Osteoporosis: Common Questions and Answers.

Osteoporosis affects 10.2% of adults older than 50 years and is expected to increase to 13.6% by 2030. Osteoporotic fractures, specifically hip fractures, significantly affect morbidity, mortality, and quality of life. Screening for osteoporosis with dual energy x-ray absorptiometry should be considered for all women 65 years and older or women who are postmenopausal with clinical risk factors. The Bone Health and Osteoporosis Foundation recommends screening men 70 years and older and men with clinical risk factors; however, the U.S. Preventive Services Task Force did not find sufficient evidence to support routine screening in men. Osteoporosis can be diagnosed by a T-score of -2.5 or less or the presence of a fragility fracture. All patients with osteoporosis should be counseled on weight-bearing exercise, smoking cessation, moderation of alcohol intake, and calcium and vita-min D supplementation. Treatment of osteoporosis is influenced by the patient's fracture risk, the effectiveness of fracture risk reduction, and medication safety. Patients at high risk of fracture should consider treatment with antiresorptive therapy, including bisphosphonates and denosumab. Anabolic agents such as teriparatide, abaloparatide, and romosozumab should be considered for patients at very high risk or with previous vertebral fractures.

Initiation of fatty acid biosynthesis in Pseudomonas putida KT2440.

Deciphering the mechanisms of bacterial fatty acid biosynthesis is crucial for both the engineering of bacterial hosts to produce fatty acid-derived molecules and the development of new antibiotics. However, gaps in our understanding of the initiation of fatty acid biosynthesis remain. Here, we demonstrate that the industrially relevant microbe Pseudomonas putida KT2440 contains three distinct pathways to initiate fatty acid biosynthesis. The first two routes employ conventional ß-ketoacyl-ACP synthase III enzymes, FabH1 and FabH2, that accept short- and medium-chain-length acyl-CoAs, respectively. The third route utilizes a malonyl-ACP decarboxylase enzyme, MadB. A combination of exhaustive in vivo alanine-scanning mutagenesis, in vitro biochemical characterization, X-ray crystallography, and computational modeling elucidate the presumptive mechanism of malonyl-ACP decarboxylation via MadB. Given that functional homologs of MadB are widespread throughout domain Bacteria, this ubiquitous alternative fatty acid initiation pathway provides new opportunities to target a range of biotechnology and biomedical applications.

Changes of Fusarium oxysporum f.sp. lactucae levels and soil microbial community during soil biosolarization using chitin as soil amendment.

Regulatory pressure along with environmental and human health concerns drive the development of soil fumigation alternatives such as soil biosolarization (SBS). SBS involves tarping soil that is at field capacity with a transparent film following amendment with certain organic materials. Heating via the greenhouse effect results in an increase of the soil temperature. The organic amendments can promote microbial activity that can enhance pest inactivation by depleting oxygen, producing biopesticidal fermentation products, and competing with pests. The properties of the organic amendments can heavily influence the type and magnitude of these effects. This study evaluated the viability of chitin as a novel SBS soil amendment to influence soil fungal and bacterial microbial communities, including control of the plant pathogen Fusarium oxysporum f.sp. lactucae (FOL). Changes to FOL and the broader soil microbiota were monitored in response to biosolarization using 0.1% (by dry weight) amendment with chitin (Rootguard). FOL suppression was only observed in chitin amended soils that were incubated at room temperature, not under solarized conditions. Conversely, it decreased solarization efficacy in the upper (0-10 cm) soil layer. The presence of chitin also showed increase in FOL under anaerobic and fluctuating temperature regime conditions. Biosolarization with chitin amendment did exhibit an impact on the overall soil microbial community. The fungal genus Mortierella and the bacterial family Chitinophagaceae were consistently enriched in biosolarized soils with chitin amendment. This study showed low potential FOL suppression due chitin amendment at the studied levels. However, chitin amendment showed a higher impact on the fungal community than the bacterial community. The impact of these microbial changes on crop protection and yields need to be studied in the long-term.

Oncologic Emergencies: Recognition and Initial Management.

