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Urinary cytology associated with human polyomavirus and indinavir therapy in HIV-infected patients.

We retrospectively analyzed 155 urine cytology samples (78 from patients treated with indinavir; 77, no indinavir) from 90 HIV+ patients to evaluate possible association between human polyomavirus and hematuria and to describe indinavir-associated urinary cytologic findings. The CD4 count also was recorded. Variables studied included the presence of cellular viral changes consistent with polyomavirus infection (PVCs), microscopic hematuria, multinucleated cells, indinavir crystals, neutrophils, and eosinophils. Twenty-two samples (15.8%) from patients with CD4 counts of more than 200/microL (>200 x 10(6)/L) showed PVCs. Multinucleated cells, of presumed histiocytic origin based on morphologic features and selective immunocytochemical findings, were present in a higher percentage of samples from indinavir-treated patients. Neutrophils were present in a higher percentage of indinavir-treated patients. Indinavir crystals were identified in 9 samples (12%) from patients receiving indinavir The lower percentage of PVCs in HIV+ patients with high CD4 counts likely represents an indirect antipolyomavirus indinavir effect by boosting immunity. Multinucleated cells (presumably histiocytic) and acute inflammation are associated with indinavir therapy. Indinavir crystals have a characteristic fan or circular lamellate appearance. Because indinavir crystals may be associated with genitourinary disease, recognizing and reporting them is clinically relevant in HIV+ patients.

BK Virus↗

Content-based searching of multimedia databases by use of approximate digital signatures.

We propose the use of approximate digital signatures of selected multimedia feature vectors for fast content-based retrieval in large multimedia databases. We adapt and extend the approximate message authentication code (AMAC), introduced by some of the authors recently in the area of message authentication, to the multimedia searching problem. An AMAC is a binary signature with the ability to reflect changes in the message it represents. The Hamming distance between two AMACs is used to measure the degree of the similarity between multimedia objects. We develop a method to compress AMAC signatures to create a direct look-up table that allows for fast searching of a database. The color histogram is used as the example feature space to show how the signature is applied. Experimental results show that the performance of the proposed method is comparable with existing methods based on other popular metrics, but it significantly decreases search time.

Journal Article↗

Methodologic issues in the conduct and interpretation of pediatric effectiveness research.

Effectiveness research represents a number of methodologic challenges not shared with randomized, controlled clinical trials. This practice-based research attempts to translate clinical practices to a wide variety of different practice settings and situations and to diverse patient subgroups. However, because study designs most often used in the conduct of effectiveness research limit the ability to establish firm causal links between medical care and outcomes, it is important to address key methodologic features to generate sound, useable findings. Such features include selection of appropriate outcome measures (with a priori hypotheses linking care to the outcomes chosen), specification of appropriate primary sampling unit, specification of unit of analysis, establishment of appropriate comparison groups, and case-mix adjustment. Conduct of this type of research in pediatrics presents a number of unique methodologic concerns that either do not apply in adult medicine or are particularly acute in pediatrics. To alert policy makers and funders to the unique aspects of pediatric health services research and to provide guidance for the conduct and interpretation of pediatric effectiveness studies, we have organized and described the methodologic issues associated with the specific type of pediatric care under study (eg, specific disease-prevention, "bundled" care for chronic disease, care for problems with social etiologies, etc). We conclude with a summary of the methodologic steps that are critical to the conduct of sound effectiveness research in pediatrics.

Child↗

Providing long-term care benefits in cash: moving to a disability model.

This paper examines the role of a disability approach to the allocation of long-term care benefits. It first highlights the important elements of long-term care that support a disability model. It then reviews the advantages and disadvantages of this approach relative to the traditional indemnity model and summarizes key features of selected domestic and international programs that offer a disability-type benefit. The paper identifies and elaborates on the major implementation challenges and concludes with a recommendation for further examination of the costs and benefits of this approach to the public coffers, the private market, and long-term care consumers.

Persons with Disabilities↗

Some difficult choices in cytogenetics.

