Methotrexate pneumonitis in a patient with gestational trophoblastic neoplasia.

Methotrexate, an immunomodulatory agent used for a wide variety of indications, can cause pulmonary toxicity in the form of pneumonitis, organising pneumonia, pulmonary fibrosis, pleural effusion, pulmonary infections or lymphoproliferative disease. We report a case of methotrexate pneumonitis in a patient with gestational trophoblastic neoplasia. The diagnosis of methotrexate pneumonitis is challenging, as the signs and symptoms can be caused by intercurrent infection, concomitant medications or an underlying disease condition. A high index of suspicion is required for diagnosis. Management consists of drug discontinuation and steroids in patients with respiratory failure.

Biological Response Modifiers in Rheumatoid Arthritis: Systematic Review and Meta-analysis of Safety.

OBJECTIVE: To analyze available evidence on the safety of different biological response modifiers which are used for a treatment of rheumatoid arthritis (RA). MATERIALS AND METHODS: We searched systematically for randomized controlled clinical trials on treatment of RA with different biological response modifiers, followed by a systematic review with meta-analysis. Trials were searched from MEDLINE and Cochrane Library databases. The following safety parameters reported in the selected trials were analyzed: number of patients suffering any adverse event (AE), withdrawal due to AEs, serious AE (SAEs), infections, serious infections, infusion reactions, injection site reactions, malignancies, and overall mortality. Undesired effects were estimated using combined relative risks (RR) and number needed to harm (NNH). Heterogeneity was evaluated by Cochrane's Q and I2 statistics. RESULTS: According to inclusion criteria, a total of 43 trials (20,504 patients) were included in this study. A total number of AEs were found more with abatacept (RR: 1.05, NNH: 21.93). Withdrawal due to AEs was found with all biologicals, highest with anakinra (RR: 3.48, NNH: 15.70). Patients receiving newer tumor necrosis factor-alpha inhibitors, golimumab, were more likely to develop SAEs (RR: 2.44, NNH: 12.72) and infection (RR: 1.25, NNH: 10.09), and in certolizumab, serious infections (RR: 2.95, NNH: 37.31) were found more. Infusion reaction develops more with rituximab (RR: 1.52, NNH: 8.47). Etanercept showed the highest risk to develop infusion site reaction (RR: 5.33, NNH: 4.65). Biologicals showed no difference to their control counterparts in malignancy and mortality risk. CONCLUSION: This meta-analysis helps to clarify some frequently encountered and unanswered safety questions of different biological response modifiers, a new class of drugs, in the clinical care of RA patients.

ACC deaminase-containing plant growth-promoting rhizobacteria protect Papaver somniferum from downy mildew.

AIMS: The aim of this study was to determine whether ACC (1-aminocyclopropane-1-carboxylic acid) deaminase-containing bacterial treatments could enhance the tolerance of poppy (Papaver somniferum L.) plants against biotic stress of downy mildew caused by Peronospora sp. METHODS AND RESULTS: Three different genotypes of P. somniferum, that is, Sampada, J-16 and I-14 were included in the experiment. The ACC deaminase-containing bacteria Pseudomonas putida (WPTe) reduced the downy mildew disease severity and significantly improved the growth and yield of P. somniferum plants. The chlorophyll content, photosynthetic rate, stomatal conductance and transpiration rate were modulated upon WPTe treatments in the poppy plants. We observed reduced synthesis of ethylene precursor (ACC) and abscisic acid (ABA), and enhanced production of indole acetic acid (IAA) in P. somniferum plants upon WPTe treatments. Moreover, WPTe treatment reduced proline and lipid peroxidation in plant leaves. CONCLUSION: These results highlight that the ACC deaminase-containing plant growth-promoting rhizobacteria (PGPR) enhance the tolerance of P. somniferum plant against downy mildew. SIGNIFICANCE AND IMPACT OF THE STUDY: ACC deaminase-containing PGPR may be used against phytopathogens which apart from protecting the plants from the disease could also be useful in reducing ethylene-induced damages in the event of abiotic stresses.

Efficacy of pectoral nerve block versus thoracic paravertebral block for postoperative analgesia after radical mastectomy: a randomized controlled trial.