Most oncologic emergencies can be classified as metabolic, hematologic, structural, or treatment related. Tumor lysis syndrome is a metabolic emergency that presents as severe electrolyte abnormalities. Stabilization is focused on vigorous rehydration, maintaining urine output, and lowering uric acid levels. Hypercalcemia of malignancy, which is associated with poor outcomes, is treated with aggressive rehydration, intravenous bisphosphonates, and subspecialty consultation. Syndrome of inappropriate antidiuretic hormone should be suspected if a patient with cancer has hyponatremia. This metabolic condition is treated with fluid restriction or hypertonic saline, depending on the speed of development. Febrile neutropenia is one of the most common complications related to cancer treatment, particularly chemotherapy. It usually requires inpatient therapy with rapid administration of empiric antibiotics. Hyperviscosity syndrome may present as spontaneous bleeding and neurologic deficits, and is usually associated with Waldenström macroglobulinemia. Treatment includes plasmapheresis followed by targeted chemotherapy. Structural oncologic emergencies are caused by direct compression of nontumor structures by metastatic disease. Superior vena cava syndrome presents as facial edema with development of collateral venous circulation. Intravascular stenting leads to superior patient outcomes and is used in addition to oncology-directed chemotherapy and radiation therapy. Malignant epidural spinal cord compression is managed in conjunction with neurosurgery, but it is classically treated using steroids and/or surgery and radiation therapy. Malignant pericardial effusion may be treated with pericardiocentesis or a more permanent surgical intervention. Complications of cancer treatment are becoming more varied because of the use of standard and newer immunologic therapies. Palliative care is increasingly appropriate as a part of the team approach for treating patients with cancer.

Effect of management of organic wastes on inactivation of Brassica nigra and Fusarium oxysporum f.sp. lactucae using soil biosolarization.

BACKGROUND: Soil biosolarization is a promising alternative to conventional fumigation. Volatile fatty acids (VFAs) produced in the soil through fermentation of amended organic matter can affect pest inactivation during biosolarization. The objective was to determine how soil amended with organic wastes that were partially stabilized through either composting or anaerobic digestion affected the inactivation of Brassica nigra (BN; a weed) and Fusarium oxysporum f. sp. lactucae (FOL; a phytopathogenic fungus). RESULTS: The mortality of BN seeds in the biosolarized soil was 12% higher than in the solarized soil, although this difference was not significant. However, a significant correlation between BN mortality and VFA accumulation was observed. The number of FOL colony-forming units (CFU) in solarized samples at 5 cm was 34 CFU g-1 of soil, whereas in the biosolarized samples levels were below the limit of quantification. At 15 cm, these levels were 100 CFU g-1 for solarized samples and < 50 CFU g-1 of soil for the biosolarized samples. Amendment addition positively affected the organic matter and potassium content after the solarization process. CONCLUSION: The organic waste stabilization method can impact downstream biosolarization performance and final pest inactivation levels. This study suggests that organic waste management practices can be leveraged to improve pest control and soil quality. © 2018 Society of Chemical Industry.

Expression of TIA1 and PAX5 in Classical Hodgkin Lymphoma at Initial Diagnosis May Predict Clinical Outcome.

Although the expression of T-cell antigens and proteins associated with tumor-infiltrating T-lymphocytes (TILs), regulatory T cells (T-regs), and B-cell development have been evaluated in classical Hodgkin lymphoma (cHL), few studies correlate these proteins' expression patterns with clinical outcome. The purpose of this study was to evaluate proteins expressed in the Reed-Sternberg cells (RSCs) and TILs of cHLs at initial diagnosis to determine their prognostic significance. The expression of 12 proteins in RSCs and TILs from 88 diagnostic cHL biopsies was quantitated and correlated to overall survival (OS) and progression-free survival (PFS). CD2, CD3, CD4, CD5, CD7, CD25, PD1, TIA1, MUM1, and ZAP70 expression in RSCs did not correlate with OS or PFS, nor did programmed death 1 (PD1) expression in TILs. High numbers of TIA1-positive TILs (≥50%) correlated with OS (P=0.027), but not PFS (P=0.993) in univariate analysis. Expression of CD2, CD3, CD4, CD5, and/or TIA1 (6%) in RSCs was associated with lymphocyte-rich/mixed-cellularity subtype (P=0.032). High International Prognostic Score (IPS; P=0.036), and high stage (P=0.046) were independent predictors of worse PFS in univariate analysis. Low IPS (P=0.003) and nodular sclerosing subtype (P=0.022) were associated with better OS in univariate analysis. Only the IPS predicted OS in multivariate (P=0.009) analysis. High TIA1+ TILs correlated with worse clinical outcomes for cHLs, as did PAX5-RSCs (P=0.024), although only 2/74 cases were shown to be negative for this marker, suggesting that the tumor microenvironment and a transcription factor crucial for B-cell development are critical biological determinants of the disease course.

Respiratory and neurological disease in rabbits experimentally infected with equid herpesvirus 1.

Equid herpesvirus type 1 (EHV-1) is an important pathogen of horses worldwide, associated with respiratory, reproductive and/or neurological disease. A mouse model for EHV-1 infection has been established but fails to reproduce some important aspects of the viral pathogenesis. Then, we investigated the susceptibility of rabbits to EHV-1 aiming at proposing this species as an alternative model for EHV-1 infection. Weanling rabbits inoculated intranasal with EHV-1 Kentucky D (10(7) TCID50/animal) shed virus in nasal secretions up to day 8-10 post-inoculation (pi), presented viremia up to day 14 pi and seroconverted to EHV-1 (virus neutralizing titers 4 to 64). Most rabbits (75%) developed respiratory disease, characterized by serous to hemorrhagic nasal discharge and mild to severe dyspnea. Some animals (20%) presented neurological signs as circling, bruxism and opisthotonus. Six animals died during acute disease (days 3-6); infectious virus and/or viral DNA were detected in the lungs, trigeminal ganglia (TG), olfactory bulbs (OBs) and cerebral cortex/brain (CC). Histological examination showed necrohemorrhagic, multifocal to coalescent bronchointerstitial pneumonia and diffuse alveolar edema. In two rabbits euthanized at day 50 pi, latent EHV-1 DNA was detected in the OBs. Dexamethasone administration at day 50 pi resulted in virus reactivation, demonstrated by virus shedding, viremia, clinical signs, and increase in VN titers and/or by detection of virus DNA in lungs, OBs, TGs and/or CC. These results demonstrate that rabbits are susceptible to EHV-1 infection and develop respiratory and neurological signs upon experimental inoculation. Thus, rabbits may be used to study selected aspects of EHV-1 biology and pathogenesis, extending and complementing the mouse model.

CD163 immunohistochemistry is superior to CD68 in predicting outcome in classical Hodgkin lymphoma.

OBJECTIVES: In recent years, research has increasingly focused on the microenvironment of classical Hodgkin lymphoma (CHL) as a predictor of treatment outcome. The focus of this study was to assess the interobserver reproducibility in interpreting macrophage-associated immunohistochemistry (IHC) for CD68 and CD163 in a retrospective cohort of 88 patients with CHL. METHODS: Staining results were correlated with clinical outcome in all patients and those with a high international prognostic score (IPS). RESULTS: The intraclass correlation (ICC) for the five hematopathologists interpreting the IHC was stronger for CD163 (0.70) than for CD68 (0.50). Using a cutoff of 25% mean macrophage reactivity and including all patients, a statistically significant difference in overall survival (OS) was seen only for CD163 (P = .0006) and not for CD68 (P = .414). Patients with a mean CD163 reactivity of 25% or more had a median OS of 71 months vs 101 months for patients with less than 25% reactivity. CD163 retained statistical significance in multivariate analysis. In patients with advanced-stage CHL with high IPS, OS was also significantly worse for those with a mean CD163 reactivity of 25% or higher. CONCLUSIONS: Our study confirms previous reports of a prognostic role of tumor-infiltrating macrophages in CHL, but only for CD163. Although most of the literature supports an increasing role of macrophage IHC as a predictor of clinical outcome, successful clinical translation will require a standardized method and reporting system.

