A Case of Cannabis Smoking Induced Leukocytosis

Background: Leukocytosis relates to infections, malignancies, stress response, and multiple intoxicants. Like other intoxicants, cannabis smoking can result in a persistent leukocytosis. Here we report a case of cannabis-induced leukocytosis. Case Presentation: A 20-year-old Hispanic female with a history of anxiety disorder presented with 3-days of nausea, vomiting, and colicky abdominal pain. She endorsed heavy marijuana smoking as self-medication and compulsive hot showers for symptom relief. She was admitted for oral intake intolerance, concerning for cannabis hyperemesis syndrome. Her history demonstrated multiple admission for cannabis hyperemesis syndrome during which she demonstrated a leukocytosis which improved with abstinence of marijuana. Her prior hematology workup was unremarkable. Upon admission, vital signs and physical exam were normal. Labs were significant for a neutrophil predominant (77.2%) leukocytosis (WBC: 26.2). The infectious workup including chest x-ray, urinalysis, blood cultures and inflammatory markers were unremarkable. Peripheral smear revealed a neutrophilic leukocytosis without blasts or immature cells attributable to inflammation. Off antibiotics her leukocytosis improved, her recovery was uneventful, and was discharged home. Conclusion: A neutrophil predominant leukocytosis can relate to heavy marijuana smoke inhalation. It has been suggested that pro-inflammatory chemicals and systemic inflammation generated from smoking marijuana cause these hematologic changes. Our case emphasizes considering heavy cannabis use among the differential for leukocytosis and recommending cannabis abstinence once other etiologies are ruled out

Rational Design of Pore Size and Functionality in a Series of Isoreticular Zwitterionic Metal-Organic Frameworks

The isoreticular expansion and functionalization of charged-polarized porosity has been systematically explored by the rational design of 11 isostructural zwitterionic metal-organic frameworks (ZW-MOFs). This extended series of general structural composition {[M3F(L1)3(L2)1.5]·guests}n was prepared by employing the solvothermal reaction of Co and Ni tetrafluoroborates with a binary ligand system composed of zwitterionic pyridinium derivatives and traditional functionalized ditopic carboxylate auxiliary ligands (HL1·Cl = 1-(4-carboxyphenyl)-4,4′-bipyridinium chloride, Hcpb·Cl; or 1-(4-carboxyphenyl-3-hydroxyphenyl)-4,4′-bipyridinium chloride, Hchpb·Cl; and H2L2 = benzene-1,4-dicarboxylic acid, H2bdc; 2-aminobenzene-1,4-dicarboxylic acid, H2abdc; 2,5-dihydroxy-1,4-benzenedicarboxylic acid, H2dhbdc; biphenyl-4,4′-dicarboxylic acid, H2bpdc; or stilbene-4,4′-dicarboxylic acid, H2sdc). Single-crystal structure analyses revealed cubic crystal symmetry (I-43m, a = 31-36 Å) with a 3D pore system of significant void space (73-81%). The pore system features three types of pores being systematically tunable in size ranging from 17.4 to 18.8 Å (pore I), 8.2 to 12.8 Å (pore II), and 4.8 to 10.4 Å (pore III) by the choice of auxiliary ligands. All members of this series have noninterpenetrating structures and exhibit robust architectures, as evidenced by their permanent porosity and high thermal stability (up to 300 °C). The structural integrity and specific surface areas could be systematically optimized using supercritical CO2 exchange methods for framework activation resulting in BET surface areas ranging from 1250 to 2250 m2/g. Most interestingly, as a structural landmark, we found the pore surfaces lined with charge gradients employed by the pyridinium ligands. This key feature results in significant adsorption of carbon dioxide and methane which is attributed to polarization effects. With this contribution we pioneer the reticulation of pyridinium building blocks into extended zwitterionic networks in which specific properties can be targeted

Developing an immunocompetent mouse model of renal cell carcinoma bone metastasis

https://openworks.mdanderson.org/sumexp23/1095/thumbnail.jp

A Systematic Literature Review of the Humanistic Burden of COPD

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, causing substantial economic and social burden. Objective: This review assessed the patient-reported humanistic burden associated with moderate to very severe COPD, specifically the impact on health-related quality of life (HRQoL), symptoms, limitations in daily life, and emotional implications, through the use of HRQoL instruments. Methods: A systematic review was conducted to retrieve relevant clinical data from published literature using a representative sample of countries where healthcare systems provide wide availability of COPD medications and/or universal coverage includes respiratory medicines (Australia, Canada, China, France, Germany, Italy, Spain, the UK, and the USA). The primary inclusion criteria were patients with moderate to very severe COPD. HRQoL was quantified with non-disease-specific and disease-specific questionnaires. Results: In total, 82 studies from 95 publications presented HRQoL data from patients with moderate to very severe COPD. Patient-reported HRQoL declined with worsening airflow limitation, advancing GOLD group, and increasing exacerbation frequency. Both increasing frequency of hospitalization for COPD exacerbations and recurrent hospitalization adversely impacted HRQoL. Comorbidity incidence was higher in patients with increased airflow limitation. It was associated with a further decline in HRQoL and increased depression and anxiety, particularly as disease-associated pain worsened. Physical activity improved HRQoL over time. Conclusion: This review highlighted the impact of exacerbations and associated hospitalizations on the humanistic burden of COPD. These findings underline the importance of managing COPD actively, including prompt and appropriate use of pharmacological and non-pharmacological therapies that can improve symptoms and reduce the risk of exacerbations, thereby lessening the humanistic burden. Future reviews could consider a broader range of countries and publications to further assess the humanistic impact of COPD in low- and middle-income economies

