the aortographic study a left (normal) aortic arch was seen, which after giving off a large left ductus arteriosus, crossed to the right and connected to a right descending aorta. In the upper part of the thorax the esophagus and trachea were displaced to the right by the left aortic arch. The esophagus in the middle and the upper inferior parts of the thorax was also displaced to the right by the descending right aortic segment. Complete vascular ring was not evident. The case--although without clinical importance--reinforces the pathogenic concept of the Rathke diagram of a complete double aortic primitive arch originating the pulmonary and supraaortic vascular structures which are formed by the obliteration or disappearance of particular segments of the structure. This knowledge explains the embryogenesis of these complex anomalies. Our case is believed to be formed by the very early disappearance of a frontal portion of the primitive left dorsal aorta.

Adult↗
PubMedDate not supplied

Pneumocystis and Trypanosoma cruzi: nomenclature and typifications.

Published phylogenetic reclassifications of Pneumocystis as a fungus resulted in a nomenclatural shift from the Zoological Code to the International Code of Botanical Nomenclature. The same may be true for all microsporidians and sundry other organisms. This resulted in the invalidation of names and subsequently precipitated changes to the botanical code to accommodate Pneumocystis and microsporidian names. The repercussions following application of the 2005 Vienna Code to Pneumocystis nomenclature are detailed. Validity of the name for the human pathogen, Pneumocystis jirovecii, is re-established from its 1976 publication under the Zoological Code, contrary to interpretation of validity under earlier botanical codes. Pneumocystis jirovecii is lectotypified and epitypified. The rat parasite, Pneumocystis carinii, is neotypified, separating it from Pneumocystis wakefieldiae. The original 1909 description of Trypanosoma cruzi, type species for Schizotrypanum, and causal agent of Chagas' disease, included parts of the life cycle of Pneumocystis. Trypanosoma cruzi is neotypified by the true Trypanosoma elements, thereby completing the nomenclatural separation from Pneumocystis and ensuring that Schizotrypanum is not applicable to Pneumocystis as an earlier name. The neotypes for P. carinii and T. cruzi represent the strains currently being investigated by their two respective genome projects. They were selected in light of their medical importance, physiological characterizations, and absence of lectotypifiable materials. The classification and nomenclature of Pneumocystis is reviewed and guidelines given for the publication of new species.

Animals↗
PubMed1998

Gram-positive anaerobic cocci.

Gram-positive anaerobic cocci (GPAC) are a heterogeneous group of organisms defined by their morphological appearance and their inability to grow in the presence of oxygen; most clinical isolates are identified to species in the genus Peptostreptococcus. GPAC are part of the normal flora of all mucocutaneous surfaces and are often isolated from infections such as deep organ abscesses, obstetric and gynecological sepsis, and intraoral infections. They have been little studied for several reasons, which include an inadequate classification, difficulties with laboratory identification, and the mixed nature of the infections from which they are usually isolated. Nucleic acid studies indicate that the classification is in need of radical revision at the genus level. Several species of Peptostreptococcus have recently been described, but others still await formal recognition. Identification has been based on carbohydrate fermentation tests, but most GPAC are asaccharolytic and use the products of protein degradation for their metabolism; the introduction of commercially available preformed enzyme kits affords a physiologically more appropriate method of identification, which is simple and relatively rapid and can be used in routine diagnostic laboratories. Recent reports have documented the isolation in pure culture of several species, notably Peptostreptococcus magnus, from serious infections. Studies of P. magnus have elucidated several virulence factors which correlate with the site of infection, and reveal some similarities to Staphylococcus aureus. P. micros is a strongly proteolytic species; it is increasingly recognized as an important pathogen in intraoral infections, particularly periodontitis, and mixed anaerobic deep-organ abscesses. Comparison of antibiotic susceptibility patterns reveals major differences between species. Penicillins are the antibiotics of choice, although some strains of P. anaerobius show broad-spectrum beta-lactam resistance.

Anti-Bacterial Agents↗
PubMed1990

[Diagnosis and therapy of acute bacterial infections of the eye].