Rituximab is associated with improved survival in Burkitt lymphoma: a retrospective analysis from two US academic medical centers.

BACKGROUND: Burkitt lymphoma (BL) is a rare, highly aggressive B-cell malignancy treated most successfully with brief-duration, high-intensity chemotherapeutic regimens. The benefit of the addition of rituximab to these regimens remains uncertain. We sought to examine the effectiveness of chemotherapy with and without rituximab in patients with BL. METHODS: This study is a retrospective cohort study of all adult patients with BL diagnosed and treated with modern, dose-intense chemotherapeutic regimens from 1998-2008 at two tertiary care institutions. All cases were confirmed by application of WHO 2008 criteria by hematopathologists. Medical records were reviewed for patient-, disease-, and treatment- related factors as well as treatment response and survival. Factors associated with survival were analyzed using Cox proportional hazards modeling. RESULTS: A total of 35 patients were analyzed: 18 patients received rituximab with chemotherapy (R-chemo) and 17 received chemotherapy (chemo) alone. The median age was 42 (range 20-74 years); 57% were male; 71% had Ann Arbor Stage IV disease; 33% had central nervous system involvement; 78% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. R-chemo was associated with significantly longer overall survival (OS) than chemo alone (5-year OS 70% and 29%, respectively, p = 0.040). On multivariate regression analysis, poor performance status and central nervous system involvement were associated with poorer survival. CONCLUSIONS: The addition of rituximab to chemotherapy was associated with improved OS in patients with Burkitt lymphoma. Poor performance status and central nervous system involvement were prognostically significant on multivariate analysis.

Ulysses: the effectiveness of a multidisciplinary cognitive behavioural pain management programme-an 8-year review.

OBJECTIVES: To characterise a cohort of patients with chronic pain registered to the Ulysses cognitive behavioural pain management programme (CBT-PMP) and to evaluate the effectiveness of the CBT-PMP 6 months post-discharge. METHODS: A review of patients referred to the Ulysses CBT-PMP from 2002 to 2010 was undertaken. The profile of patients was established. Domains measured included pain, physical and psychological function. Relationships between these factors were explored. Clinically significant changes in outcome measures were established at the 6-month follow-up. RESULTS: In total 553 patients registered to the CBT-PMP, pre-post data were available for 91 % of patients and 52 % at 6 months. The majority of patients were female and aged between 40 and 50 years. Most patients had significant psychological morbidity (76 % depression, 84.5 % anxiety), moderate reports of pain [numerical rating scale, mean (SD) 6.0 (2.2)], and low levels of functional activity. At 6 months follow-up, statistically significant positive findings for physical and psychological outcome measures are supplemented by results showing their clinical significance. With regard to psychological function, a clinically significant change (depending on outcome measure) was shown between 1 in 2 and 1 in 10 patients. Improvements in physical function were lower with rates of 1 in 4 to 1 in 14 reporting significant gains. CONCLUSION: The effectiveness of the Ulysses CBT-PMP is established with measures of clinically significant change for physical and psychological outcomes contributing to the evidence for this novel approach of analysis. Future research determining benchmarks for CBT-PMP outcomes will assist clinicians in monitoring and enhancing patient's progress in clinical practice.

Brentuximab vedotin and crizotinib in anaplastic large-cell lymphoma.

Systemic anaplastic large-cell lymphoma (ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. Anaplastic large-cell lymphoma cells express the surface antigen CD30, and more than half express the anaplastic lymphoma kinase (ALK) protein. These 2 proteins provide unique therapeutic targets in ALCL. Remission rates in ALCL with combination chemotherapy are approximately 80%, but relapse after first-line therapy is common. Brentuximab vedotin is a US Food and Drug Administration-approved, antibody-drug conjugate that combines an anti-CD30 antibody with monomethylauristatin E, a potent antimicrotubule agent. Response rates to brentuximab vedotin in patients with relapsed/refractory ALK and ALK ALCL have exceeded 80% with frequent complete responses and a median duration of response greater than 1 year. Brentuximab vedotin in combination with chemotherapy is being explored as a first-line therapy in ALCL. Crizotinib is an inhibitor of ALK tyrosine kinase that has been approved for the treatment of ALK non-small cell lung cancer. Successful treatment of ALK ALCL with crizotinib has been reported in pediatric patients and small case series leading to ongoing trials in relapsed/refractory ALCL. Brentuximab vedotin and crizotinib represent major advances in the treatment of ALK and ALK ALCL and will likely result in marked improvement in prognosis for this subset of aggressive lymphomas.