Understanding the impact of chronic obstructive pulmonary disease exacerbations on patient health and quality of life

Exacerbations of chronic obstructive pulmonary disease (COPD) represent a significant clinical problem, and are associated with decreased lung function, worsening quality of life and decreased physical activity levels, with even a single exacerbation having detrimental effects. The occurrence of COPD exacerbations can also have a considerable impact on healthcare costs and mortality rates, with over one-fifth of patients hospitalized for a COPD exacerbation for the first time dying within one year of discharge. This highlights the need for COPD exacerbations to be a major focus in clinical practice. Furthermore, the substantial effect that COPD exacerbations can have on patient mental health should not be underestimated. Despite their clinical importance, COPD exacerbations are poorly recognized and reported by patients, and improving patient understanding and reporting of exacerbations to ensure prompt treatment may minimize their deleterious effects. Renewed focus on improving current clinical practice with support from evidence-based guidelines is required. This also raises a challenge to payors, healthcare systems and government policies to do more to tackle the considerable outstanding burden of COPD exacerbations

Actinomycosis of the parotid masquerading as malignant neoplasm.

BACKGROUND: Primary actinomycosis of the parotid gland is of rare occurrence and can mimic a malignant neoplasm both clinically as well as radiologically. CASE PRESENTATION: We present here a case of primary actinomycosis of the parotid gland presenting with a parotid mass lesion with erosion of skull bones. CONCLUSIONS: Clinical presentation of cervico-facial actinomycosis is characterized by the presence of a suppurative or indurative mass with discharging sinuses. The lesion demonstrates characteristic features on fine needle aspiration cytology and histology, however at times the findings are equivocal

Evidence for Two Modes of Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia in Human Colon Cancer Cells

Colorectal cancer is the third leading cause of cancer-related mortality in the world-- the main cause of death from colorectal cancer is hepatic metastases, which can be treated with isolated hepatic perfusion (IHP). Searching for the most clinically relevant approaches for treating colorectal metastatic disease by isolated hepatic perfusion (IHP), we developed the application of oxaliplatin concomitantly with hyperthermia and humanized death receptor 4 (DR4) antibody mapatumumab (Mapa), and investigated the molecular mechanisms of this multimodality treatment in human colon cancer cell lines CX-1 and HCT116 as well as human colon cancer stem cells Tu-12, Tu-21 and Tu-22. We showed here, in this study, that the synergistic effect of the multimodality treatment-induced apoptosis was caspase dependent and activated death signaling via both the extrinsic apoptotic pathway and the intrinsic pathway. Death signaling was activated by c-Jun N-terminal kinase (JNK) signaling which led to Bcl-xL phosphorylation at serine 62, decreasing the anti-apoptotic activity of Bcl-xL, which contributed to the intrinsic pathway. The downregulation of cellular FLICE inhibitory protein long isoform (c-FLIPL) in the extrinsic pathway was accomplished through ubiquitination at lysine residue (K) 195 and protein synthesis inhibition. Overexpression of c-FLIPL mutant (K195R) and Bcl-xL mutant (S62A) completely abrogated the synergistic effect. The successful outcome of this study supports the application of multimodality strategy to patients with colorectal hepatic metastases who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway. © 2013 Song et al

Benznidazole biotransformation and multiple targets in <i>Trypanosoma</i> cruzi revealed by metabolomics

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methodology/Principal findings&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Parasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions/significance&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Our data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi

Metallation and mismetallation of iron and manganese proteins in vitro and in vivo: the class I ribonucleotide reductases as a case study

How cells ensure correct metallation of a given protein and whether a degree of promiscuity in metal binding has evolved are largely unanswered questions. In a classic case, iron- and manganese-dependent superoxide dismutases (SODs) catalyze the disproportionation of superoxide using highly similar protein scaffolds and nearly identical active sites. However, most of these enzymes are active with only one metal, although both metals can bind in vitro and in vivo. Iron(II) and manganese(II) bind weakly to most proteins and possess similar coordination preferences. Their distinct redox properties suggest that they are unlikely to be interchangeable in biological systems except when they function in Lewis acid catalytic roles, yet recent work suggests this is not always the case. This review summarizes the diversity of ways in which iron and manganese are substituted in similar or identical protein frameworks. As models, we discuss (1) enzymes, such as epimerases, thought to use Fe[superscript II] as a Lewis acid under normal growth conditions but which switch to Mn[superscript II] under oxidative stress; (2) extradiol dioxygenases, which have been found to use both Fe[superscript II] and Mn[superscript II], the redox role of which in catalysis remains to be elucidated; (3) SODs, which use redox chemistry and are generally metal-specific; and (4) the class I ribonucleotide reductases (RNRs), which have evolved unique biosynthetic pathways to control metallation. The primary focus is the class Ib RNRs, which can catalyze formation of a stable radical on a tyrosine residue in their β2 subunits using either a di-iron or a recently characterized dimanganese cofactor. The physiological roles of enzymes that can switch between iron and manganese cofactors are discussed, as are insights obtained from the studies of many groups regarding iron and manganese homeostasis and the divergent and convergent strategies organisms use for control of protein metallation. We propose that, in many of the systems discussed, “discrimination” between metals is not performed by the protein itself, but it is instead determined by the environment in which the protein is expressed.National Institutes of Health (U.S.) (Grant GM81393

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD