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Background Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. Results In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1 -knockout and patient-derived cellular models, and in HNT1 -knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. Conclusion Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

This manuscript reviews 25 years of experience that include developing the practice of pharmaceutical care and initiating new practices. The impact this practice has on practitioners in the ambulatory setting is described as well as data that reflect its clinical and economic impact. There is a great need to prepare new practitioners to provide pharmaceutical care. A focused training program was developed and delivered to over 300 practitioners. The practitioners were prepared by providing direct patient care. They learned the philosophy of pharmaceutical care practice, to identify, resolve and prevent drug therapy problems, to document care using a specially designed software program called the Assurance Pharmaceutical Care(c) program. The practitioners who participated in the training program reported that the average amount of time spent with patients increased three-fold, they now see four times more patients than prior to training, and the number of new patients referred by physicians increased nine-fold as a result of the program. These practitioners have now provided care to more than 25,000 patients in their practices. These data have now been consolidated and analyzed, and a portion of these results is reported here. The clinical and economic outcomes from 2,985 adult patients, who received pharmaceutical care between January, 2000 and December, 2003, are presented. At the first assessment by the pharmaceutical care practitioner, 61% of the patients had one or more drug therapy problems identified and resolved. This resulted in an improvement in the clinical status or maintaining a stable status in 83% of the patients. The health care savings realized from pharmaceutical care were $1,134,162. This represented a benefit to cost ratio of 2:1. Physicians who collaborate with pharmaceutical care practitioners have validated the work of the practitioners, and patients are recognizing the benefits of pharmaceutical care.

Background Beta-lactam resistance in Haemophilus influenzae due to ftsI mutations causing altered penicillin-binding protein 3 (PBP3) is increasing worldwide. Low-level resistant isolates with the N526K substitution (group II low-rPBP3) predominate in most geographical regions, while high-level resistant isolates with the additional S385T substitution (group III high-rPBP3) are common in Japan and South Korea. Knowledge about the molecular epidemiology of rPBP3 strains is limited. We combined multilocus sequence typing (MLST) and ftsI /PBP3 typing to study the emergence and spread of rPBP3 in nontypeable H. influenzae (NTHi) in Norway. Results The prevalence of rPBP3 in a population of 795 eye, ear and respiratory isolates (99% NTHi) from 2007 was 15%. The prevalence of clinical PBP3-mediated resistance to ampicillin was 9%, compared to 2.5% three years earlier. Group II low-rPBP3 predominated (96%), with significant proportions of isolates non-susceptible to cefotaxime (6%) and meropenem (20%). Group III high-rPBP3 was identified for the first time in Northern Europe. Four MLST sequence types (ST) with characteristic, highly diverging ftsI alleles accounted for 61% of the rPBP3 isolates. The most prevalent substitution pattern (PBP3 type A) was present in 41% of rPBP3 isolates, mainly carried by ST367 and ST14. Several unrelated STs possessed identical copies of the ftsI allele encoding PBP3 type A. Infection sites, age groups, hospitalization rates and rPBP3 frequencies differed between STs and phylogenetic groups. Conclusions This study is the first to link ftsI alleles to STs in H. influenzae . The results indicate that horizontal gene transfer contributes to the emergence of rPBP3 by phylogeny restricted transformation. Clonally related virulent rPBP3 strains are widely disseminated and high-level resistant isolates emerge in new geographical regions, threatening current empiric antibiotic treatment. The need of continuous monitoring of beta-lactam susceptibility and a global system for molecular surveillance of rPBP3 strains is underlined. Combining MLST and ftsI /PBP3 typing is a powerful tool for this purpose.

Background The problem of emerging ciprofloxacin resistance is compounded by its frequent association with multiresistance, the reason for which is not fully understood. In this study we compare multiresistance, clonal similarities and phylogenetic group in urinary tract isolates of Escherichia coli sensitive and resistant to the quinolone antimicrobials nalidixic acid and ciprofloxacin. Results Quinolone resistant isolates were more resistant to non-quinolone antibiotics than sensitive isolates, with resistance to ampicillin, mecillinam, sulphonamide, trimethoprim, tetracycline, kanamycin and chloramphenicol significantly increased. Fifty-one percent of quinolone-resistant isolates were multiresistant. Although multiresistance was most prevalent (63%) in isolates showing high-level ciprofloxacin resistance, it was still highly prevalent (41%) in nalidixic acid resistant isolates with low-level ciprofloxacin resistance. Multiresistance was more frequent among singleton isolates (61%) than clonal isolates (40%) of quinolone resistant Escherichia coli. Ciprofloxacin resistance was associated with certain specific clones, among them the globally distributed clonal Group A. However, there was no significant difference in the overall degree of clonality between quinolone sensitive and resistant isolates. Ciprofloxacin resistance was positively associated with phylogroup D and negatively associated with phylogroup B2. This correlation was not associated with clonal isolates. Conclusion This study supports earlier findings of association between ciprofloxacin resistance and resistance to other antibiotics. The prevalence of multiresistance in quinolone-resistant isolates that have not yet developed high-level ciprofloxacin resistance suggest that multiresistance arises early in the development of quinolone resistance. This is consistent with exposure to quinolones causing quinolone resistance by mutations and mobilization of multiresistance elements by induction of the SOS response. The spread of clones seems to be less important than previously reported in regard to emergence of quinolone resistance and multiresistance as both are associated primarily with singleton isolates.

Recent studies have demonstrated that both heterozygous and biallelic variants in MME (encoding the metalloprotease neprilysin) are a frequent cause of LOCMT2 (MIM: 617017).1–3 The heterozygotes variants cause a milder phenotype with reduced penetrance. Besides the large spectrum of rare or even single pathogenic MME variants, the frameshift deletion c.467del p.(Pro156Leufs*14) and the splice site mutation c.440–2A>C have been recurrently reported in patients with autosomal dominant and autosomal recessive LOCMT2.2–4 Although PCR is considered to be a robust technology and a reliable tool to be used for routine diagnosis, allele-specific sequence variations occasionally may provoke amplification failure of one of the two alleles at a given locus.5 Such an allele dropout has also been shown for the c.467del mutation in MME in one consanguineous family.4 In this study, registries at the Medical University of Vienna and Telemark Hospital Trust were searched for LOCMT2 individuals carrying the MME variants NM_007289.3:c.467del p.(Pro156Leufs*14) and NM_007289.3:c.440–2A>C. We ascertained 28 individuals from 16 families (MH1-MH16) afflicted with LOCMT2. A full list of the primers, enzymes and conditions used is described in the online supplemental material 1. [...]the length of the intronic AT-repeats was assessed on 179 selected DNA samples by using NGS data, fragment length analysis (FLA) and/or multiplex ligation-dependent probe amplification (MLPA). Patient ID are listed according to the numbers on the pedigrees (figure 1A). *Due to lack of DNA, complete testing was not possible, but a homozygous long allele can be concluded from results obtained in the control group (data not shown). [...]we investigated whether the use of different PCR enzymes circumvents allelic dropouts.

Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.

To compare drug therapy problems identified by pharmacists in two patient samples, the Minnesota Sample and the South Australian Sample. Two patient samples were selected for this comparison. Both sets of patients received pharmaceutical care services from pharmaceutical care practitioners between March 1999 and February 2000. The two databases were then compared for common drug therapy problems. Comparison of drug therapy problems in the two samples. Both patient samples included patients who were 40 years of age or older. The Minnesota Sample included 1,598 individual patients, of whom 70% experienced one or more drug therapy problems at some time during their care. The South Australian Sample included a total of 982 patients of whom 90% experienced one or more drug therapy problems at some time during their care. Conditions common to both patient samples include hypertension, diabetes, arthritis, ischemic heart disease, and osteoporosis. Frequently occurring drug therapy problems in the Minnesota Sample included the need for additional drug therapy, dosage too low and non-compliance and in the South Australian Sample included non-compliance, additional drug therapy and ineffective drug therapy. Frequent drug therapy problems associated with medical conditions in the Minnesota Sample included addition of new therapies for conditions such as arthritis, hypertension, hyperlipidemia and allergic rhinitis, while for the South Australian Sample included compliance issues with conditions such as asthma, diabetes mellitus, angina and digestive disorders. Frequent drug therapy problems with associated drug classes in the Minnesota Sample included additional therapy for classes such as salicylates and calcium supplements, while in the South Australian Sample included the need for therapy for pneumococcal vaccines, salicylates, calcium supplements and tetanus vaccines. These data demonstrate that this age group has significant drug therapy problems and therefore emphasize the need for pharmaceutical care services in this population. The provision of pharmaceutical care by experienced practitioners can result in improved recognition of the full range of drug therapy problems confronting patients. Analyses such as those presented here provide information to better focus the training of practitioners based on the most frequently encountered health problems and the nature of common drug therapy problems in the community setting.

In Table 4 and Supplemental Table 1 of the published paper entitled “Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing” [1], we classified two variants as likely pathogenic. These two variants (NM_001126131.1:c.[1491G>C(;)2243G>C]), identified in the POLG gene, were carried by one patient (ID 62). As it was not possible to examine whether the two variants were in cis or trans, that is, situated on the same or different alleles, these two variants should have been reported as uncertain pathogenic variants.