Fatal listeria meningitis in an immunocompromised infant: Therapeutic implications

Infection with Listeria monocytogenes is rare in infants and children. Listeriosis has been made a notifiable condition in the State of California since 1985. From January 1985 to December 1990, only seven cases of listeriosis have been reported in children less than or equal to 13 years of age. This brief report summarises the features of a fatal case of listeria meningitis in an immunocompromised 4-month-old infant, discusses diagnostic and therapeutic implications, and describes the other six cases.     

Aortic Arch Morphology and Late Systemic Hypertension Following Correction of Coarctation of Aorta

Objective. To reproduce in an adult population a pediatric study that found an association between aortic arch geometry and late systemic hypertension following successful repair of aortic coarctation. Design and Results. Fifty‐one patients with successful repair of coarctation of the aorta had blood pressure measurement at rest and during exercise. After cross‐sectional imaging of the aortic arch, patients were assigned to 1 of 3 previously defined morphological categories: normal, gothic, or crenel. The degree of residual stenosis and the ratio of the height/transverse diameter of the arch (A/T ratio) were calculated. No relationship was found between arch geometry and either resting‐ or exercise‐induced hypertension. Conclusions. We found the classification into 3 morphological types difficult and did not find an association between gothic arch or a high A/T ratio and hypertension.     

Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease

Presenilin (PSEN) pathogenic mutations cause familial Alzheimer’s disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed γ-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall γ-secretase activity levels, and therefore, loss of overall (endopeptidase) γ-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (γ-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like γ-secretase activity with γ-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase-like γ-secretase activities. However and interestingly, a few SAD patient samples display γ-secretase dysfunction, suggesting that γ-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-β (Aβ) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aβ products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations.Early-onset familial Alzheimer’s disease (AD [FAD]), starting before age 65, is mainly caused by mutations in the Presenilin 1/2 (PSEN1/2) or the amyloid precursor protein (APP) genes and represents less than 0.1% of the total AD cases (Campion et al., 1999). Although rare, FAD offers a unique model to gain insights into the molecular mechanisms and etiology of sporadic AD (SAD).PSEN is the catalytic subunit of the γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999), an intramembrane multimeric protease involved in the processing of many type 1 transmembrane proteins; among them, the Notch receptors and APP have received much attention because of their association with crucial cell signaling events or with AD pathogenesis, respectively (for a review see Jurisch-Yaksi et al. [2013]). Nicastrin (Nct), PSEN enhancer 2 (Pen2), and anterior pharynx defective 1 (APH1) are, together with PSEN, essential components of the protease complex (De Strooper, 2003).More than 150 pathogenic mutations in PSEN1 have been reported so far (http://www.molgen.ua.ac.be/ADMutations); and notably, the vast majority are missense substitutions distributed throughout the primary structure of PSEN1. PSEN/γ-secretase hydrolyzes peptide bonds in a process called regulated intramembrane proteolysis, which allows translation of extracellular signals into the cell. Compelling evidence indicates that γ-secretase cuts membrane proteins sequentially: the first endopeptidase cleavage (ε) releases a soluble intracellular domain (ICD), which may translocate to the nucleus to regulate gene expression while the remaining N-terminal transmembrane domain (TMD) fragment is successively cut by the carboxypeptidase-like activity of γ-secretase (γ-cleavages). Endopeptidase products, either amyloid-β49 (Aβ49) or Aβ48, are then processed along two major product lines: Aβ49 → Aβ46 → Aβ43 → Aβ40 or Aβ48 → Aβ45 → Aβ42 → Aβ38 (Takami et al., 2009). Every γ-cleavage removes a short C-terminal peptide from the TMD, reducing its hydrophobicity and increasing the probability of release. Secretion of an N-terminal fragment into the extracellular/luminal space terminates this sequence (Qi-Takahara et al., 2005; Yagishita et al., 2008; Takami et al., 2009). Importantly, the efficiency of the endopeptidase cleavage determines ICD product levels, which acquires high physiological relevance in the case of the Notch substrate. The carboxypeptidase-like efficiency, the number of cuts per substrate, determines the length of the N-terminal products; the level of efficiency is pathologically very relevant in the case of the APP substrate, as lower efficiency results in the production of longer and more aggregation-prone Aβ peptides (Chávez-Gutiérrez et al., 2012).How mutations in the PSENs cause FAD remains a hotly debated topic in the field. Because FAD is an autosomal-dominant disorder (patients carry both healthy and mutant alleles), a major unknown in the discussion remains the role of the healthy allele and, to a lesser extent, the role of the brain environment on the total (normal + mutant proteases) γ-secretase activity. To what degree do normal and mutant complexes contribute to total γ-secretase activity in the patient brain? Does the healthy allele compensate for the disease allele effects? Despite their relevance, those questions have not been addressed.Only one group, i.e., Potter et al. (2013), have estimated the Aβ production kinetics in the FAD brain by measuring isotope-labeled Aβ peptides in the cerebrospinal fluid of patients (stable isotope-labeled kinetics [SILK]). Feeding the in vivo metabolic labeling patient data into a mathematical model, specifically generated for their approach, they described higher Aβ42 production rates in the central nervous system of PSEN mutation carriers (Potter et al., 2013). Accordingly, Potter et al. (2013) suggest that increments in Aβ42 play a decisive pathogenic role in AD.In contrast, a “revised” loss-of-function (LOF) hypothesis has recently been proposed by Xia et al. (2015). In this view, loss of PSEN/γ-secretase physiological cell signaling function causes neurodegeneration, whereas changes in Aβ peptides are only secondary byproducts that arise from but do not trigger the disease (Xia et al., 2015). The idea is only tenable if FAD-linked PSEN mutations exert a LOF effect on PSEN/γ-secretase and, in addition, a dominant-negative effect on the healthy PSEN allele (normal γ-secretase) in patients, a key part of this hypothesis (Heilig et al., 2013; Xia et al., 2015). However, it should be stressed that γ-secretase haploinsufficiency caused by nonsense, frameshift, and splice site mutations in genes coding for essential subunits of γ-secretase (Nct, Pen2, and PSEN) is pathogenic in nature; such haploinsufficiency causes a chronic inflammatory disease of hair follicles known as familial acne inversa. Most importantly, no clinical association between this disorder and AD has been reported (for a review see Pink et al. [2013]). Furthermore, if FAD-linked PSEN mutations were truly LOF mutations, resulting in “inactive” γ-secretase complexes, homozygous individuals for the disease allele would not be viable because of disturbances in Notch signaling during embryonic development. However, six individuals with homozygous PSEN1 E280A gene mutation have been identified (Kosik et al., 2015).An alternative view to both hypotheses is that pathogenic mutations in PSEN cause disease by qualitative shifts in Aβ profile production (γ-secretase dysfunction; Chávez-Gutiérrez et al., 2012). We have demonstrated that loss of endopeptidase activity is not necessarily observed in γ-secretase complexes containing PSEN1/2 FAD-linked mutations, but reduced carboxypeptidase-like efficiency (γ-secretase dysfunction) is the constant denominator. Furthermore, FAD PSEN mutations may affect the carboxypeptidase-like γ-secretase activity at multiple turnovers, resulting in increased Aβ43 and Aβ42 levels as well as in other longer Aβ peptides, such as Aβ45 and Aβ46 (Quintero-Monzon et al., 2011; Chávez-Gutiérrez et al., 2012; Fernandez et al., 2014). These data support a model in which relative, rather than absolute, changes in Aβ product profiles are at the basis of PSEN/γ-secretase–mediated pathogenicity. However, these findings were based on studies conducted in PSEN1/2-deficient MEFs, which does not fully recapitulate the in vivo heterozygous situation in the FAD patient’s brain.In the current study, we investigated processing of APP by the γ-secretase complex in postmortem human brain samples from FAD and SAD patients and healthy control subjects. Our investigation is the first to directly assess γ-secretase activity in brain material from FAD mutant carriers and to address how the FAD-linked mutant heterozygous situation in patients affects γ-secretase function in brain.     

