Search

•Whole-genome sequencing of Mycobacterium tuberculosis(MTB) isolates.•21 isolates (72.4%) were multidrug-resistant (MDR) and 1 (3.4%) was extensively-drug resistant (XDR-TB).•The most common mutations observed for isoniazid and rifampicin resistance were katG(S315T) and rpoB(S450L), respectively.•The most common mutations observed for ofloxacin and kanamycin resistance were gyrA(A90V) and rrs(A1401G), respectively.•The isolates belonged mainly to lineages 2 and 3, with most MDR-TB among lineage 2 isolates.

Uncertainty is a key technical factor in hazardous waste site remediations. It can lead to unreasonable data gathering exercises if the point of diminishing information returns is not recognized. Engineering under uncertainty, however, is not unique to hazardous waste site remediation. Approaches have been used elsewhere to recognize and respond to substantial uncertainty. The observational method, traditionally applied in geotechnical engineering, has a number of key elements applicable to hazardous waste site remediation. The key contributions of the observational method are: 1 Remedial design based on most probable site conditions; 2 identification of reasonable deviations from those conditions; 3 identification of parameters to observe so as to detect deviations during remediation; and 4 preparation of contingency plans for each potential deviation. This paper describes an approach for incorporating the observational method into the current USEPA Superfund process and provides a detailed discussion of that process in the context of groundwater remediation. Explicitly recognizing uncertainty in a proper application of the observational method offers the opportunity to reduce project time and costs as well as risks.

OBJECTIVE To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD). PARTICIPANTS AND DESIGN A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLD-TDP cases and all of the GRN− FTLD-TDP cases. RESULTS Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P < .001), as was age at death (median, 65.5 vs 69.0 years; P < .001). Concomitant motor neuron disease was much less common in GRN+ FTLD-TDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P < .001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations. CONCLUSION GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.Arch Neurol. 2011;68(4):488-497--

OBJECTIVE To describe the clinical, neuropsychologic, and radiologic features of a family with a C31LfsX35 mutation in the progranulin gene CCDS11483.1). DESIGN Case series. PATIENTS A large British kindred (DRC255) with a PGRN mutation was assessed. Affected individuals presented with a mean age of 57.8 years (range, 54-67 years) and a mean disease duration of 6.1 years (range, 2-11 years). RESULTS All patients exhibited a clinical and radiologic phenotype compatible with frontotemporal lobar degeneration based on current consensus criteria. However, unlike sporadic frontotemporal lobar degeneration, parietal deficits, consisting of dyscalculia, visuoperceptual /visuospatial dysfunction, and/or limb apraxia, were a common feature, and brain imaging showed posterior extension of frontotemporal atrophy to involve the parietal lobes. Other common clinical features included language output impairment with either dynamic aphasia or nonfluent aphasia and a behavioral syndrome dominated by apathy. CONCLUSION We suggest that parietal deficits may be a prominent feature of PGRN mutations and that these deficits may be caused by disruption of frontoparietal functional pathways.Arch Neurol. 2008;65(4):506-513--

This review addresses the latest developments in the genetics of frontotemporal lobar degeneration. ‘Frontotemporal lobar degeneration’ is the clinical term used to describe a heterogeneous neurodegenerative syndrome that includes frontotemporal dementia, semantic dementia, progressive nonfluent aphasia and progressive apraxia. Up to 40% of patients with frontotemporal lobar degeneration have a family history of a similar disorder in a first-degree relative, highlighting a significant genetic contribution to the aetiology of this disorder.

We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the presenilin-1 (PSEN1) gene was identified in the proband, but analyses in plasma and CSF suggested a mechanism of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed relatively linear change over the initial 4 years of assessment. Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in the exon 1 splice donor site (IVS1+1G→A) which is predicted to destroy the 5′-splice site of exon 1 and remove the start methionine codon and hence completely block any PGRN protein from being generated. These findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1G→A mutation in PGRN causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease—the ‘hypoprogranulinopathies’.

Over 30 different mutations have now been identified in MAPt that cause frontotemporal dementia (FTD). However, there are several families with FTD that show definite linkage to the region on chromosome 17 that contains MAPt, in which no mutation(s) has been identified. Although these families could have a complex mutation of the MAPt locus that has evaded detection it is also possible that another gene in this region is associated with FTD. This possibility is supported by neuropathological findings in these families, which consist of neuronal inclusions that are immunoreactive for ubiquitin (ub-ir) but not for tau. In addition to neuronal cytoplasmic inclusions, several chromosome 17-linked families are reported to have ub-ir neuronal intranuclear inclusions (NII); a finding which is uncommon in sporadic FTD. Here, we describe detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions. We have demonstrated that this family is linked to a 19.06 cM region of chromosome 17q21 with a maximum multipoint LOD score of 3.911 containing MAPt. By combining the results of our genetic analysis with those previously published for other families with similar pathology, we have further refined the minimal region to a 3.53 cM region of chromosome 17q21. We did not identify point mutations in MAPt by direct sequencing or any gross MAPt gene alterations using fluorescent in situ hybridization. In addition, tau protein extracted from members of this family was unremarkable in size and quantity as assessed by western blotting. Neuropathological characterization of the ub-ir NII in this family shows that they are positive for promyelocytic leukaemia protein (PML) and SUMO-1 that suggests that these inclusions form in the nuclear body and suggests a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21.