New knowledge in the understanding of infection immunology and the development of more effective antibiotics will influence the therapeutic options for extra- and intraocular bacterial diseases. The role of mucin with its high sIgA content, the glycoconjugate-mediated bacterial adherence phenomena of the cornea and conjunctiva, and the exact biomicroscopic classification can be constrated with the highly effective topically and systemically applicable antibiotics (e.g., Cephalosporins, Aminoglycosides, New Quinolones and Carbapenems). Recognition of the fact that the amplification mechanisms of the immune system are already fully activated when the clinical features of a serpent ulcer appear and that the destructive phase only represents an unwanted side-effect of the host defense mechanisms towards its own structures has resulted in the application of corticosteroids with simultaneous antibiotic medication and early tectonic perforating keratoplasty. Many intraocular inflammations of heretofore unknown etiology may be detected by modern diagnostic approaches as being localized manifestations of a systemic disease that can be properly treated (e.g., borreliosis, atypical syphilis). The incidence of "metastatic" endophthalmitis could be diminished in high-risk inpatients by preventive measures, including the elimination of potentially pathogenic agents with antibiotics (and antifungal drugs). Infection-associated intraocular inflammations ("Reiter's syndrome") have been linked to persisting pathogenic organisms at distant sites, thereby rendering themselves etiologically treatable (e.g., infections from Yersinia, Campylobaster, Urea-plasma, and Chlamydia). Except for a very few cases (use of monoclonal antibodies, serological methods and immunoblots), the diagnosis of bacterial infections is based on isolation of the organism concerned, which also represents a requirement for antibiotic susceptibility testing and, consequently a specific medication. Close cooperation with microbiologists and the direct culturing of isolates within ophthalmology clinics have seen a revival since the days of Theodor Axenfeld.

Anti-Bacterial Agents↗
PubMed1998

[Asymptomatic bacteriuria in women diagnosed with systemic lupus erythematosus (SLE)].

The aims of our research were: estimation of asymptomatic bacteriuria (a.b.) incidence in population of women with systemic lupus erythematodes (SLE), evaluation its clinical significance and examination of bacterial colonisation of nostrils and pharynx in SLE patients with a.b. 85 women aged 24-77 (mean 49.3) with mean SLE duration 7.8 (range 1-32) years were examined. All of them fulfilled ARA criteria for the classification of SLE. Among group of patients with a.b. were counted women who had significant bacteriuria > or = 10(4) in ml urine in two cultures. Asymptomatic bacteriuria was found in 14 cases of 85 women with SLE (16.5%). In two following urine cultures bacteria from family Enterobacteriaceae were dominated: the same types of bacteria were in 85.7%--bacteriuria persistens, in others 14.3% were observed change of bacteria--bacteriuria transistens. In 9 from 14 patients with (64.3%) a.b. very massive growth of Staphylococcus aureus in culture from vestibulae of the nose swab was, in other cultures very massive growth of physiological flora was seen. All patients with a.b. were in clinical remission of SLE and they had no clinical symptoms of infection in urinary tract in 5 months of observation. However clinical significance of asymptomatic bacteriuria and pathogenic bacteria colonisation of nostrils as a precedence to symptomatic infections needs further investigations.

Adult↗
PubMedDate not supplied

[Physiopathology of adult onset external hydrocephalus].

AIMS: In this paper we report on a new disorder known as adult onset external hydrocephalus. DEVELOPMENT: There is sufficient evidence to be able to establish the pathogenic hypotheses proposed here. Adult onset external hydrocephalus is related with traumatic injuries, surgery, subarachnoid haemorrhages and neurosurgical treatment of aneurysms. This disorder is produced by an expansion of the subarachnoid and subdural space due to the rupture of some part of the arachnoid membrane, which then allows fluid to flow into this compartment. In all cases there are three essential factors: the presence of some kind of intracranial bleeding, tearing of the arachnoid membrane and an excessive quantity of cerebrospinal fluid (CSF), probably because of reduced reabsorption by the arachnoid granulations. The degree to which reabsorption of CSF is affected is what conditions the prognosis in these patients rather than the accumulation within the subarachnoid or subdural cavity. Once this type of hydrocephalus is confirmed the patient requires a ventricular CSF shunt. We offer a classification of the different types of presentation. It is not very clear exactly when this shunt should be inserted or how to treat the isolated extra axial collection in absence of ventricular dilatation. CONCLUSIONS: The physiopathology of adult onset external hydrocephalus is a scientific challenge that will lay down the foundations for treatment with ventriculoperitoneal shunts

Adult↗
PubMed2025

A genome-wide analysis of the shared genetic risk architecture of complex neurological and psychiatric disorders.

