Management of Chronic Pain in Patients with Substance Use Disorders.

Understanding the risks for substance use disorders (SUDs) and how to diagnose and treat is essential to the safe and effective treatment of patients with chronic noncancer pain (CNCP). Because of the common neurologic pathways underlying addiction and chronic pain and common comorbid mental health and psychosocial challenges, these conditions should be treated concurrently. Depending on setting and comfort level of the provider, primary care clinicians may have the resources to provide office-based treatment or may consider referral to specialty treatment.

Severity Adjusted Risk of Long-term Adverse Sequelae Among Children With Osteomyelitis.

Background: The purpose of this investigation was to evaluate the risk for long-term, adverse outcomes among children with osteomyelitis.

Methods: Children with osteomyelitis were prospectively enrolled from 2012 to 2014. Care was accomplished by a multidisciplinary team according to an institutional algorithm.

Arthroscopic Quantification of Syndesmotic Instability in a Cadaveric Model.

Purpose: To investigate whether arthroscopy or stress radiography can identify instability resulting from single-ligament injury of the ankle syndesmosis and to determine whether either modality is capable of differentiating between various levels of ligament injury.

Methods: Syndesmotic/deltoid ligament sectioning was performed in 10 cadaver legs. Arthroscopic evaluation and fluoroscopic stress testing were completed after each sectioning.

Numeracy among trainees: are we preparing physicians for evidence-based medicine?

Introduction: In the era of evidence-based medicine, all physicians who communicate with patients need numerical literacy (numeracy). Single-institution studies suggest imperfect numeracy among medical students. Therefore, we sought to examine numeracy and understanding of risk analysis among medical students and surgical residents at several institutions.

Radiographic correction of stage III posterior tibial tendon dysfunction with a modified triple arthrodesis.

Background: The literature supports fusion as the surgical treatment of choice for stage III posterior tibial tendon dysfunction (PTTD). The present study reports the radiographic correction following a modified triple arthrodesis (fusions of the subtalar, talonavicular, and first tarsometatarsal joints) in patients with stage III PTTD.

Methods: An institutional review board-approved retrospective study was performed to assess the radiographic outcome of a modified triple arthrodesis in 21 patients (22 feet).

Cooperative and antagonistic contributions of two heterochromatin proteins to transcriptional regulation of the Drosophila sex determination decision.

Eukaryotic nuclei contain regions of differentially staining chromatin (heterochromatin), which remain condensed throughout the cell cycle and are largely transcriptionally silent. RNAi knockdown of the highly conserved heterochromatin protein HP1 in Drosophila was previously shown to preferentially reduce male viability. Here we report a similar phenotype for the telomeric partner of HP1, HOAP, and roles for both proteins in regulating the Drosophila sex determination pathway.

Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma.

Human leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell-mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell-mediated lysis.

Drosophila ATM and ATR checkpoint kinases control partially redundant pathways for telomere maintenance.

In higher eukaryotes, the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) checkpoint kinases play distinct, but partially overlapping, roles in DNA damage response. Yet their interrelated function has not been defined for telomere maintenance. We discover in Drosophila that the two proteins control partially redundant pathways for telomere protection: the loss of ATM leads to the fusion of some telomeres, whereas the loss of both ATM and ATR renders all telomeres susceptible to fusion.

Mutations in the heterochromatin protein 1 (HP1) hinge domain affect HP1 protein interactions and chromosomal distribution.

Heterochromatin Protein 1 (HP1) is a conserved component of the highly compact chromatin found at centromeres and telomeres. A conserved feature of the protein is multiple phosphorylation. Hyper-phosphorylation of HP1 accompanies the assembly of cytologically distinct heterochromatin during early embryogenesis.

Novel Drosophila heterochromatin protein 1 (HP1)/origin recognition complex-associated protein (HOAP) repeat motif in HP1/HOAP interactions and chromocenter associations.

Association of the highly conserved heterochromatin protein, HP1, with the specialized chromatin of centromeres and telomeres requires binding to a specific histone H3 modification of methylation on lysine 9. This modification is catalyzed by the Drosophila Su(var)3-9 gene product and its homologues. Specific DNA binding activities are also likely to be required for targeting this activity along with HP1 to specific chromosomal regions.

Is HP1 an RNA detector that functions both in repression and activation?

Heterochromatin is defined as regions of compact chromatin that persist throughout the cell cycle (Heitz, 1928). The earliest cytological observations of heterochromatin were followed by ribonucleotide labeling experiments that showed it to be transcriptionally inert relative to the more typical euchromatic regions that decondense during interphase. Genetic studies of rearrangements that place euchromatic genes next to blocks of heterochromatin also pointed out the repressive nature of heterochromatin (Grigliatti, 1991; and references therein).

HP1/ORC complex and heterochromatin assembly.

We have used the highly conserved heterochromatin component, heterochromatin protein 1 (HP1), as a molecular tag for purifying other protein components of Drosophila heterochromatin. A complex of HP1 associated with the origin recognition complex (ORC) and an HP1/ORC-associated protein (HOAP) was purified from the maternally loaded cytoplasm of early Drosophila embryo. We propose that the DNA-binding activities of ORC and HOAP function to recruit underphosphorylatedisoforms of HP1 to sites of heterochromatin nucleation.

HP1 complexes and heterochromatin assembly.