Injection of Plasmodium salivary gland sporozoites into the vertebrate host by Anopheles mosquitoes initiates malaria infection. Sporozoites develop within oocysts in the mosquito midgut and then enter and mature in the salivary glands. Although morphologically similar, oocyst sporozoites and salivary gland sporozoites differ strikingly in their infectivity to the mammalian host, ability to elicit protective immune responses, and cell motility. Here, we show that differential gene expression coincides with these dramatic phenotypic differences. Using suppression subtractive cDNA hybridization we identified highly up-regulated mRNAs transcribed from 30 distinct genes in salivary gland sporozoites. Of those genes, 29 are not significantly expressed in the parasite's blood stages. The most frequently recovered transcript encodes a protein kinase. Developmental up-regulation of specific mRNAs in the infectious transmission stage of Plasmodium indicates that their translation products may have unique roles in hepatocyte infection and/or development of liver stages.

Purification from calf thymus of a DNA N-glycosylase activity (HMUDG) that released 5-hydroxymethyluracil (5hmUra) from the DNA of Bacillus subtilisphage SPO1 was undertaken. Analysis of the most purified fraction by SDS-polyacrylamide gel electrophoresis revealed a multiplicity of protein species making it impossible to identify HMUDG by inspection. Therefore, we renatured the enzyme after SDS-polyacrylamide gel electrophoresis and assayed slices of the gel for DNA N-glycosylase activity directed against 5hmUra. Maximum enzymatic activity was identified between molecular mass markers 30 and 34 kDa. Protein was extracted from gel slices and subjected to tryptic digestion and analysis by mass spectrometry. Analysis revealed the presence of 11 peptides that were homologous or identical to the sequence of the recently characterized human single-stranded monofunctional uracil DNA N-glycosylase (hSMUG1). The cDNA of hSMUG1 was isolated and expressed as a recombinant glutathione S-transferase fusion protein that was shown to release 5hmUra with 20× the specific activity of the most purified bovine fraction. We conclude that hSMUG1 and HMUDG are the same protein.

The presenilins (PSs) are components of large molecular complexes that contain β-catenin and function as γ-secretase. We report here a striking correlation between amyloid angiopathy and the location of mutation in PS-1 linked Alzheimer’s disease. The amount of amyloid β protein, Aβ42(43), but not Aβ40,deposited in the frontal cortex of the brain is increased in 54 cases of early-onset familial Alzheimer’s disease, encompassing 25 mutations in the presenilin-1 (PS-1) gene, compared to sporadic Alzheimer’s disease. The amount of Aβ40in PS-1 Alzheimer’s disease varied according to the copy number of ε4 alleles of the Apolipoprotein E gene. Although the amounts of Aβ40and Aβ42(43)deposited did not correlate with the genetic location of the mutation in a strict linear sense, the histological profile did so vary. Cases with mutations between codon 1 and 200 showed, in frontal cortex, many diffuse plaques, few cored plaques, and mild or moderate amyloid angiopathy. Cases with mutations occurring after codon 200 also showed many diffuse plaques, but the number and size of cored plaques were increased (even when ε4 allele was not present) and these were often clustered around blood vessels severely affected by amyloid angiopathy. Similarly, diverging histological profiles, mainly according to the degree of amyloid angiopathy, were seen in the cerebellum. Mutations in the PS-1 gene may therefore alter the topology of the PS-1 protein so as to favor Aβ formation and deposition, generally, but also to facilitate amyloid angiopathy particularly in cases in which the mutation lies beyond codon 200. Finally we report that the amount of Aβ42(43)deposited in the brain correlated with the amount of this produced in culture by cells bearing the equivalent mutations.

Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. Here we have investigated the frequency of the ϵ4 allele of the Apolipoprotein (APOE) gene in FTD and in other non-Alzheimer forms of dementia related to FTD such as Motor Neurone disease dementia, semantic dementia, progressive aphasia, progressive supranuclear palsy, and corticobasal degeneration. In none of these diagnostic groups did we find a significant increase in the APOE ϵ4 allelic frequency, compared to population values. Neither did we observe any affects of the ϵ4 allele upon age at onset or duration of disease. We conclude therefore that polymorphic variations in the APOE gene do not modulate either the occurrence or progression of these non-Alzheimer forms of dementia.