Although neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathophysiological mechanisms. However, the extent to which these heritable disorders share genetic influences remains unclear. Here we performed a comprehensive analysis of genome-wide association study data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic signal and biological associations. Using complementary statistical tools, we demonstrate that a large set of common genetic variants impacts the risk of multiple neurological and psychiatric disorders, even in the absence of genetic correlations. Furthermore, genome-wide association studies on psychiatric disorders consistently implicate neuronal biology, whereas neurological diseases are associated with diverse neurobiological processes. Together, this study elucidates the genetic relationship between complex neurological and psychiatric disorders, indicating a larger degree of genetic pleiotropy than previously recognized. The findings have implications for disease classification, precision medicine and clinical practice.

Humans↗
PubMed1980

Predictable clinical disorders related to serum and saliva Ig-levels and the number of circulating T cells in asthmatic chidren.

An examination was made of 221 children with bronchial asthma, who were divided into six groups according to serum and saliva Ig levels and the number of circulating T cells. Absence or small amounts of IgA and low or low-normal numbers of T cells were associated with (1) atopic dermatitis, (2) hypersensitivity to house dust mite and animal danders, (3) previous hospital admissions due to respiratory tract infections with pathogenic bacteria and (4) a high family incidence of allergic diseases. In a group of patients with IgA deficiency and elevated serum and saliva IgM, respiratory tract infections were not common, and furthermore, in another group of IgA-deficient patients with normal numbers of circulating T cells, atopic dermatitis was rare. In the latter patients, allergic rhinitis occurred very frequently, and in that respect they resembled a group of patients with combined high IgM/high IgE levels. Another group of asthmatic children with normal Ig levels represented an intermediate type of patient with regard to hypersensitivity to different allergens and family incidence of allergy on the one hand, and the occurrence of atopic dermatitis and allergic rhinitis on the other. Investigations on Ig levels and circulating T cells in asthmatic children may provide important clues into disease classification and mechanisms of such patients.

Asthma↗
PubMed2000

Behavioral, psychological, and physical characteristics of female athletes with subclinical eating disorders.

The purpose of this study was to delineate and further define the behavioral, psychological, and physical characteristics of female athletes with subclinical eating disorders. Subjects consisted of 24 athletes with subclinical eating disorders (SCED) and 24 control athletes. Group classification was determined by scores on the Eating Disorder Inventory (EDI), the Body Shape Questionnaire (BSQ), and a symptom checklist for eating disorders (EDI-SC). Characteristics representative of the female athletes with subclinical eating disorders were derived from an extensive health and dieting history questionnaire and an in-depth interview (the Eating Disorder Examination). Energy intake and expenditure (kcal/d) were estimated using 7-day weighed food records and activity logs. The characteristics most common in the female athletes with subclinical eating disorders included: (a) preoccupation with food, energy intake, and body weight; (b) distorted body image and body weight dissatisfaction; (c) undue influence of body weight on self-evaluation; (d) intense fear of gaining weight even though at or slightly below ( approximately 5%) normal weight; (e) attempts to lose weight using one or more pathogenic weight control methods; (g) food intake governed by self-hatred upon breaking a rule; (h) absence of medical disorder to explain energy restriction, weight loss, or maintenance of low body weight; and (i) menstrual dysfunction. Awareness of these characteristics may aid in more timely identification and treatment of female athletes with disordered eating patterns and, perhaps, prevent the development of more serious, clinical eating disorders.

Adult↗
PubMed2003

Relationship between transmission of Porphyromonas gingivalis and fimA type in spouses.