Brentuximab vedotin for the treatment of CD30+ lymphomas.

Brentuximab vedotin is a novel antibody-drug conjugate consisting of the anti-CD30 antibody cAC10 chemically conjugated to monomethylauristatin E, a potent antimicrotubule agent. Preliminary response rates of 75% in relapsed/refractory Hodgkin's lymphoma and 87% in relapsed/refractory systemic anaplastic large-cell lymphoma were recently reported in large Phase II trials. Brentuximab vedotin is well tolerated with manageable side effects including peripheral sensory neuropathy. This antibody-drug conjugate is currently under investigation in numerous clinical trials, including in combination with front-line chemotherapy for high-risk Hodgkin's lymphoma and in a placebo-controlled, Phase III trial for patients with Hodgkin's lymphoma at high risk for residual disease following autologous stem cell transplant. The impressive response rates and limited toxicity of brentuximab vedotin are very promising for relapsed/refractory patients with few treatment options. In addition, the possibilities for incorporation into front-line therapies for both Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma are intriguing.

Anti-CD30 Antibodies for Hodgkin lymphoma.

Treatment of refractory or relapsed classical Hodgkin lymphoma (HL) remains challenging, but targeted immunotherapy has recently emerged as a potential treatment option for these patients. Although first-generation monoclonal anti-CD30 antibodies proved disappointing, current efforts to modify anti-CD30 antibodies to improve binding of effector cells and enhance activity appears more promising, as does the development of novel antibody-drug conjugates (ADCs). ADCs offer the potential to deliver potent therapies with minimal toxicity. One highly active ADC, brentuximab vedotin (SGN-35), combines an anti-CD30 monoclonal antibody and the antitubulin agent monomethyl auristatin E. Initial phase 1 studies of brentuximab vedotin showed a 52% overall response rate in relapsed HL, with minimal toxicity. This article highlights the development of anti-CD30 antibodies and ADCs for relapsed or refractory classical HL.

Sweet syndrome associated with celiac disease.

Neutrophilic dermatoses are a spectrum of diseases with varying presentations and similar clinical and histologic features. The association of neutrophilic dermatosis with celiac disease has not previously been described. We report a 43-year-old man with a history of diverticulitis who presented with mildly pruritic, ulcerating pustules of the dorsal hands, face, elbow, and neck, clinico-pathologically consistent with the neutrophilic dermatosis Sweet syndrome. Remission was achieved with prednisone taper, dapsone, and a gluten-free diet.

Pulmonary vein isolation and the Cox maze procedure only partially denervate the atrium.

OBJECTIVES: The effects of ablation lines on myocardial innervation and response to autonomic stimuli are unclear. This study examined the effects of radiofrequency ablation on atrial autonomic innervation and compared pulmonary vein isolation and the biatrial Cox maze procedure. METHODS: In 12 acute canines right and left vagosympathetic trunks and right and left stellate ganglia were isolated. Each nerve was stimulated before bipolar ablation, after pulmonary vein isolation, and after the Cox maze procedure. Nadolol (n = 6) and atropine (n = 6) were administered to block sympathetic and parasympathetic responses, respectively. Changes in heart rate and atrioventricular interval were compared. Changes in QRST area relative to an isoelectric baseline (index of local innervation) were calculated. RESULTS: Sympathetic stimulation of each nerve and parasympathetic stimulation of the vagosympathetic trunks caused significant changes in heart rate and atrioventricular interval. After pulmonary vein isolation, the effect of 33% of the nerves on heart rate changes was eliminated. The Cox maze procedure eliminated right stellate sympathetic effects on heart rate. Fifty percent of the nerves caused heart rate changes after the Cox maze procedure. There was no significant effect of either lesion set on atrioventricular interval changes. Stimulation of 50% of nerves after pulmonary vein isolation produced local area changes significantly different from control area. After the Cox maze procedure, a different 50% of the nerves produced local changes different from those seen after pulmonary vein isolation. CONCLUSIONS: Surgical ablation procedures disrupted innervation, affecting heart rate but not atrioventricular interval. Autonomic innervation affecting the atria was changed by pulmonary vein isolation and additionally by the Cox maze procedure. Residual autonomic effects were present even after the complete Cox maze procedure.