In making a selection of features of these technologies, it is inevitable that some will be omitted that other cytogeneticists feel should have been included. The author could probably justifiably be accused of bias. However, based on experience in a laboratory that has used almost every type of assay mentioned in this chapter, the following opinions are offered about their current value in providing a routine malignancy cytogenetics service: 1. The foundation is still a conventional cytogenetic study, preferably with the use of an automated karyotyping system. 2. Added to this, there should be the capability of performing FISH studies using chromosome paints and gene-specific probes. Cytogenetics and FISH form a powerful partnership when backed by experienced cytogeneticists. MFISH or SKY are also useful if the laboratory can afford the considerable extra expense. CGH and fibre FISH are generally better suited to research projects, and at present have few applications in a routine diagnostics service. 3. At present, molecular methods such as RT-PCR mostly tend to produce results that have a greater need of confirmation by other techniques before they can be used for clinical management.

Cytogenetics↗

Effects of tumors on inhaled pharmacologic drugs: II. Particle motion.

Computer simulations were conducted to describe drug particle motion in human lung bifurcations with tumors. The computations used FIDAP with a Cray T90 supercomputer. The objective was to better understand particle behavior as affected by particle characteristics, airflow conditions, and disease-modified airway geometries. The results indicated that increases in particle sizes, breathing intensities and tumor sizes could enhance drug deposition on the tumors. The modeling suggested that targeted drug delivery could be achieved by regulating breathing parameters and designing (selecting physical features of) aerosolized drugs. We present the theoretical work as a step towards improving aerosol therapy protocols. Since modeling describes factors affecting dose, it is complementary to considerations of the molecular aspects of drug formulation and pharmacokinetics.

Administration, Inhalation↗

The role of growth factors in the pathogenesis of diabetic retinopathy.

Diabetic retinopathy (DR) is the most severe of several ocular complications of diabetes. The earliest clinical signs of DR are microaneurysms and haemorrhages. Later signs include dilated, tortuous irregular veins and retinal non-profusion, leading to retinal ischaemia that ultimately results in neovascularisation. Diabetic macular oedema, which involves the breakdown of the blood-retinal barrier, also occurs and is responsible for a major part of vision loss, particularly in Type 2 diabetes. The pathogenesis of DR is very complex. Many biochemical mechanisms have been proposed as explanations for the development and progression of DR. Chronic hyperglycaemia leads to oxidative injury, microthrombi formation, cell adhesion molecule activation, leukostasis and cytokine activation. Next, ischaemia-mediated overexpression of growth factors and cytokines occurs. These factors include vascular endothelial growth factor, insulin-like growth factor-1, angiopoetin-1 and -2, stromal-derived factor-1, fibroblast growth factor-2 and tumour necrosis factor. Because of the complex interplay between these factors, targeting a single growth factor will be unlikely to result in therapeutic inhibition of angiogenesis. These growth factors no doubt act in synergy to mediate the steps of angiogenesis, including protease production, endothelial cell proliferation, migration and tube formation. This review attempts to provide an overview of perspectives regarding the pathogenesis of this disease. The focus, however, is on describing the unique features of selected relevant factors and how each growth factor may act in a synergistic manner with other factors.

Animals↗

Current and emerging therapies for the lysosomal storage disorders.

Targeted treatments for the lysosomal storage disorders (LSDs), in the form of enzyme replacement and/or substrate depletion, have been shown to be relatively safe and effective in reversing core disease features in selected clinical subtypes (including Gaucher disease types I and III, Fabry disease and the Hurler-Scheie syndrome). These approaches have expanded the therapeutic options available to patients with rare genetic disorders, beyond palliative measures (such as liver or kidney transplantation for end-organ failure) and cellular replacement through bone marrow transplantation. Present efforts are focused on the development of novel strategies, including chaperone-mediated enzyme enhancement and genetically engineered stem cell therapy. In the coming decades, a broadening therapeutic horizon for patients with inborn errors of metabolism is anticipated, and the growing experience in the management of patients with LSDs will serve as an instructive model. Among the many challenges will be determination of the extent to which these therapies have modified the course of disease beyond merely extending the age of survival, but also enabling a meaningful patient quality of life, and the minimisation of current resource use. The projected lifetime acquisition costs of newly introduced therapeutic options also raises several issues, related to equitable access and the large opportunity costs for other therapeutic areas, that will need to be addressed by healthcare policy makers and third-party payers.

Animals↗

Peptides derived from apoptotic Bax and Bid reproduce the poration activity of the parent full-length proteins.

Bax and Bid are proapoptotic proteins of the Bcl-2 family that regulate the release of apoptogenic factors from mitochondria. Although they localize constitutively in the cytoplasm, their apoptotic function is exerted at the mitochondrial outer membrane, and is related to their ability to form transbilayer pores. Here we report the poration activity of fragments from these two proteins, containing the first alpha-helix of a colicinlike hydrophobic hairpin (alpha-helix 5 of Bax and alpha-helix 6 of Bid). Both peptides readily bind to synthetic lipid vesicles, where they adopt predominantly alpha-helical structures and induce the release of entrapped calcein. In planar lipid membranes they form ion conducting channels, which in the case of the Bax-derived peptide are characterized by a two-stage pattern, a large conductivity and lipid-charge-dependent ionic selectivity. These features, together with the influence of intrinsic lipid curvature on the poration activity and the existence of two helical stretches of different orientations for the membrane-bound peptide, suggest that it forms mixed lipidic/peptidic pores of toroidal structure. In contrast, the assayed Bid fragment shows a markedly different behavior, characterized by the formation of discrete, steplike channels in planar lipid bilayers, as expected for a peptidic pore lined by a bundle of helices.

Amino Acid Sequence↗

Isochores exhibit evidence of genes interacting with the large-scale genomic environment.

The genomes of mammals and birds can be partitioned into megabase-long regions, termed isochores, with consistently high, or low, average C + G content. Isochores with high CG contain a mixture of CG-rich and AT-rich genes, while high-AT isochores contain predominantly AT-rich genes. The two gene populations in the high-CG isochores are functionally distinguishable by statistical analysis of their gene ontology categories. However, the aggregate of the two populations in CG isochores is not statistically distinct from AT-rich genes in AT isochores. Genes tend to be located at local extrema of composition within the isochores, indicating that the CG-enriching mechanism acted differently when near to genes. On the other hand, maximum-likelihood reconstruction of molecular phylogenetic trees shows that branch lengths (evolutionary distances) for third codon positions in CG-rich genes are not substantially larger than those for AT-rich genes. In the context of neutral mutation theory this argues against any strong positive selection. Disparate features of isochores might be explained by a model in which about half of all genes functionally require AT richness, while, in warm-blooded organisms, about half the genome (in large coherent blocks) acquired a strong bias for mutations to CG. Using mutations in CG-rich genes as convenient indicators, we show that approximately 20% of amino acids in proteins are broadly substitutable, without regard to chemical similarity.

Animals↗

A randomized clinical trial of the management of esophageal coins in children.

CONTEXT: Children frequently ingest coins. When lodged in the esophagus, the coin may cause complications and must either be removed or observed to pass spontaneously. OBJECTIVES: (1) To compare relatively immediate endoscopic removal to a period of observation followed by removal when necessary and (2) to evaluate the relationship between select clinical features and spontaneous passage. DESIGN/SETTING: Randomized, prospective study of children <21 years old who presented to an emergency department with esophageal coins in the esophagus. Exclusion criteria were (1) history of tracheal or esophageal surgery, (2) showing symptoms, or (3) swallowing the coin >24 hours earlier. Children were randomized to either endoscopic removal (surgery) or admission for observation, with repeat radiographs approximately 16 hours after the initial image. OUTCOME MEASURES: Proportion of patients requiring endoscopic removal, length of hospital stay, and the number of complications observed. RESULTS: Among 168 children who presented with esophageal coins lodged in the esophagus, 81 were eligible. Of those eligible, 60 enrolled, 20 refused consent, and 1 was not approached. In the observation group, 23 of 30 (77%) children required endoscopy compared with 21 of 30 (70%) in the surgical group. Total hospital length of stay was longer in the randomized-to-observation group compared with the randomized-to-surgery group (mean: 19.4 [SD: +/-8.0] hours vs 10.7 [SD: +/-7.1] hours, respectively). There were no complications in either group. Spontaneous passage occurred at similar rates in both groups (23% vs 30%). Spontaneous passage was more likely in older patients (66 vs 46 months) and male patients (odds ratio: 3.7; 95% confidence interval: 0.98-13.99) and more likely to occur when the coin was in the distal one third of the esophagus (56% vs 27% [95% confidence interval: 1.07-5.57]). CONCLUSIONS: Because 25% to 30% of esophageal coins in children will pass spontaneously without complications, treatment of these patients may reasonably include a period of observation, in the range of 8 to 16 hours, particularly among older children and those with distally located coins.

Child↗

Panton-Valentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children.

BACKGROUND: Staphylococcus aureus strains carrying the genes encoding Panton-Valentine leukocidin (pvl-positive [pvl+]) are associated with more febrile days and higher complication rates of osteomyelitis in children than are pvl-negative (pvl-) strains. OBJECTIVES: Selected clinical, laboratory, and radiographic findings in children with osteomyelitis caused by pvl+ and pvl- S aureus strains were compared. METHODS: The demographics, selected clinical features, laboratory values, and radiographic findings of children with community-acquired S aureus osteomyelitis prospectively identified at Texas Children's Hospital between August 2001 and July 2004 were reviewed. Polymerase chain reaction was performed to detect the genes for pvl (luk-S-PV and luk-F-PV) and fibronectin-binding protein (fnbB) in S aureus isolates. Chi2, 2-sample t test, and multiple logistic regression were used for statistical analysis. RESULTS: Methicillin-susceptible and methicillin-resistant S aureus (MSSA and MRSA, respectively) caused osteomyelitis in 33 and 56 children, respectively. Twenty-six isolates were pvl- (26 MSSA), 59 were pvl+ (3 MSSA, 56 MRSA), and 4 were not available for analysis (4 MSSA). On univariate analysis, patients with pvl+ S aureus isolates had significantly higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level both at presentation and as a maximum value during hospitalization and were more likely to have a blood culture positive for S aureus during their admission. Patients with pvl+ S aureus isolates were significantly more likely to have concomitant myositis or pyomyositis compared with patients with pvl- S aureus isolates on MRI. In a multivariate analysis pvl remained significantly associated with ESR and CRP levels at presentation and blood culture positive for S aureus. pvl+ status and younger age were associated with myositis on MRI. CONCLUSIONS: Osteomyelitis caused by pvl+ S aureus strains were associated with more severe local disease and a greater systemic inflammatory response compared with osteomyelitis caused by pvl- S aureus.

Acute Disease↗

Pre-speech in children with cleft lip and palate or cleft palate only: phonetic analysis related to morphologic and functional factors.

Pre-speech in 35 children with clefts of the lip and palate or palate only were analyzed for place and manner of articulation. Transcriptions were made from tape recorded babbling sequences. Two children without clefts were used as reference. All of the children with clefts were treated according to a regimen of early surgical repair of the velum cleft and delayed closure of the cleft in the hard palate. The frequency of selected phonetic features was calculated. Correlations between phonetic/perceptual and functional and morphological factors were tested. Supraglottal articulation dominated among all the children indicating a sufficient velopharyngeal mechanism. The results also showed correlations between cleft type and place of articulation. Anteriorly placed sounds (i.e., bilabial, dental, and alveolar sounds) occurred frequently among the children with cleft palate only and in the noncleft children. In children with cleft lip and palate, posteriorly placed articulations predominated. It was postulated that early intervention may have a positive effect on articulatory development.

Age Factors↗

Lamivudine treatment in patients with HBV-related hepatocellular carcinoma--using an untreated, matched control cohort.

Lamivudine is widely used to treat patients with hepatitis B. However, the outcomes in patients with hepatocellular carcinoma (HCC) treated with lamivudine have not been established. This study was conducted to evaluate the outcomes of lamivudine treatment for patients with HCC using an untreated, matched control group. Thirty patients with controlled HCC orally received lamivudine. As controls, 40 patients with HCC who were not treated with lamivudine and matched for clinical features were selected. The lamivudine-treated and untreated groups were compared with respect to changes in liver function, HCC recurrence, survival, and cause of death. In the lamivudine-treated group, there was significant improvement in the Child-Pugh score at 24 months after starting treatment, while no improvement was observed in the untreated group. There was no significant difference in the cumulative incidence of HCC recurrence and survival between the groups. However, there was a significant difference in the cumulative incidence of death due to liver failure (P= 0.043). A significant improvement in liver function was achieved by lamivudine treatment, even in patients with HCC. These results suggest that lamivudine treatment for patients with HCC may prevent death due to liver failure. Further prospective randomized studies using a larger number of patients are required.

Adult↗

HINN: Hierarchical Input Neural Network identifies multi-omics biomarker for cognitive decline.

