Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral centre.

AIMS: Hereditary transthyretin amyloidosis (ATTRv) is one of the leading aetiologies of systemic amyloidosis with more than 135 mutations described and a broad spectrum of clinical manifestations. We aimed to provide a systematic description of a population of individuals carrying pathogenic mutations of transthyretin (TTR) gene and to investigate the major clinical events during follow-up. METHODS AND RESULTS: This was an observational, retrospective, cohort study including consecutive patients with mutations of TTR gene, admitted to a tertiary referral centre in Bologna, Italy, between 1984 and 2022. Three hundred twenty-five patients were included: 106 asymptomatic carriers, 49 cardiac phenotype, 49 neurological phenotype, and 121 mixed phenotype. Twenty-two different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most common. After a median follow-up of 51 months, 111 patients (38.3%) died and 9 (11.5%) of the 78 asymptomatic carriers developed ATTRv. Carriers had a prognosis comparable with healthy population, while no significant differences were seen among the three phenotypes adjusted by age. Age at diagnosis, New York Heart Association class III, left ventricular ejection fraction, modified polyneuropathy disability score IV, and disease-modifying therapy were independently associated with survival. CONCLUSION: This study offers a wide and comprehensive overview of ATTRv from the point of view of a tertiary referral centre in Italy. Three main phenotypes can be identified (cardiac, neurological, and mixed) with specific clinical and instrumental features. Family screening programmes are essential to identify paucisymptomatic affected patients or unaffected carriers of the mutation, to be followed through the years. Lastly, disease-modifying therapy represents an evolving cornerstone of the management of ATTRv, with a great impact on mortality.

A total of 325 consecutive patients harbouring a pathogenic mutation in the TTR gene, admitted to a tertiary referral centre in Bologna, Italy, between 1984 and 2022, were included in the study.These patients exhibited significant clinical diversity: 106 were asymptomatic carriers, 49 presented with a cardiac phenotype, 49 had a neurological phenotype, and 121 had a mixed phenotype.Asymptomatic carriers demonstrated a prognosis comparable with healthy population, but some of them may develop signs and symptoms of the disease during follow-up.Survival curves adjusted by age are similar among the three phenotypes.Age at diagnosis, New York Heart Association class, modified polyneuropathy disability score, left ventricular ejection fraction, and disease-modifying therapy were identified as independent factors associated with prognosis.

Prevalence and mechanisms of ciprofloxacin resistance in Escherichia coli isolated from hospitalized patients, healthy carriers, and wastewaters in Iran.

BACKGROUND: This study was aimed to evaluate the prevalence and molecular characteristics of ciprofloxacin resistance among 346 Escherichia coli isolates collected from clinical specimens (n = 82), healthy children (n = 176), municipal wastewater (n = 34), hospital wastewater (n = 33), poultry slaughterhouse wastewater (n = 12) and livestock (n = 9) slaughterhouse wastewater in Iran. METHODS: Ciprofloxacin minimum inhibitory concentration (MIC) was determined by agar dilution assay. Phylogroups and plasmid-mediated quinolone resistance (PMQR) genes were identified using PCR. Mutations in gyrA, gyrB, parC, and parE genes and amino acid alterations were screened through sequencing assay. The effect of efflux pump inhibitor (PAßN) on ciprofloxacin MICs in ciprofloxacin-resistant isolates was investigated using the microdilution method. RESULTS: In total, 28.03% of E. coli isolates were phenotypically resistant to ciprofloxacin. Based on sources of isolation, 64.63%, 51.51%, 33.33%, 14.70%, 10.22% and 8.33% of isolates from clinical specimens, hospital wastewater, livestock wastewater, municipal wastewater, healthy children and poultry wastewater were ciprofloxacin-resistant, respectively. Eighty-one point eighty-one percent (Ser-83 → Leu + Asp-87 → Asn; 78.78% and Ser-83 → Leu only; 3.03% (of ciprofloxacin-resistant E. coli isolates showed missense mutation in GyrA subunit of DNA gyrase, while no amino-acid substitution was noted in the GyrB subunit. DNA sequence analyses of the ParC and ParE subunits of topoisomerase IV exhibited amino-acid changes in 30.30% (Ser-80 → Ile + Glu-84 → Val; 18.18%, Ser-80 → Ile only; 9.10% and Glu-84 → Val only; 3.03%0 (and 15.38% (Ser-458 → Ala) of ciprofloxacin-resistant E. coli isolates, respectively. The PMQR genes, aac(6')-Ib-cr, qnrS, qnrB, oqxA, oqxB, and qepA were detected in 43.29%, 74.22%, 9.27%, 14.43%, 30.92% and 1.03% of ciprofloxacin-resistant isolates, respectively. No isolate was found to be positive for qnrA and qnrD genes. In isolates harboring the OqxA/B efflux pump, the MIC of ciprofloxacin was reduced twofold in the presence of PAßN, as an efflux pump inhibitor. The phylogroups B2 (48.45%) and A (20.65%) were the most predominant groups identified in ciprofloxacin-resistant isolates. CONCLUSIONS: This study proved the high incidence of ciprofloxacin-resistant E. coli isolates in both clinical and non-clinical settings in Iran. Chromosomal gene mutations and PMQR genes were identified in ciprofloxacin resistance among E. coli population.