Longterm changes in creatinine clearance after laparoscopic renal surgery.

BACKGROUND: Controversy exists about the impact of ischemia on renal function. We evaluated the creatinine clearance of patients having undergone laparoscopic renal extirpative and ablative surgery. STUDY DESIGN: The records of patients undergoing laparoscopic procedures for renal masses from February 2000 to March 2004 were examined. Creatinine clearance (CrCl) for each patient was determined using the Cockcroft-Gault equation and ideal body weight. We compared CrCl changes of patients undergoing laparoscopic partial nephrectomy (without renal ischemia [LPN-none], with warm ischemia [LPN-warm], and with cold ischemia [LPN-cold]) with patients undergoing laparoscopic radical nephrectomy (LRN) and laparoscopic cryoablation. Patients predisposed to medical renal disease were substratified and evaluated. RESULTS: All patients who underwent LRN or LPN-warm sustained a significant drop in CrCl on the first postoperative day, compared with patients who had LPN without ischemia or cryoablation (p < 0.01). The CrCl decrease correlated directly with warm ischemia time. Six months postoperatively, CrCl changes were no longer significant. Patients with medical renal disease risk factors were more likely to sustain longterm (1 year postoperatively) renal damage if they had renal ischemia, trending toward statistical significance. CONCLUSIONS: Ischemia causes acute renal damage, which is apparently reversible in patients without evidence of medical renal disease. Patients with known medical renal disease have substantial longterm changes in renal function associated with unilateral renal ischemia. Considering the insensitivity of creatinine-based renal function metrics, only eliminating ischemic time will realize the goal of maximal nephron preservation, particularly in patients with preexisting medical renal disease.

Alteration in irrigant flow and deflection of flexible ureteroscopes with nitinol baskets.

BACKGROUND AND PURPOSE: Introduction of an instrument into the working channel of ureteroscopes adversely affects flow and deflection. We evaluated the alterations in ureteroscope channel flow and deflection caused by available Nitinol(R) baskets. MATERIALS AND METHODS: We compared the effects of 11 Nitinol baskets on irrigation flow and deflection of three flexible ureteroscopes (Olympus P3, ACMI DUR8, and ACMI DUR8 Elite). ANOVA was used to compare the loss of flow and deflection for each basket, with P values adjusted for multiple comparisons by the Tukey method. RESULTS: Ureteroscope flow and deflection were progressively adversely affected by all baskets as their diameter increased. The average baseline irrigant flow (46.6 mL/min) was decreased significantly: by 78.5% (to 9.9 mL/min), with the smaller baskets (Microvasive 1.9F and Cook 2.2F) and by 99.1% (to 0.4 mL/min) with the larger baskets (ACMI 3.0F and Microvasive 3.0F). Similarly, the mean baseline upward deflection (162 degrees) decreased by 2 degrees (1.2%) for the Cook 2.4F N-Compass and by 20 degrees (12.3%) for the ACMI 3.0F. Loss of downward deflection from baseline (170 degrees) ranged from 6 degrees (3.5%) for the Microvasive 1.9F to 17 degrees (10%) for the Microvasive 2.6F grasping forceps. The least deterioration in flow and deflection occurred with the two smallest baskets (Microvasive 1.9F and Cook 2.2F). CONCLUSION: Ureteroscope irrigation flow and deflection deteriorate progressively with larger-caliber Nitinol baskets. The Microvasive 1.9F and Cook 2.2F baskets resulted in the least deterioration of irrigation and deflection metrics. However, basket size is not the only factor responsible for changes in flow and ureteroscope deflection.