Understanding complex diseases requires models that can integrate diverse layers of biological data while yielding insights that are biologically interpretable. Although multi-omics integration with machine learning (ML) has advanced disease prediction and biomarker discovery, most existing approaches overlook the hierarchical and regulatory relationships that connect these molecular layers. Here, we present the Hierarchical Input Neural Network (HINN), a deep learning framework that incorporates known cross-omics relationships directly into its architecture, capturing the flow of information from genomics to epigenomics, transcriptomics, and downstream biological processes. By embedding these relationships, HINN improves both predictive performance and biological interpretability. We applied HINN to blood-derived multi-omics data from individuals with Alzheimer's disease or mild cognitive impairment to predict cognitive scores from standardized assessments. HINN outperformed both baseline and state-of-the-art models and pinpointed multi-omics biomarkers-including SNPs and promoter-region CpG sites in ATP6V1C1 and RCHY1 -that were significantly correlated with plasma p-Tau181 levels. These features map to biologically relevant processes with potential implications for cognitive decline. Our findings demonstrate how combining deep learning with biological knowledge can uncover interpretable, blood-based biomarkers for cognitive decline due to complex diseases such as Alzheimer's. All code and data are openly available at https://github.com/bozdaglab/HINN.

Alzheimer&#x2019;s disease↗

Molecular targets and therapeutic strategies in Huntington's disease.

This article provides an overview of the molecular mechanisms associated with striatal neuronal degeneration in Huntington's disease (HD), the most studied of the diseases caused by polyglutamine expansion. We discuss the current status of research in cellular and animal models of HD, in which protein aggregation, excitotoxicity, mitochondrial dysfunction, transcription deregulation, trophic factor starvation and the disruption of axonal transport appear to be key features for selective striatal neurodegeneration. We further emphasize some of the most promising current strategies in HD treatment. We delineate the molecular and cellular rationale underlying the development of new pharmaceutical interventions that offer new hope of future treatment for HD patients worldwide.

Animals↗

Flexible and frozen sugar-modified nucleic acids--modulation of biological activity through furanose ring dynamics in the antisense strand.

A comparison of carbohydrate modified nucleic acids has identified key structural characteristics in antisense oligonucleotides (AON) that are necessary for sufficient clinical utility, including increased duplex stability towards RNA complements and improved hydrolytic resistance towards general serum and cellular nucleases. As such, the exogenous addition of short, synthetic oligonucleotides can influence cellular RNA metabolism at any or all levels of replication, transcription or translation by tight and specific hybridization with a chosen target and subsequently stop further function at that site. Furthermore, appropriate modification of the sugar residue may prove to be a vital design element in future AONs that operate by promoting enzyme assisted catalytic destruction of the mRNA target. Unfortunately, many of the current AON designs have provided little insight on the particular structural role of the AON towards enzymatic discrimination of the resultant hybrid. The use of RNase H as a cellular vehicle to assist the inhibitory potency of an AON as well as possible ways of enhancing activity in pre-existing antisense candidates are presented. Of the emerging criteria in this aspect, a balance between flexibility and rigidity within the AON appears to be a critical mediator of the RNase H assisted antisense effect. Accordingly, this review describes the conformational features and selected biological attributes of some of the more prominent AON contenders with a focus on the conformational criteria by which ribonuclease H activity is recruited to a particular hybrid target.

Humans↗

Developmental patterns and characteristic symptoms of petroclival meningiomas.

Thirty-six cases of petroclival meningiomas with clearly defined anatomical features were selected to analyze the site of tumor attachment and the displacement of the trigeminal nerve. The tumors were classified into four categories according to the origin and extension of the tumor: clival origin medial to the trigeminal nerve (upper clivus type), clival origin with dumbbell extension to the cavernous sinus (cavernous sinus type), tentorial origin over the trigeminal nerve (tentorium type), and petrous apex origin lateral to the trigeminal nerve (petrous apex type). Patients with tumors in each category had characteristic neurological symptoms. Patients with the upper clivus type had oculomotor nerve paresis as a single symptom, if suprasellar tumor extension was present. Patients with the cavernous sinus type commonly presented with abducens nerve paresis caused by epidural tumor invasion around Dorello's canal. Dumbbell tumor extension along the venous drainage of the cavernous sinus was a significant problem for surgical removal in this type. Half of the patients with the tentorium type had a characteristic symptom of trigeminal neuralgia caused by retrograde tumor invasion into Meckel's cave from its orifice, but the cavernous sinus was not involved. The main complaint of patients with the petrous apex type was hearing disturbance, but no epidural or parasellar extension was present. Clinical symptoms and magnetic resonance imaging provide important information about the origin and extension patterns of these tumors, especially the presence or absence of tumor extension into the cavernous sinus. Abducens nerve paresis or trigeminal neuralgia suggests tumor invasion into the cavernous sinus or Meckel's cave, respectively.

Adult↗