Modern trends in minimally invasive versus open hepatectomy for colorectal liver metastasis: an analysis of ACS-NSQIP.

BACKGROUND: Surgical resection of colorectal liver metastasis (CRLM) provides the best opportunity for prolonged survival. Eligibility for metastasectomy has expanded with technical advancements including parenchymal-sparing hepatectomy (PSH). Meanwhile, enthusiasm for minimally invasive surgery (MIS) has increased, though this approach may be preferentially utilized for technically straightforward cases. The purpose of this study is to characterize modern trends in open versus MIS approaches to partial hepatectomy and anatomic hepatectomy for CRLM within a nationwide cohort. METHODS: The American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) was used to investigate trends in MIS versus open hepatectomy for CRLM from 2015 to 2019. We examined baseline clinicopathologic and disease-related characteristics and compared trends in treatments over the study period. RESULTS: A total of 7457 patients undergoing hepatectomy for CRLM were identified (1367 MIS, 6090 open). Patients had similar clinicopathologic features between the two groups. Patients undergoing MIS resection less frequently received neoadjuvant therapy (51.1% vs 64.0%, p < 0.001) or concurrent intraoperative ablation (15.0% vs 21.3%, p < 0.001). Patients with tumors < 2 cm (34.9% vs 26.8%, p < 0.001) or only one to two tumors (82.8% vs 65.0%, p < 0.001) more commonly underwent MIS. MIS and open partial hepatectomies both significantly increased over the study period, but open partial hepatectomy increased at a greater rate than MIS (p < 0.001). Rates of anatomic resections have remained the same, with a greater proportion performed using an open approach (34.9% vs 16.4%, p < 0.001). Rates of operations consisting of > 1 concurrent partial hepatectomy are stable, but significantly more likely to be performed open (p < 0.001). CONCLUSIONS: Hepatectomy for CRLM has increased from a rise in partial hepatectomy, potentially translating to increased use of PSH. Current trends suggest MIS approaches appear to be increasing, but selectively implemented for patients with less technically demanding disease characteristics. Educational efforts should be directed towards increased dissemination of parenchymal-sparing MIS techniques for more complex resections.

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 µg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.

Impact of 5 fluorouracil chemotherapy on gut inflammation, functional parameters, and gut microbiota.

Emerging evidence suggests that gut microbiota may influence the response to chemotherapy. We sought to characterize the effects of 5 fluorouracil (5FU) chemotherapy on colon inflammation and functional measures in colorectal cancer (CRC) and to further determine whether gut microbiota can influence this response. 50 C57BL/6 were randomized into four groups; Control + Vehicle (n = 10), Control + 5FU (n = 10), AOM/DSS + Vehicle (n = 15), and AOM/DSS + 5FU (n = 15). CRC was induced chemically by a single 10 mg/kg injection of azoxymethane (AOM) followed by two cycles (2% and 1%) of dextran sodium sulfate (DSS). Mice were then treated with 3 cycles of vehicle or 5FU (cycle 1: 40 mg/kg, cycle 2 + 3: 20 mg/kg). Functional tests (grip strength and run-to-fatigue) were performed prior to 5FU treatment (baseline) and at the completion of the second cycle of 5FU. Following the third 5FU cycle, mice were euthanized and the colon was evaluated for expression of inflammatory genes using RT-qPCR and stool samples were profiled using 16S rRNA sequencing. A second experiment used fecal microbiota transplantation from 5FU treated mice to control mice (n = 10-15/group) to determine whether 5FU associated changes in the microbiota could influence functional measures and colon inflammation. 5FU reduced grip strength (p < 0.05) and caused a trending decrease in run-to-fatigue performance in cancer mice (p = 0.06). Select intestinal inflammatory genes were significantly elevated with 5FU treatment and this was further exacerbated with cancer (p < 0.05). Microbiota analysis revealed increased dissimilarity and alterations in bacterial taxonomy in 5FU and AOM/DSS-treated mice (p < 0.05). Fecal transplant from 5FU treated mice reduced functional performance (p < 0.05) and altered select colon inflammatory markers (p < 0.05). This study provides evidence of an effect of 5FU on inflammatory responses and functional measures in a mouse model of CRC and suggests that gut microbes may play a role in some, but not all, 5FU related perturbations.

A systematic surveillance programme for infectious salmon anaemia virus supports its absence in the Pacific Northwest of the United States.