BACKGROUND: Porphyromonas gingivalis is one of the major microbial pathogens associated with chronic periodontitis. To eradicate such pathogens by periodontal therapy, it is essential to clarify the source of infection. Recent findings suggest that the genotype of the fimbriae is one of the important factors in infection by P. gingivalis. The objectives of the present study were to investigate the transmission of P. gingivalis between spouses and to determine the relationship between P. gingivalis fimA type and colonization. METHODS: A total of 14 couples were selected to investigate the transmission of P. gingivalis and its association with the fimA types. To examine the distribution of fimA type in the general population, 32 subgingival plaque samples from 47 patients with periodontitis were also tested. The transmission of P. gingivalis strains was determined by using pulsed field gel electrophoresis (PFGE). P. gingivalis strains isolated from the couples and subgingival dental plaque samples were studied for fimA classification. RESULTS: The PFGE patterns of P. gingivalis strains from matched husbands and wives were identical for six of the 14 couples. In five of these six couples (83.3%), P. gingivalis strains harboring the type II fimA gene were present. The proportion of type II fimA in the strains isolated from couples with probable intrafamilial transmission was significantly higher than that in patients with periodontitis or in the group of samples isolated from one member of a couple. CONCLUSION: This study suggests that fimA type II, even though widely distributed in patients with periodontitis, may be an important factor in the transmission of P. gingivalis between spouses.

Adult↗
PubMed2001

Relationship between teat-end callosity and occurrence of clinical mastitis.

A longitudinal study in 15 herds, with a total of 2157 cows, was conducted to examine the relationship between teat-end callosity (TEC) and the incidence of clinical mastitis. During the 1.5-yr study period, clinical mastitis was diagnosed by the farmers based on clinical signs. Teat-end callosity was scored every month according to a teat-end callosity classification system, which discriminates between teat-end callosity thickness (TECT) and roughness (TECR). Differences in TECT between healthy and clinical mastitis quarters within infected cows were small but significant 3 mo before (0.13 higher), in the month during which the clinical mastitis occurred (0.08 higher), and in the following 2 mo (0.06 and 0.05 higher). To compare TECT and TECR between cows with and without clinical mastitis, 199 cows with clinical mastitis were paired with control cows based on herd, days in milk, and parity. Clinical mastitis cows had more TEC than their healthy herd mates, particularly when clinical mastitis occurred between the second and fifth months of lactation. Clinical Escherichia coli mastitis in the second or third month of lactation occurred in cows with less TEC than in cows with clinical mastitis caused by other pathogens. Clinical culture-negative, yeast, Klebsiella pneumoniae, and Enterobacter aerogenes mastitis cows had more TECT and TECR than other cows with clinical mastitis in the same month of lactation. Pointed teat ends had higher TECT and TECR than flat or inverted teat ends. Teat-end callosity thickness increased with a higher milk yield at peak production.

Animals↗
PubMed1995

Crucial residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired in secretion or function.

The last exon of the C1-1NH gene was screened for point mutations in 36 unrelated hereditary angioedema patients. Mutations were found in eight patients, predicting changes in the short COOH-terminal region which anchors the reactive site loop on its COOH-terminal side. The effects of each of these mutations were examined in transiently transfected Cos-7 cells. Complete intracellular retention or degradation was observed with substitutions in the COOH-terminal strands 4B or 5B: Leu459-->Pro, Leu459-->Arg, and Pro467-->Arg were all blocked at early stages of intracellular transport, but differences in the immunofluorescence patterns indicated that a significant fraction of the Leu459-->Pro and of the Pro467-->Arg proteins reached a compartment distinct from the endoplasmic reticulum. In line with previous findings with alpha 1-antitrypsin, chain termination within strand 5B resulted in rapid degradation. Mutant Val451-->Met, in strand 1C, and mutant Pro476-->Ser, replacing the invariant proline near the COOH terminus, yielded reduced secretion, but these extracellular proteins were unable to bind the target protease C1s. Presence of low levels of both dysfunctional proteins in patient plasmas defies the conventional classification of C1 inhibitor deficiencies as type I or type II. These data point to a key role of certain residues in the conserved COOH-terminal region of serpins in determining the protein foldings compatible with transport and proper exposure of the reactive site loop.

Amino Acid Sequence↗