LRRK2 and parkin immunoreactivity in multiple system atrophy inclusions

Certain genetic defects in LRRK2 and parkin are pathogenic for Parkinson’s disease (PD) and both proteins deposit in the characteristic Lewy bodies. LRRK2 is thought to be involved in the early initiation of Lewy bodies. The involvement of LRRK2 and parkin in the similar cellular deposition of fibrillar α-synuclein in glial cytoplasmic inclusions (GCI) in multiple system atrophy (MSA) has not yet been assessed. To determine whether LRRK2 and parkin may be similarly associated with the abnormal deposition of α-synuclein in MSA GCI, paraffin-embedded sections from the basal ganglia of 12 patients with MSA, 4 with PD and 4 controls were immunostained for LRRK2, parkin, α-synuclein and oligodendroglial proteins using triple labelling procedures. The severity of neuronal loss was graded and the proportion of abnormally enlarged oligodendroglia containing different combinations of proteins assessed in 80–100 cells per case. Parkin immunoreactivity was observed in only a small proportion of GCI. In contrast, LRRK2 was found in most of the enlarged oligodendroglia in MSA and colocalised with the majority of α-synuclein-immunopositive GCI. Degrading myelin sheaths containing LRRK2-immunoreactivity were also observed, showing an association with one of the earliest oligodendroglial abnormalities observed in MSA. The proportion of LRRK2-immunopositive GCI was negatively associated with an increase in neuronal loss and α-synuclein-immunopositive dystrophic axons. Our results indicate that an increase in LRRK2 expression occurs early in association with myelin degradation and GCI formation, and that a reduction in LRRK2 expression in oligodendroglia is associated with increased neuronal loss in MSA.     

Transmission and epidemiology of HIV/AIDS: a global view

Since the first recognition of the condition that is now called AIDS, much has been learned. We now know that AIDS results from infection with HIV types 1 and 2. Advancements in approaches to treatment, in the form of new types of medications, have changed the trajectory of illness by slowing progression and decreasing the incidence of HIV-associated opportunistic infections in the millions of people living with HIV infection, particularly in developed countries. In less developed areas of the world, HIV infection looks different, in part because of the differential availability of medications and health care. This article focuses on epidemiology of HIV infection and AIDS in the United States and worldwide, and on transmission, including susceptibility factors.     

An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies

The pathological distinctions between the various clinical and pathological manifestations of frontotemporal lobar degeneration (FTLD) remain unclear. Using monoclonal antibodies specific for 3- and 4-repeat isoforms of the microtubule associated protein, tau (3R- and 4R-tau), we have performed an immunohistochemical study of the tau pathology present in 14 cases of sporadic forms of FTLD, 12 cases with Pick bodies and two cases without and in 27 cases of familial FTLD associated with 12 different mutations in the tau gene (MAPT), five cases with Pick bodies and 22 cases without. In all 12 cases of sporadic FTLD where Pick bodies were present, these contained only 3R-tau isoforms. Clinically, ten of these cases had frontotemporal dementia and two had progressive apraxia. Only 3R-tau isoforms were present in Pick bodies in those patients with familial FTLD associated with L266V, Q336R, E342V, K369I or G389R MAPT mutations. Patients with familial FTLD associated with exon 10 N279K, N296H or +16 splice site mutations showed tau pathology characterised by neuronal neurofibrillary tangles (NFT) and glial cell tangles that contained only 4R-tau isoforms, as did the NFT in P301L MAPT mutation. With the R406W mutation, NFT contained both 3R- and 4R-tau isoforms. We also observed two patients with sporadic FTLD, but without Pick bodies, in whom the tau pathology comprised only of 4R-tau isoforms. We have therefore shown by immunohistochemistry that different specific tau isoform compositions underlie the various kinds of tau pathology present in sporadic and familial FTLD. The use of such tau isoform specific antibodies may refine pathological criteria underpinning FTLD.     

Promoting oral health among the inner city homeless: a community-academic partnership

Oral health care resources for the homeless are scarce, underfunded, and generally inadequate to meet the oral health needs of this population. The purpose of this program was to improve oral health among the urban homeless in a faith-based inner city mission through education, screening, and improved access to oral health care. The program provided for expanded delivery of oral health care services to the homeless while preparing students in the health professions for community-based practice with at-risk and vulnerable populations. By proactively addressing oral health needs through prevention and earlier diagnosis and treatment, morbidity, quality of life, and cost can be positively affected. Innovative, cross-disciplinary, community delivery models that involve key stakeholders at all levels are needed to address the oral health needs of the homeless and underserved adequately.     

Prevalence and correlates of conduct disorder and problem behavior in Caribbean and Filipino immigrant adolescents

This study investigates the prevalence and subtypes of conduct disorder (CD) and behavioral problems among youth in two communities characterized by prolonged parent-child separation upon immigration. CD and problem behaviors were assessed in 252 Caribbean-Canadian and Filipino-Canadian adolescents (12-19-year-old) using the DISC-C, the YSR and the CBCL cross-informant construct. Adolescents reported less problem behaviors than their host country peers, despite immigrant background or parent-child separation. The high adolescent-onset CD rate supports the hypothesis that psychosocial stressors play a role in the emergence of the disorder. Specifically, high levels of perceived racism and low collective self-esteem predicted problem behaviors in these youngsters.