Since its discovery almost two decades ago, heterochromatin protein 1 (HP1) has emerged as a major player in the transcriptional regulation of both heterochromatic and euchromatic genes as well as the mechanics of chromosome segregation and the functional and structural organization of the interphase nucleus. Recent years have brought the identification of a myriad of HP1-interacting proteins. Each of these is discussed in relationship to its role in heterochromatin assembly and HP1 function.

The Drosophila HOAP protein is required for telomere capping.

HOAP (HP1/ORC-associated protein) has recently been isolated from Drosophila melanogaster embryos as part of a cytoplasmic complex that contains heterochromatin protein 1 (HP1) and the origin recognition complex subunit 2 (ORC2). Here, we show that caravaggio, a mutation in the HOAP-encoding gene, causes extensive telomere-telomere fusions in larval brain cells, indicating that HOAP is required for telomere capping. Our analyses indicate that HOAP is specifically enriched at mitotic chromosome telomeres, and strongly suggest that HP1 and HOAP form a telomere-capping complex that does not contain ORC2.

Gag proteins of the two Drosophila telomeric retrotransposons are targeted to chromosome ends.

Drosophila telomeres are formed by two non-LTR retrotransposons, HeT-A and TART, which transpose only to chromosome ends. Successive transpositions of these telomeric elements yield arrays that are functionally equivalent to the arrays generated by telomerase in other organisms. In contrast, other Drosophila non-LTR retrotransposons transpose widely through gene-rich regions, but not to ends.

Drosophila heterochromatin protein 1 (HP1)/origin recognition complex (ORC) protein is associated with HP1 and ORC and functions in heterochromatin-induced silencing.

Heterochromatin protein 1 (HP1) is a conserved component of the highly compact chromatin of higher eukaryotic centromeres and telomeres. Cytogenetic experiments in Drosophila have shown that HP1 localization into this chromatin is perturbed in mutants for the origin recognition complex (ORC) 2 subunit. ORC has a multisubunit DNA-binding activity that binds origins of DNA replication where it is required for origin firing.

Chromatin boundaries: punctuating the genome.

Transcriptional enhancers are constrained to act within domains defined by boundary elements. How these elements work is a mystery. A recent study emphasizes their autonomous activity; another emphasizes their dependence on nuclear organization.

Distinct cytoplasmic and nuclear fractions of Drosophila heterochromatin protein 1: their phosphorylation levels and associations with origin recognition complex proteins.

The distinct structural properties of heterochromatin accommodate a diverse group of vital chromosome functions, yet we have only rudimentary molecular details of its structure. A powerful tool in the analyses of its structure in Drosophila has been a group of mutations that reverse the repressive effect of heterochromatin on the expression of a gene placed next to it ectopically. Several genes from this group are known to encode proteins enriched in heterochromatin.

Association of the origin recognition complex with heterochromatin and HP1 in higher eukaryotes.

The origin recognition complex (ORC) is required to initiate eukaryotic DNA replication and also engages in transcriptional silencing in S. cerevisiae. We observed a striking preferential but not exclusive association of Drosophila ORC2 with heterochromatin on interphase and mitotic chromosomes.

Heterochromatin protein 1 is required for correct chromosome segregation in Drosophila embryos.

Heterochromatin protein 1 is associated with centromeric heterochromatin in Drosophila, mice, and humans. Loss of function mutations in the gene encoding heterochromatin protein 1 in Drosophila, Suppressor of variegation2-5, decrease the mosaic repression observed for euchromatic genes that have been juxtaposed to centromeric heterochromatin. These heterochromatin protein 1 mutations not only suppress this position-effect variegation, but also cause recessive embryonic lethality.

Heterochromatin protein 1 distribution during development and during the cell cycle in Drosophila embryos.

Heterochromatin protein 1 (HP1) was initially discovered as a protein that is associated with the heterochromatin at the chromocenter of polytene chromosomes in Drosophila larval salivary glands. In this paper we investigate the localization of heterochromatin protein 1 in the diploid nuclei of Drosophila embryos. We focus on its association with the interphase heterochromatin in fixed embryos before and during cycle 14, the developmental time at which heterochromatin becomes most conspicuous, and also follow its localization during mitosis.

The Drosophila GAGA transcription factor is associated with specific regions of heterochromatin throughout the cell cycle.

In virtually all eukaryotes the centromeric regions of chromosomes are composed of heterochromatin, a specialized form of chromatin that is rich in repetitive DNA sequences and is transcriptionally relatively silent. The Drosophila GAGA transcription factor binds to GA/CT-rich sequences in many Drosophila promoters, where it activates transcription, apparently by locally altering chromatin structure and allowing other transcription factors access to the DNA. Here we report the paradoxical finding that GAGA factor is associated with specific regions of heterochromatin at all stages of the cell cycle.

A group of scs elements function as domain boundaries in an enhancer-blocking assay.

Chromosomes of higher eukaryotes are thought to be organized into a series of discrete and topologically independent higher-order domains. In addition to providing a mechanism for chromatin compaction, these higher-order domains are thought to define independent units of gene activity. Implicit in most models for the folding of the chromatin fiber are special nucleoprotein structures, the domain boundaries, which serve to delimit each higher-order chromosomal domain.

A position-effect assay for boundaries of higher order chromosomal domains.

Eukaryotic chromosomes are thought to be organized into a series of discrete higher order chromatin domains. This organization is believed to be important not only in the compaction of the chromatin fiber, but also in the utilization of genetic information. Each domain would define an independent unit of gene activity, insulated from the regulatory influences of adjacent domains.