High Prevalence of blaCTX-M in Fecal Commensal Escherichia coli from Healthy Children.

BACKGROUND: Antibiotic-resistant Escherichia coli can colonize the intestinal tract of healthy children, causing concern when antibiotic resistance is related to the presence of transferable mechanisms, such as extended-spectrum ß-lactamases (ESBLs). MATERIALS AND METHODS: Fecal samples from 41 healthy children from two villages of rural Peru were cultured on ceftriaxone-disks. ESBL production was confirmed with double disk synergy. In all ESBL-produced isolates, antibiotic susceptibility to 12 antibacterial agents was established by disk diffusion, while clonal relationships were determined by repetitive extragenic palindromic-polymerase chain reaction (REP-PCR). Presence of ST131 was determined using PCR. RESULTS: Ceftriaxone-resistant microorganisms were recovered from 39 samples belonging to 22 out of 41 children (53.7%). Of these, 80 ceftriaxone-resistant and two ceftriaxone-intermediate E. coli from inside ceftriaxone-halos were confirmed as ESBL-producers. All isolates were multidrug-resistant. In 79/80 (98.8%) ceftriaxone-resistant isolates, the presence of blaCTX-M was detected alone (58 isolates, or together with other ß-lactamase (blaTEM, 17 isolates; blaOXA-1-like, 3 isolates; blaTEM + blaOXA-1-like, 1 isolate), while in one isolate no such ESBL was identified. The two ceftriaxone-intermediate isolates recovered from the same sample, carried a blaTEM and blaSHV respectively. Thirty-four different clones were identified, with 4 clones being recovered from different samples from the same child. Twelve clones were disseminated among different children, including 5 clones disseminated between both villages. Two clones, accounting for 3 isolates and both recovered from the same children, belonged to E. coli ST131. CONCLUSION: This study demonstrates high prevalence of ESBL-carriers among healthy children living in a rural area of Peru, stressing the need for continuous surveillance and search for public health control measures.

Effect of a high fructose diet on metabolic parameters in carriers for hereditary fructose intolerance.

BACKGROUND & AIMS: Hyperuricemia is an independent risk factor for the metabolic syndrome and cardiovascular disease. We hypothesized that asymptomatic carriers for hereditary fructose intolerance (OMIM 22960) would have increased uric acid and altered component of the metabolic syndrome when exposed to fructose overfeeding. METHODS: Six heterozygotes for HFI (hHFI) and 6 controls (Ctrl) were studied in a randomized, controlled, crossover trial. Participants ingested two identical test meals containing 0.7 g kg-1 glucose and 0.7 g kg-1 fructose according to a cross-over design, once after a 7-day on a low fructose diet (LoFruD, <10 g/d) and on another occasion after 7 days on a high fructose diet (HiFruD, 1.4 g kg-1 day-1 fructose + 0.1 g kg-1 day-1 glucose). Uric acid, glucose, and insulin concentrations were monitored in fasting conditions and over 2 h postprandial, and insulin resistance indexes were calculated. RESULTS: HiFruD increased fasting uric acid (p < 0.05) and reduced fasting insulin sensitivity estimated by the homeostasis model assessment (HOMA) for insulin resistance (p < 0.05), in both groups. Postprandial glucose concentrations were not different between hHFI and Ctrl. However HiFruD increased postprandial plasma uric acid, insulin and hepatic insulin resistance index (HIRI) in hHFI only (all p < 0.05). CONCLUSIONS: Seven days of HiFruD increased fasting uric acid and slightly reduced fasting HOMA index in both groups. In contrast, HiFruD increased postprandial uric acid, insulin concentration and HIRI in hHFI only, suggesting that heterozygosity for pathogenic Aldolase B variants may confer an increased susceptibility to the effects of dietary fructose on uric acid and hepatic insulin sensitivity. This trial was registered at the U.S. Clinical Trials Registry as NCT03545581.

Why Is Eradicating Typhoid Fever So Challenging: Implications for Vaccine and Therapeutic Design.

Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi, namely typhoidal Salmonellae, are the cause of (para) typhoid fever, which is a devastating systemic infectious disease in humans. In addition, the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) S. Typhi in many low and middle-income countries poses a significant risk to human health. While currently available typhoid vaccines and therapeutics are efficacious, they have some limitations. One important limitation is the lack of controlling individuals who chronically carry S. Typhi. However, due to the strict host specificity of S. Typhi to humans, S. Typhi research is hampered. As a result, our understanding of S. Typhi pathogenesis is incomplete, thereby delaying the development and improvement of prevention and treatment strategies. Nonetheless, to better combat and contain S. Typhi, it is vital to develop a vaccine and therapy for controlling both acutely and chronically infected individuals. This review discusses how scientists are trying to combat typhoid fever, why it is so challenging to do so, which approaches show promise, and what we know about the pathogenesis of S. Typhi chronic infection.

Identification of Escherichia albertii from healthy carriers in Zigong, Sichuan Province, China / 中国人兽共患病学报

We investigated the carrying situation of Escherichia albertii from healthy people engaged in breeding and slaughtering poultry for a long time.We collected stool samples from people engaged in breeding and slaughtering poultry and other healthy people.After enriched with EC broth,eae-positive enrichment culture was directly streaked on MacConkey,and eaepositive lactose non-fermenting isolate was retained for further investigation.The 16S rDNA sequencing and multilocus sequence typing (MLST) were applied in the identification of E.albertii from suspected strains.Intimin subtypes and cdtB types of E.albertii strains were detected.Pulsed-field gel electrophoresis (PFGE) was used to detected genetic polymorphism of strains from this study and animal source ones.Results showed that two isolates were identified as E.albertii from 189 stools of people exposed to slaughtering chickens and ducks and one from 58 stools in control groups.No isolate was identified as E.albertii from 138 stools samples of people exposed to breeding poultry.Intimin subtypes of three isolates from stool samples were subtyped as sigma,iota 2,nu,and cdtB types were closely related to types Ⅱ/Ⅲ/Ⅴ.PFGE patterns of the three strains was distinguishable (＜80％ similarity),and appeared in different cluster with chickens,ducks and other sources of E.albertii strains.The rate of carrying E.albertii to a certain extent exist in healthy people engaged in slaughtering chickens and ducks,and the relationship between these strains and strains from poultry should be further investigated.

Factors associated with Staphylococcus aureus nasal carriage among healthy people in Northern China.

There is still limited knowledge about the prevalence and risk factors of nasal carriage for Staphylococcus aureus among healthy carriers in China. We investigated 2448 healthy adults (≥18 years of age) from Beijing (n = 1530) and Harbin (n = 918) by nasal screening. Participants were checked for carriage of S. aureus, and health-related and demographic information between 2009 and 2011 was gathered. A total of 403 S. aureus (403/2448, 16.5%) were recovered, 8 of which were methicillin resistant (8/2448, 0.33%). Three factors were independently associated with S. aureus nasal carriage: Harbin as city of residence (odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1.41 to 2.85), age ≤24 years (OR = 1.77, 95% CI = 1.30-2.44) and non-Han ethnicity (OR = 1.58, 95% CI = 1.05 to 2.38). On the basis of population genetic analysis using multiple locus variable number of tandem repeats analysis (MLVA) and spa typing, MLVA complex (MC) 398 and MC5a were the most prevalent clonal lineages in this collection. In multivariate models, residing in Harbin (OR = 1.77, 95% CI = 1.07-2.92) and having household members in the healthcare profession (OR = 3.69, 95% CI = 1.14-11.92) were factors associated with carriage of clonal lineage MC398. On the other hand, female sex (OR = 3.15, 95% CI = 1.35-7.33) and a history of chronic liver disease (OR = 16.93, 95% CI = 2.91-98.59) were associated with the clonal lineage MC5a. The three most common spa types were t571 (10.9%), t189 (9.9%) and t701 (7.2%). These findings provide insight into the determinants of nasal carriage and ecology for some of the most successful strains of S. aureus among healthy people in Northern China.

[Proteinase activity in Candida albicans strains isolated from the oral cavity of immunocompromised patients, with oral candidiasis and in healthy subjects]. / Actividad de la proteinasa en cepas de Candida albicans aisladas de la cavidad oral de pacientes inmunodeprimidos, con candidiasis oral y sujetos sanos.

BACKGROUND: Candida albicans has a variety of virulence factors, including secreted aspartyl proteases, which are determinant factors in the pathogenesis of this yeast in immunocompromised patients. AIMS: Proteinase activity was identified in C. albicans strains isolated from the oral cavity of immunocompromised patients with cancer, diabetes and HIV+, with oral candidiasis and in healthy subjects. METHODS: Two hundred and fifty C. albicans strains were analyzed, distributed in 5 different groups: patients with cancer, diabetes, HIV+, with oral candidiasis and healthy subjects. RESULTS: Proteolytic activity was identified in 46% of the strains from cancer patients, 54% from HIV+ patients, 60% from diabetics, 70% from oral candidiasis patients, and 42% from healthy subjects. Activity was higher in strains from immunocompromised and oral candidiasis patients than in healthy subjects. Differences were observed between the candidiasis-healthy, candidiasis-HIV+, and diabetic-healthy groups. No differences were observed between the oral candidiasis, diabetes and cancer patients, between the diabetes and HIV+ patients, or between the cancer patients, HIV+ patients and healthy subjects. CONCLUSIONS: The present results suggest that although secreted aspartyl proteases are important in the pathogenesis of C. albicans, their activity depends on host conditions.

Isolation of community-acquired methicillin-resistant Staphylococcus aureus in healthy carriers in a Mexican community.

OBJECTIVES: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) clones are spreading rapidly among the population in many regions worldwide. Little information is available on CA-MRSA in Mexico. The aim of this study was to identify CA-MRSA strains in the nose and throat of healthy people in a Mexican community. METHODS: A total of 131 MRSA strains from the nose and throat obtained from healthy people in Mexico City were characterized. The genes mecA, lukS-PV/lukF-PV, and ACME-arcA were detected by PCR. Staphylococcal cassette chromosome mec (SCCmec), pulsed-field gel electrophoresis (PFGE), and spa typing were performed. RESULTS: Bacteria that had a Panton-Valentine leukocidin (PVL)-positive gene and SCCmec type IV or V were designated as CA-MRSA strains. We found that 21.4% of MRSA strains were CA-MRSA and that the percentage of CA-MRSA strains was similar in the nose and the throat. A great diversity of profiles was found in the strains identified by PFGE pattern and spa typing. Only one strain similar to the USA300 genotype was found; this strain carried the ACME-arcA gene. CONCLUSIONS: CA-MRSA strains were detected in the nose and throat of healthy people. We identified a high level of genetic diversity among CA-MRSA strains in healthy people of Mexico City, which were different from the USA and pandemic clone profiles.

No evidence so far for the dissemination of carbapenemase-producing Enterobactericeae in the community in Switzerland.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae represent an increasing threat to public health and to the treatment of serious nosocomial infections. The aim of this study was to screen for the presence of carbapenemase-producing Enterobacteriaceae in human carriers in community settings in Switzerland, a country representative of central Europe. FINDINGS: Three hundred and fourteen stool samples of healthy staff members of a meat-processing company and 291 fecal swabs from primary care patients were recovered in Switzerland between April 2012 and July 2012 and were tested for carbapenemase-producing Enterobacteriaceae isolates by selecting for growth on a carbapenem-containing selective medium. Six resulting isolates (5 Escherichia coli and 1 Citrobacter youngae) were subjected to antimicrobial susceptibility tests and PCR analysis by screening for the carbapenemase genes bla OXA-48, bla VIM, bla NDM-1, and bla KPC as well as for the extended-spectrum ß-lactamase genes bla TEM, bla SHV, bla CTX-M and bla CMY-2. No carbapenemase genes were detected. Resistance to ß-lactam antibiotics was due to carriage of the extended-spectrum ß-lactamase CTX-M-15 in 4 isolates, to CTX-M-14 in one further isolate and to the plasmidic AmpC-ß-lactamase CMY-2 in one isolate. CONCLUSIONS: These results show that carbapenemase-producing Enterobacteriaceae are as yet not present in the community. Continuous surveillance is necessary to anticipate future trends in the prevalence and dissemination of carbapenem resistant isolates in the population.

Leprosy reactions: the effect of gender and household contacts

Various host-related factors have been reported as relevant risk factors for leprosy reactions. To support a new hypothesis that an antigenic load in local tissues that is sufficient to trigger the immune response may come from an external supply of Mycobacterium leprae organisms, the prevalence of reactional leprosy was assessed against the number of household contacts. The number of contacts was ascertained at diagnosis in leprosy patients coming from an endemic area of Brazil. The prevalence of reactions (patients with reactions/total patients) was fitted by binomial regression and the risk difference (RD) was estimated with a semi-robust estimation of variance as a measure of effect. Five regression models were fitted. Model 1 included only the main exposure variable "number of household contacts"; model 2 included all four explanatory variables ("contacts", "fertile age", "number of skin lesions" and "bacillary index") that were found to be associated with the outcome upon univariate analysis; models 3-5 contained various combinations of three predictors. Male and female patients were analyzed separately. In females, household contacts were a significant predictor for leprosy reactions in model 1 [crude RD = 0.06; 95 percent confidence interval (CI) = 0.01; 0.12] and model 5 (RD = 0.05; CI = 0.02; 0.09), which included contacts, bacillary index and skin lesions as predictors. Other models were unsatisfactory because the joint presence of fertile age and bacillary index was a likely source of multicollinearity. No significant results were obtained for males. The likely interpretation of our findings might suggest that in female patients, leprosy reactions may be triggered by an external spreading of M. leprae by healthy carrier family members. The small number of observations is an obvious limitation of our study which requires larger confirmatory studies.

Alta prevalência de crianças portadoras de Streptococcus pneumoniae resistentes à penicilina em creches públicas / High prevalence of children colonized with penicillin-resistant Streptococcus pneumoniae in public day-care centers

OBJETIVOS: Investigar a prevalência de Streptococcus pneumoniae (pneumococos) na nasofaringe de crianças sadias atendidas em creches municipais da cidade de Umuarama (PR). Avaliar a susceptibilidade aos antimicrobianos dos pneumococos isolados. MÉTODOS: Secreção da nasofaringe de 212 crianças foi coletada no período de abril a outubro de 2008. Após semeadura dos espécimes em ágar sangue e incubação a 37 °C por 24-48 horas, as colônias suspeitas de pertencerem a S. pneumoniae foram identificadas pela α-hemólise, sensibilidade à optoquina e bile solubilidade. A susceptibilidade à penicilina foi investigada pelos testes de disco-difusão e de diluição. A susceptibilidade aos demais antimicrobianos indicados no tratamento das infecções pneumocócicas foi realizada por disco-difusão RESULTADOS: A prevalência de pneumococos na nasofaringe foi de 43,4 por cento (92/212), sendo maior em crianças com idade entre 2 e 5 anos (p = 0,0005). Não houve diferença significativa entre os sexos. Resistência intermediária e resistência plena à penicilina foram encontradas respectivamente em 34,8 (32/92) e 22,8 por cento (21/92) dos isolados. Sessenta e sete amostras (72,8 por cento) foram resistentes ao sulfametoxazol-trimetoprim, oito (8,7 por cento) à eritromicina e seis (6,5 por cento) à tetraciclina. Uma amostra apresentou resistência à clindamicina (1,1 por cento), e outra ao cloranfenicol (1,1 por cento). Todas as amostras foram sensíveis a levofloxacina, ofloxacina, rifampicina, telitromicina, linezolide e vancomicina. Nove amostras foram consideradas multirresistentes, por apresentarem resistência a três ou mais classes de antimicrobianos. CONCLUSÕES: O presente estudo registrou uma alta prevalência de crianças portadoras sadias de amostras de S. pneumoniae resistentes à penicilina que podem constituir importantes reservatórios desse patógeno na comunidade.

OBJECTIVES: To investigate the prevalence of Streptococcus pneumoniae (pneumococci) in the nasopharynx of healthy children enrolled in public day-care centers of the municipality of Umuarama, state of Paraná, Brazil. The susceptibility of the pneumococcal strains to antimicrobial agents was also studied. METHODS: Nasopharyngeal specimens from 212 children were collected from April to October 2008. After the specimens were seeded in blood agar and incubated at 37 °C for 24-48 hours, the colonies suspected of belonging to S. pneumoniae were identified using α-hemolysis, optochin sensitivity, and bile solubility test. Penicillin susceptibility was investigated using the disk diffusion and dilution tests. Susceptibility to the other antimicrobial agents indicated for the treatment of pneumococcal infections was investigated using the disk diffusion test. RESULTS: The prevalence of nasopharyngeal pneumococci was 43.4 percent (92/212), with higher rates in children between 2 and 5 years old (p = 0.0005). There was no significant difference between sexes. Intermediate and full resistance to penicillin were found in 34.8 (32/92) and 22.8 percent (21/92) isolates, respectively. Sixty-seven strains (72.8 percent) were resistant to sulfamethoxazole-trimethoprim, eight (8.7 percent) were resistant to erythromycin, and six (6.5 percent) to tetracycline. One strain was resistant to clindamycin (1.1 percent) and another was resistant to chloramphenicol (1.1 percent). All strains were sensitive to levofloxacin, ofloxacin, rifampicin, telithromycin, linezolid, and vancomycin. Nine strains were considered multiresistant because they were resistant to three or more classes of antimicrobial agents. CONCLUSIONS: The present study detected a high prevalence of healthy children colonized with penicillin-resistant S. pneumoniae strains who may be important reservoirs of this pathogen in the community.

Occurrence of campylobacter species in healthy well-nourished and malnourished children

The occurrence of Campylobacter species in healthy, well-nourished and healthy, malnourished children of low socioeconomic level in Southern Chile was determined. Campylobacter carriers were significantly most frequent among malnourished (31.4 percent) than among well-nourished (9.9 percent) children. Six species were isolated from malnourished children whereas four were found among well-nourished children. C. upsaliensis was the most frequent (13.3 percent) species isolated from malnourished children, followed by C. lari (7.6 percent) and C. fetus ssp. fetus (1.9 percent).

A ocorrência de espécies de Campylobacter em crianças mal nutridas e bem nutridas, sem diarréia e de baixo nível socioeconômico, foi determinada. Os portadores de Campylobacter foram mais freqüentes entre as crianças mal nutridas (31,4 por cento) do que entre as crianças bem nutridas (9,9 por cento). Seis espécies de Campylobacter foram isoladas das crianças mal nutridas e quatro das crianças bem nutridas. C. upsaliensis foi a espécie mias freqüentemente isolada (13,3 por cento) das crianças mal nutridas, seguida de C. lari (7,6 por cento) e C. fetus ssp. fetus (1,9 por cento).

Occurrence of campylobacter species in healthy well-nourished and malnourished children.

The occurrence of Campylobacter species in healthy, well-nourished and healthy, malnourished children of low socioeconomic level in Southern Chile was determined. Campylobacter carriers were significantly most frequent among malnourished (31.4%) than among well-nourished (9.9%) children. Six species were isolated from malnourished children whereas four were found among well-nourished children. C. upsaliensis was the most frequent (13.3%) species isolated from malnourished children, followed by C. lari (7.6%) and C. fetus ssp. fetus (1.9%).