Uncertainty is a key technical factor in hazardous waste site remediations. It can lead to unreasonable data gathering exercises if the point of diminishing information returns is not recognized. Engineering under uncertainty, however, is not unique to hazardous waste site remediation. Approaches have been used elsewhere to recognize and respond to substantial uncertainty. The observational method, traditionally applied in geotechnical engineering, has a number of key elements applicable to hazardous waste site remediation. The key contributions of the observational method are: (1) Remedial design based on most probable site conditions; (2) identification of reasonable deviations from those conditions; (3) identification of parameters to observe so as to detect deviations during remediation; and (4) preparation of contingency plans for each potential deviation. This paper describes an approach for incorporating the observational method into the current USEPA Superfund process and provides a detailed discussion of that process in the context of ground‐water remediation. Explicitly recognizing uncertainty in a proper application of the observational method offers the opportunity to reduce project time and costs as well as risks.

Mutations in presenilin-1 (PSEN1) cause autosomal dominant Alzheimer's disease and mutations in MAPT cause the familial tauopathy Frontotemporal dementia linked to chromosome 17 (FTDP-17). However, there have been reports of mutations in PSEN1 and MAPT associated with cases of FTD with ubiquitin-positive tau-negative inclusion pathology. Here, we demonstrate that the MAPT variants are almost certainly rare benign polymorphisms as all of these cases harbour mutations in Progranulin (PGRN). Mutations in PGRN were recently shown to cause ubiquitin-positive FTDP-17.

ABSTRACTStaphylococcus aureusis a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community. High mortality from infection emphasizes the need for improved methods for prevention and treatment. Although S. aureuspossesses an arsenal of virulence factors that contribute to evasion of host defenses, few studies have examined long-term humoral and B-cell responses. Adults with acute-phase skin and soft tissue infections were recruited; blood samples were obtained; and S. aureusisolates, including methicillin-resistant strains, were subjected to genomic sequence analysis. In comparisons of acute-phase sera with convalescent-phase sera, a minority (37.5%) of patients displayed 2-fold or greater increases in antibody titers against three or more S. aureusantigens, whereas nearly half exhibited no changes, despite the presence of toxin genes in most infecting strains. Moreover, enhanced antibody responses waned over time, which could reflect a defect in B-cell memory or long-lived plasma cells. However, memory B cells reactive with a range of S. aureusantigens were prevalent at both acute-phase and convalescent-phase time points. While some memory B cells exhibited toxin-specific binding, those cross-reactive with structurally related leucocidin subunits were dominant across patients, suggesting the targeting of conserved epitopes. Memory B-cell reactivity correlated with serum antibody levels for selected S. aureusexotoxins, suggesting a relationship between the cellular and humoral compartments. Overall, although there was no global defect in the representation of anti-S. aureusmemory B cells, there was evidence of restrictions in the range of epitopes recognized, which may suggest potential therapeutic approaches for augmenting host defenses.IMPORTANCEThe contribution of B-cell memory and long-term antibody responses to host defenses against S. aureusexotoxins remains poorly understood. Our studies confirmed that infection did not commonly lead to enhanced long-term humoral responses. Whereas circulating memory B cells against S. aureussecreted exotoxins were prevalent, they were dominated by cross-reactivity with structurally related leucocidin subunits, consistent with recognition of conserved epitopes. These findings also provide the first evidence of a relationship between the reactivity of antistaphylococcal circulating memory B cells and serum antibody levels. In general, infection was not associated with a global defect in B-cell memory for S. aureussecreted factors, and responses were highly dominated by cross-reactivity to structurally related exotoxins, which arguably may alone be suboptimal in providing host defenses. Our studies illuminate aspects of the S. aureus-host relationship that may better inform strategies for the development of an effective protective vaccine.

• A 57-year-old man had a tumor for five years on the plantar surface of his foot. It was treated successfully by surgical curettage. Clinical and pathological features of the tumor are identical to descriptions of the rare tumor of the foot designated as epithelioma cuniculatum.(Arch Dermatol 112:1295-1296, 1976)

Many older treatments should not be discarded because of newer modalities. Various dermatologic disorders may be controlled effectively by prescribing these older topical agents.

Most patients with frontotemporal dementia do not have taupathology as shown by immunohistochemistry. The use of the term tauopathy to classify frontotemporal dementia is inappropriate.

TO THE EDITOR.— We read with great interest the paper, "An Unusual Case of Syringoma" by Drs. Zalla and Perry (Arch Derm103:215-217, 1971). We have seen a rather similar case of syringoma localized to the vulva. This patient was a 9-year-old black girl seen recently because of a scaling pruritic eruption of the eyelids, diagnosed as seborrheic dermatitis. At that time papules were evident on the labia majora (Fig 1). The eyelid lesions cleared with the topical use of a steroid but no change occurred in the vulvar area. A biopsy specimen contained a fairly well circumscribed area of fibrous tissue around epithelial ducts and solid cords resembling sweat ducts (Fig 2). The diagnosis was syringoma. The lesions have remained unchanged. No other syringomas were found. She complains occasionally of pruritis in the area for which she was given a shake lotion treatment. There is no family history