In response to reported findings of infectious salmon anaemia virus (ISAV) in British Columbia (BC), Canada, in 2011, U.S. national, state and tribal fisheries managers and fish health specialists developed and implemented a collaborative ISAV surveillance plan for the Pacific Northwest region of the United States. Accordingly, over a 3-1/2-year period, 4,962 salmonids were sampled and successfully tested by real-time reverse-transcription PCR. The sample set included multiple tissues from free-ranging Pacific salmonids from coastal regions of Alaska and Washington and farmed Atlantic salmon (Salmo salar L.) from Washington, all representing fish exposed to marine environments. The survey design targeted physiologically compromised or moribund animals more vulnerable to infection as well as species considered susceptible to ISAV. Samples were handled with a documented chain of custody and testing protocols, and criteria for interpretation of test results were defined in advance. All 4,962 completed tests were negative for ISAV RNA. Results of this surveillance effort provide sound evidence to support the absence of ISAV in represented populations of free-ranging and marine-farmed salmonids on the northwest coast of the United States.

Health care provider communication training in rural Tanzania empowers HIV-infected patients on antiretroviral therapy to discuss adherence problems.

OBJECTIVES: Self-reported adherence assessment in HIV-infected patients on antiretroviral therapy (ART) is challenging and may overestimate adherence. The aim of this study was to improve the ability of health care providers to elicit patients' reports of nonadherence using a "patient-centred" approach in a rural sub-Saharan African setting. METHODS: A prospective interventional cohort study of HIV-infected patients on ART for ≥ 6 months attending an HIV clinic in rural Tanzania was carried out. The intervention consisted of a 2-day workshop for health care providers on patient-centred communication and the provision of an adherence assessment checklist for use in the consultations. Patients' self-reports of nonadherence (≥ 1 missed ART dose/4 weeks), subtherapeutic plasma ART concentrations (< 2.5th percentile of published population-based pharmacokinetic models), and virological and immunological failure according to the World Health Organization definition were assessed before and after (1-3 and 6-9 months after) the intervention. RESULTS: Before the intervention, only 3.3% of 299 patients included in the study reported nonadherence. Subtherapeutic plasma ART drug concentrations and virological and immunological failure were recorded in 6.5%, 7.7% and 14.5% of the patients, respectively. Two months after the intervention, health care providers detected significantly more patients reporting nonadherence compared with baseline (10.7 vs. 3.3%, respectively; P < 0.001), decreasing to 5.7% after 6-9 months. A time trend towards higher drug concentrations was observed for efavirenz but not for other drugs. The virological failure rate remained unchanged whereas the immunological failure rate decreased from 14.4 to 8.7% at the last visit (P = 0.002). CONCLUSIONS: Patient-centred communication can successfully be implemented with a simple intervention in rural Africa. It increases the likelihood of HIV-infected patients reporting problems with adherence to ART; however, sustainability remains a challenge.

Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders.

RATIONALE: The mechanisms underlying dyspnea in interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are unknown. OBJECTIVES: To examine whether the relationship between inspiratory neural drive to the diaphragm and exertional dyspnea intensity is different in ILD and COPD, given the marked differences in static respiratory mechanics between these conditions. METHODS: We compared sensory-mechanical relationships in patients with ILD, patients with COPD, and healthy control subjects (n = 16 each) during incremental cycle exercise with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements. MEASUREMENTS AND MAIN RESULTS: In patients with mild to moderate ILD or COPD with similarly reduced inspiratory capacity, the peak oxygen uptake, work rate, and ventilation were lower (P < 0.05) than in healthy control subjects. EMGdi expressed as a percentage of the maximum (EMGdi/EMGdi,max), respiratory effort (esophageal pressure expressed as percentage of the maximum), and ventilation were higher (P < 0.05) at rest and during exercise in both patients with ILD and patients with COPD than in control subjects. Each of these measurements was similar in the ILD and COPD groups. A Vt inflection and critically reduced inspiratory reserve volume occurred at a lower (P < 0.05) ventilation in the ILD and COPD groups than in control subjects. Patients with ILD had greater diaphragmatic activity, whereas patients with COPD had greater expiratory muscle activity. The relationship between dyspnea intensity and EMGdi/EMGdi,max during exercise was similar in all three groups. In ILD and COPD, descriptors alluding to inspiratory difficulty were selected more frequently, with a greater disparity between EMGdi/EMGdi,max and Vt. CONCLUSIONS: Disease-specific differences in mechanics and respiratory muscle activity did not influence the key association between dyspnea intensity and inspiratory neural drive to the diaphragm.

Correlating HIV tropism with immunological response under combination antiretroviral therapy.

OBJECTIVES: A significant percentage of patients infected with HIV-1 experience only suboptimal CD4 cell recovery while treated with combination therapy (cART). It is still unclear whether viral properties such as cell tropism play a major role in this incomplete immune response. This study therefore intended to follow the tropism evolution of the HIV-1 envelope during periods of suppressive cART. METHODS: Viruses from two distinct patient groups, one with good and another one with poor CD4 recovery after 5 years of suppressive cART, were genotypically analysed for viral tropism at baseline and at the end of the study period. RESULTS: Patients with CCR5-tropic CC-motif chemokine receptor 5 viruses at baseline tended to maintain this tropism to the study end. Patients who had a CXCR4-tropic CXC-motif chemokine receptor 4 virus at baseline were overrepresented in the poor CD4 recovery group. Overall, however, the majority of patients presented with CCR5-tropic viruses at follow-up. CONCLUSIONS: Our data lend support to the hypothesis that tropism determination can be used as a parameter for disease progression even if analysed long before the establishment of a poorer immune response. Moreover, the lasting predominating CCR5-tropism during periods of full viral control suggests the involvement of cellular mechanisms that preferentially reduce CXCR4-tropic viruses during cART.

Association of IL-37 gene polymorphisms with susceptibility to tuberculosis in Saudi subjects.

Tuberculosis (TB) is one of the most common infectious diseases worldwide. IL-37, a novel member of the IL-1 family, has anti-inflammatory activity. Various cytokine genes polymorphisms are reportedly associated with susceptibility to TB infection. However, an association between genetic variations in the IL-37 gene and susceptibility to TB infection has not been investigated. The aim of this case-control study was therefore to identify such an association in Saudi subjects, in which five single-nucleotide polymorphisms (SNPs) in the IL-37 gene were assessed. Serum concentrations of IL-37 were evaluated using ELISA, and genetic variants genotyped by multiplex PCR and ligase detection reaction. It was found that the C/C genotype of rs2723176 (-6962 A/C) occurs significantly more frequently in patients with active TB and that the C allele of this SNP is associated with TB. In addition, the C allele of rs2723176 SNP was associated with high circulating concentrations of IL-37. However, the genotype and allele frequency of the other four SNPs (rs3811046, rs3811047, rs2723186 and rs2723187) were not significantly associated with TB infection. In conclusion, the present data suggest that rs2723176 SNP of IL-37 is involved in the development of TB infection. Furthermore, high circulating concentrations of IL-37 may have a negative effect on protective immunity against TB infection.

Characteristics, detection methods and treatment of questionable occlusal carious lesions: findings from the national dental practice-based research network.

Questionable occlusal carious lesions (QOC) can be defined as an occlusal tooth surface with no cavitation and no radiographic radiolucencies, but caries is suspected due to roughness, surface opacities or staining. An earlier analysis of data from this study indicates 1/3 of patients have a QOC. The objective of this report has been to quantify the characteristics of these common lesions, the diagnostic aids used and the treatment of QOC. A total of 82 dentist and hygienist practitioner-investigators from the USA and Denmark in the National Dental Practice-Based Research Network participated. When consenting patients presented with a QOC, information was recorded about the patient, tooth, lesion and treatments. A total of 2,603 QOC from 1,732 patients were analyzed. The lesions were usually associated with a fissure, on molars, and varied from yellow to black in color. Half presented with a chalky luster and had a rough surface when examined with an explorer. There was an association between color and luster: 10% were chalky-light, 47% were shiny-dark and 42% were mixtures. A higher proportion of chalky than of shiny lesions were light (22 vs. 9%; p < 0.001). Lesions light in color were less common in adults than in pediatric patients (9 vs. 32%; p < 0.001). Lesions that were chalky and light were more common among pediatric than among adult patients (22 vs. 6%; p < 0.001). This is the first study to investigate characteristics of QOC in routine clinical practice. Clinicians commonly face this diagnostic uncertainty. Determining the characteristics of these lesions is relevant when making diagnostic and treatment decisions.

A systems biology analysis of the Drosophila phagosome.

Phagocytes have a critical function in remodelling tissues during embryogenesis and thereafter are central effectors of immune defence. During phagocytosis, particles are internalized into 'phagosomes', organelles from which immune processes such as microbial destruction and antigen presentation are initiated. Certain pathogens have evolved mechanisms to evade the immune system and persist undetected within phagocytes, and it is therefore evident that a detailed knowledge of this process is essential to an understanding of many aspects of innate and adaptive immunity. However, despite the crucial role of phagosomes in immunity, their components and organization are not fully defined. Here we present a systems biology analysis of phagosomes isolated from cells derived from the genetically tractable model organism Drosophila melanogaster and address the complex dynamic interactions between proteins within this organelle and their involvement in particle engulfment. Proteomic analysis identified 617 proteins potentially associated with Drosophila phagosomes; these were organized by protein-protein interactions to generate the 'phagosome interactome', a detailed protein-protein interaction network of this subcellular compartment. These networks predicted both the architecture of the phagosome and putative biomodules. The contribution of each protein and complex to bacterial internalization was tested by RNA-mediated interference and identified known components of the phagocytic machinery. In addition, the prediction and validation of regulators of phagocytosis such as the 'exocyst', a macromolecular complex required for exocytosis but not previously implicated in phagocytosis, validates this strategy. In generating this 'systems-based model', we show the power of applying this approach to the study of complex cellular processes and organelles and expect that this detailed model of the phagosome will provide a new framework for studying host-pathogen interactions and innate immunity.

Concentrations of nonesterified fatty acids and glucose in blood of periparturient dairy cows are indicative of pregnancy success at first insemination.

Greater blood concentrations of nonesterified fatty acids (NEFA) and lesser blood concentrations of glucose are indicative of the normal process of nutrient partitioning that occurs in early postpartum dairy cows. The objective was to determine the relationship between blood NEFA and glucose concentrations and subsequent conception at first insemination in postpartum dairy cows. Holstein (n=148) and Guernsey (n=8) dairy cows were blood sampled at approximately d 10, 7, and 3 prepartum, on the day of calving and 3, 7, 14, and 21 d postpartum for measurement of NEFA and glucose concentrations. Serum and plasma were harvested and used for measurement of NEFA and glucose concentrations, respectively. Cows were given a presynchronization treatment (2 injections of PGF(2α) 14 d apart) with the second PGF(2α) injection occurring 14 d before the initiation of the timed AI (TAI) protocol. Blood for determination of progesterone concentrations was collected at each presynchronization injection and at the initiation of the TAI protocol that was used for first insemination (74±7 d postpartum). Cows were considered noncycling if serum progesterone concentrations at the 2 presynchronization PGF(2α) injections (d 37 and 51±7 postpartum) and at the initiation of the TAI protocol (d 65±7 postpartum) were ≤1 ng/mL, and there was no indication of ovulation or presence of a corpus luteum by ultrasound examination at the initiation of the TAI protocol. Pregnancy was determined at 33 d and again at 61 d after first insemination by using ultrasound. Across all days, serum NEFA and plasma glucose concentrations were not different between cows that ovulated before the initiation of the TAI program (cycling) compared with those that did not ovulate (noncycling). Serum NEFA concentrations, however, were less and plasma glucose concentrations were greater during the early postpartum period for cows that subsequently became pregnant at first insemination compared with those that failed to become pregnant. Logistic regressions were used to predict the probability of pregnancy based on NEFA and glucose concentrations from individual days. The prediction with the greatest likelihood ratio was for d 3 postpartum NEFA and glucose concentrations. Nutritional status during the early postpartum period (within 1 wk after calving), as indicated by blood NEFA and glucose concentrations, may affect subsequent fertility by a mechanism that is independent from interval to first ovulation.

Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca2+ fluxes in oxidative cell death.

Oxidative DNA damage to cells activates poly(ADP-ribose)polymerase-1 (PARP-1) and the poly(ADP-ribose) formed is rapidly degraded to ADP-ribose by poly(ADP-ribose)glycohydrolase (PARG). Here we show that PARP-1 and PARG control extracellular Ca(2+) fluxes through melastatin-like transient receptor potential 2 channels (TRPM2) in a cell death signaling pathway. TRPM2 activation accounts for essentially the entire Ca(2+) influx into the cytosol, activating caspases and causing the translocation of apoptosis inducing factor (AIF) from the inner mitochondrial membrane to the nucleus followed by cell death. Abrogation of PARP-1 or PARG function disrupts these signals and reduces cell death. ADP-ribose-loading of cells induces Ca(2+) fluxes in the absence of oxidative damage, suggesting that ADP-ribose is the key metabolite of the PARP-1/PARG system regulating TRPM2. We conclude that PARP-1/PARG control a cell death signal pathway that operates between five different cell compartments and communicates via three types of chemical messengers: a nucleotide, a cation, and proteins.

Effect of partial pressure of CO2 on the production of thermostable alpha-amylase and neutral protease by Bacillus caldolyticus.

Controlling the concentration of dissolved oxygen is a standard feature in aerobic fermentation processes but the measurement of dissolved CO2 concentrations is often neglected in spite of its influence on the cellular metabolism. In this work room air and room air supplemented with 5% and 10% carbon dioxide were used for aeration during the cultivation of the thermophilic microorganism Bacillus caldolyticus (DSM 405) on starch to produce alpha-amylase (E.C. 3.2.1.1) and neutral protease (E.C. 3.4.24.27/28). The increased CO2 concentrations resulted in a 22% raise in activity of secreted alpha-amylase and a 43% raise in protease activity when compared with aeration with un-supplemented room air. There was no effect on the final biomass concentration. Furthermore, the lag-phase of fermentation was reduced by 30%, further increasing the productivity of alpha-amylase production. Determinations of dissolved CO2 in the culture broth were conducted both in situ with a probe as well as using exhaust gas analysis and both the methods of quantification showed good qualitative congruence.

Clinical profile, risk factors and outcomes of ric COVID-19: a retrospective cohort multicentre study in Saudi Arabia.

OBJECTIVE: To describe the risk factors, clinical profile and outcomes of COVID-19 in the paediatric population. DESIGN: Multicentre, retrospective observational study. SETTING: Four tertiary hospitals in Saudi Arabia. PATIENTS: We recruited 390 paediatric patients aged 0-18 years who presented from March to December 2020 and tested positive for COVID-19 on PCR. MAIN OUTCOME MEASURES: We retrospectively analysed medical records for sociodemographics, health indicators, clinical presentations, laboratory findings, clinical complications, and outcomes. RESULTS: The mean participant age was 5.66±4.90 years, and the mean hospital stay was 2.17±3.48 days. Forty patients, mostly school-aged children (16, 40.00%; p=0.005) and children with comorbidities (25, 62.50%; p<0.001), received more than just supportive care. Complications were seen in 15 (3.9%) patients, bacterial infection being the most common (6, 40.00%). Patients presented with dyspnoea (OR 6.89; 95% CI 2.89 to 20.72), abnormal chest radiographs (OR 6.11; 95% CI 1.26 to 29.38), lethargy (OR 9.04; 95% CI 2.91 to 28.06) and elevated ferritin (OR 14.21; 95% CI 4.18 to 48.37) and D-dimer (OR 48.40; 95% CI 14.32 to 163.62), with higher odds of developing complications. The odds of paediatric intensive care unit (ICU) admission were higher for patients with dyspnoea (adjusted OR 4.66; 95% CI 1.24 to 17.50) and elevated white blood cell count (adjusted OR 3.54; 95% CI 1.02 to 12.30). CONCLUSIONS: COVID-19 complications were limited among our patients. However, dyspnoea, abnormal chest radiographs, lethargy and elevated ferritin and D-dimer were associated with an increased risk of complications. Dyspnoea, leucocytosis, comorbidities and abnormal chest radiographs at presentation increased the risk of ICU admission.

Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein.

Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)2-Cys-(X)4-His-(X)4-Cys (CCHC). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapside CCHC zinc fingers are highly conserved among retroviruses. These CCHC domains are required during both the early and late phases of retroviral replication, making them attractive targets for antiviral agents. toward that end, we have identified a number of antiviral chemotypes that electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains. Such nucleocapside inhibitors were directly virucidal by preventing the initiation of reverse transcription and blocked formation of infectious virus from cells through modification of CCHC domains within Gag precursors. Herein we report that azodicarbonamide (ADA) represents a new compound that inhibits HIV-1 and a broad range of retroviruses by targeting the the nucleocapsid CCHC domains. Vandevelde et al. also recently disclosed that ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for advanced AIDS. These studies distinguish ADA as the first known nucleocapsid inhibitor to progress to human trials and provide a lead compound for drug optimization.

[Axonal damage and its significance for the concept of neurodegeneration in multiple sclerosis]. / Die Bedeutung axonaler Pathologie für das Konzept der Neurodegeneration bei der Multiplen Sklerose.

In spite of tremendous scientific effort, the mechanisms underlying multiple sclerosis (MS) still remain to be elucidated. The prevalent pathogenetic concept adheres to the assumption of a strict hierarchical sequence of the triad inflammation, demyelination and axonal damage. However, recent studies have provided evidence that axonal pathology can occur independently of inflammation and demyelination. The present article critically re-evaluates the traditional paradigm of MS pathology. Potential cellular, humoral and metabolic mechanisms of axonal pathology are delineated and the development of isolated axonal damage is assessed. A better understanding of the pathological processes underlying MS is likely to result in an improvement of current therapeutic strategies. These should not only target the inflammatory, but also the neurodegenerative component of the disease.

Relevance of microbial coculture fermentations in biotechnology.

The purpose of this article is to review coculture fermentations in industrial biotechnology. Examples for the advantageous utilization of cocultures instead of single cultivations include the production of bulk chemicals, enzymes, food additives, antimicrobial substances and microbial fuel cells. Coculture fermentations may result in increased yield, improved control of product qualities and the possibility of utilizing cheaper substrates. Cocultivation of different micro-organisms may also help to identify and develop new biotechnological substances. The relevance of coculture fermentations and the potential of improving existing processes as well as the production of new chemical compounds in industrial biotechnology are pointed out here by means of more than 35 examples.

Casein phosphopeptide-amorphous calcium phosphate shows promise for preventing caries.

DATA SOURCES: To find studies to include in the review, searches were made using Biomed Central, Cochrane Oral Health Reviews, Cochrane Library, the Directory of Open Access Journals, PubMed, Science Direct and the Research Findings Electronic Register. STUDY SELECTION: English language clinical trials [randomised clinical trials (RCT) or quasi-RCT; in situ or in vivo] or systematic reviews (with or without meta-analysis) of published trials were selected that reported on the efficacy of phosphopeptide-amorphous calcium phosphate (CPP-ACP) using any mode of delivery. Studies were reviewed and their quality assessed independently. DATA EXTRACTION AND SYNTHESIS: Data was extracted by two reviewers independently. Trials that were considered clinically and methodologically homogenous and that reported on similar outcomes were pooled for meta-analyses. RESULTS: Twelve articles were included of which five in-situ RCT could be pooled for meta-analyses. The pooled in-situ results showed a weighted mean difference (WMD) of the percentage remineralisation scores in favour of chewing gum with 18.8 mg CPP-ACP, compared with chewing gum without CPP-ACP of -8.01 [95% confidence interval (CI), -10.54- -5.48; P 0.00001], and compared with no intervention of -13.56 (95% CI, -16.49- -10.62; P 0.00001). A significantly higher remineralisation effect was also observed after exposure to 10.0 mg CPP-ACP (WMD, -7.75; 95% CI, -9.84- -5.66; P 0.00001). One long-term in vivo RCT (24 months) with a large sample size (N = 2720) found that the odds of a tooth surface's progressing to caries was 18% less in subjects who chewed sugar-free gum containing 54 mg CPP-ACP than in control subjects who chewed gum without CPP-ACP (P 0.03). CONCLUSIONS: Within the limitations of this systematic review with meta-analysis, the results of the clinical in-situ trials indicate a short-term remineralisation effect of CPP-ACP. Additionally, the promising in-vivo RCT results suggest a caries-preventing effect for long-term clinical CPP-ACP use. Further RCT are needed in order to confirm these initial results in vivo.

Virus-induced transformation without cell division.

Interference with the cell cycle by vinblastine sulfate immediately after cells were infected with Rous sarcoma virus had little effect on the a development of two metabolic changes that occur in transformed cells. These results, along with an earlier demonstration of morphological changes developing in infected nondividing cells, demonstrate that the phenotypic development of the malignant state can occur without the intervention of cell divisions after infection by Rous sarcoma virus.

Inhibitors of HIV nucleocapsid protein zinc fingers as candidates for the treatment of AIDS.

Strategies for the treatment of human immunodeficiency virus-type 1 (HIV-1) infection must contend with the obstacle of drug resistance. HIV-1 nucleocapsid protein zinc fingers are prime antiviral targets because they are mutationally intolerant and are required both for acute infection and virion assembly. Nontoxic disulfide-substituted benzamides were identified that attack the zinc fingers, inactivate cell-free virions, inhibit acute and chronic infections, and exhibit broad antiretroviral activity. The compounds were highly synergistic with other antiviral agents, and resistant mutants have not been detected. Zinc finger-reactive compounds may offer an anti-HIV strategy that restricts drug-resistance development.