BACKGROUND: Pectoral nerve (PecS) block is a recently introduced technique for providing surgical anaesthesia and postoperative analgesia during breast surgery. The present study was planned to compare the efficacy and safety of ultrasound-guided PecS II block with thoracic paravertebral block (TPVB) for postoperative analgesia after modified radical mastectomy. METHODS: Forty adult female patients undergoing radical mastectomy were randomly allocated into two groups. Group 1 patients received a TPVB with ropivacaine 0.5%, 25 ml, whereas Group 2 patents received a PecS II block using same volume of ropivacaine 0.5% before induction of anaesthesia. Patient-controlled morphine analgesia was used for postoperative pain relief. RESULTS: The duration of analgesia was significantly prolonged in patients receiving the PecS II block compared with TPVB [mean (sd), 294.5 (52.76) vs 197.5 (31.35) min in the PecS II and TPVB group, respectively; P<0.0001]. The 24 h morphine consumption was also less in the PecS II block group [mean (sd), 3.90 (0.79) vs 5.30 (0.98) mg in PecS II and TPVB group, respectively; P<0.0001]. Postoperative pain scores were lower in the PecS II group compared with the TVPB group in the initial 2 h after surgery [median (IQR), 2 (2-2.5) vs 4 (3-4) in the Pecs II and TPVB group, respectively; P<0.0001]. Seventeen patients in the PecS II block group had T2 dermatomal spread compared with four patients in the TPVB group (P<0.001). No block-related complication was recorded. CONCLUSIONS: We found that the PecS II block provided superior postoperative analgesia than the TPVB in patients undergoing modified radical mastectomy without causing any adverse effect. CLINICAL TRIAL REGISTRATION: CTRI/2014/06/004692.

Comparison of ultrasound-guided supraclavicular, infraclavicular and below-C6 interscalene brachial plexus block for upper limb surgery: a randomised, observer-blinded study.

This prospective, randomised, observer-blinded study was conducted to compare the ease of performance and surgical effectiveness of interscalene block below the C6 nerve root with supraclavicular and infraclavicular techniques of brachial plexus block for upper arm and forearm surgery. Sixty adult patients of American Society of Anesthesiologists grade 1 to 3, undergoing upper limb surgery, were randomly allocated into three groups. Group SC received supraclavicular blockade, group IC received infraclavicular blockade and Group IS received interscalene blockade. All blocks were guided by ultrasound with nerve stimulator confirmation. The anaesthetic mixture consisted of 0.5 ml/kg of equal volumes of 0.75% ropivacaine and 2% lignocaine-adrenaline. The imaging and block performance time, onset time, success rate, duration of block, and duration of postoperative analgesia were recorded by a blinded observer. The onset time was significantly longer in the interscalene group as compared with supraclavicular and infraclavicular approaches. The imaging time and block performance time were comparable between groups. No significant differences were observed between the three groups in terms of block-related pain scores, success rates, duration of block or of postoperative analgesia. Two patients in the interscalene group developed clinically detectable phrenic nerve palsy. Our findings indicate that, although interscalene block below the C6 nerve root can provide surgical anaesthesia for forearm and hand surgery, it appears to have a longer onset time than supra- and infraclavicular approaches and an unacceptable incidence of phrenic nerve palsy.

Comparison of palonosetron with palonosetron-dexamethasone combination for prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy.

BACKGROUND: This randomized double-blind study was designed to compare palonosetron with palonosetron-dexamethasone combination for prevention of post operative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy. METHODS: Eighty-four adult ASA 1-2 patients were randomly allocated into two groups. Group P patients received 0.075 mg palonosetron and group PD patients received 0.075 mg palonosetron and 8 mg dexamethasone intravenously before induction of anesthesia. Anesthesia was induced with propofol and fentanyl and maintained with N2O-isoflurane in oxygen. All patients received port-site infiltration with bupivacaine and intravenous diclofenac for postoperative analgesia. Metoclopramide was used as rescue antiemetic. Patients were observed for the incidence of PONV and requirement of rescue antiemetic for 48 h after surgery. RESULTS: The complete response rate (no vomiting) was significantly higher in group DP as compared to group P between 0-24 h (P=0.004). 18 (42.9%) patients reported nausea and 14 (33.3%) patients had vomiting in group P while 6 (14.4%) patients had nausea and 5 (11.9%) patients complained of vomiting in group DP during 0-24 h. Two patients in group P reported nausea while none in group PD during 24-48 h. No patient had vomiting in either of the groups between 24-48 h. The requirement of rescue antiemetic was also less in group DP as compared to group P. Patients in group DP required less postoperative analgesia and were more satisfied with PONV treatment than group P patients. CONCLUSION: The palonosetron-dexamethasone combination was more effective as compared to only palonosetron for reducing PONV after laparoscopic cholecystectomy.

Postoperative analgesic effect of intravenous (i.v.) clonidine compared with clonidine administration in wound infiltration for open cholecystectomy.

OBJECTIVES: This randomized double-blind study was designed to compare the postoperative analgesic effect of clonidine administered intravenously or in wound infiltration with bupivacaine. METHODS: Sixty adults of ASA grade I-II undergoing open cholecystectomy were randomly allocated into three groups. Group 1 (control group) patients received wound infiltration with 30 ml of 0.25% bupivacaine at the end of surgery. Group 2 patients received 3 µg kg(-1) clonidine intravenously after resection of gall bladder plus wound infiltration with 30 ml of 0.25% bupivacaine. Group 3 patients received wound infiltration with 3 µg kg(-1) clonidine with 30 ml of 0.25% bupivacaine. A standard general anaesthesia technique was used. Postoperative analgesia was provided with i.v. diclofenac and morphine on demand. Postoperative pain, number of patients requiring rescue analgesia and total morphine consumption during 24 h after operation was recorded. RESULTS: Postoperative morphine consumption was significantly less in patients receiving clonidine by either route when compared with the control group (P<0.0001). All patients in the control group required supplemental morphine, with nine patients in the i.v. clonidine group and 11 patients in the wound infiltration group (P<0.002). Pain scores were lower at rest for 12 h and on cough for 6 h in both clonidine groups when compared with the control group (P<0.01). Patients receiving i.v. clonidine had more hypotension (P<0.01) and sedation (P<0.001) compared with other groups. CONCLUSIONS: Clonidine 3 µg kg(-1) provided effective postoperative analgesia and reduced morphine requirement when administered intravenously or in wound infiltration with bupivacaine. However, the incidence of complications was less with wound infiltration. CLINICAL TRIAL REGISTRY OF INDIA: (www.ctri.nic.in/), registration number CTRI/2012/12/003258.

The analgesic effect of intrathecal dexmedetomidine or clonidine, with bupivacaine, in trauma patients undergoing lower limb surgery: a randomised, double-blind study.

This randomised, double-blind study was designed to compare the duration of analgesia and adverse effects following intrathecal administration of dexmedetomidine or clonidine, both with bupivacaine, in trauma patients. Ninety adult trauma patients of American Society of Anesthesiologists physical status I-II, scheduled for lower limb surgery under subarachnoid block, were randomly allocated to one of three groups. All groups received hyperbaric bupivacaine 0.5% 3 ml, to which was added saline 0.5 ml (Group B): clonidine 50 µg (Group C) or dexmedetomidine 5 µg (Group D). The onset and duration of sensory and motor blockade, severity of postoperative pain, time to first rescue analgesia and total analgesic requirement for 24 hours were noted. There was no significant difference in the onset time of the block but the duration of sensory and motor blockade was prolonged in Groups C and D, compared with Group B. The time to analgesia was significantly prolonged in Group D (824±244 minutes) compared with Group C (678±178 minutes; P=0.01), the latter being longer than Group B (406±119 minutes; P=0.0001). Postoperative pain scores were lower in Groups C and D compared with group b. The requirement for rescue analgesia during the first 24 postoperative hours was significantly less in Groups C and D as compared to Group B (P=0.0001), but comparable between Groups C and D (P=0.203). In conclusion, dexmedetomidine 5 µg added to intrathecal bupivacaine 15 mg produces longer postoperative analgesia than clonidine 50 µg among trauma patients undergoing lower limb surgery.

Physiological and Welfare Consequences of Transport, Relocation, and Acclimatization of Chimpanzees (Pan troglodytes).

Manipulations of the environments of captive nonhuman primates often have welfare consequences to the animals, including behavioral effects, and for certain manipulations, physiological effects as well. The processes of transporting, relocating, and acclimatizing nonhuman primates across facilities represent manipulations that are likely to have welfare, behavioral, and physiological consequences to the relocated animals. Seventy-two chimpanzees were relocated from the Primate Foundation of Arizona (PFA) in Arizona to the Keeling Center (KCCMR) in Texas. Animals were transported for approximately 21 h in single cages in a USDA-approved, climate-controlled trailer. Chimpanzees were weighed, anesthetized, and blood samples were collected 1) immediately prior to departure from PFA, 2) immediately upon arrival at the KCCMR, and 3) at additional time point(s) between 3 and 12 weeks after arrival at the KCCMR. Chimpanzees were quarantined in familiar pairs or social groups for 60-90 days at the KCCMR. Blood samples were analyzed for hematological and clinical chemistry parameters and compared across time points. In addition, samples from a subset of animals were assayed for cell-mediated immune parameters. Comparisons of the data obtained just prior to transport, to the data obtained immediately upon arrival, revealed numerous statistically significant differences in hematological, clinical chemistry, and immunological parameters. Some of these were indicative of stress, and thus, changes in welfare state, although many remained within the published normal ranges for chimpanzees. Additional analyses showed that many of the clinical chemistry values collected 3 to 12 weeks after arrival at the KCCMR had returned to pre-transport values. In contrast, of the cell-mediated immune parameters that were affected by transport and relocation, few had returned to pre-transport levels 8 weeks after transport, and three of the four hematology variables analyzed had not returned to pre-transport levels 12 weeks after transport. Comparisons of body weights before and immediately after transport revealed that animals lost an average of 2.5 kg during the 21-h transport, a statistically significant reduction that some animals never regained. These results demonstrate that transport and relocation affect a variety of physiological parameters with potential welfare implications and that some of these effects last as long as 3 months. These findings have important implications for the welfare and use of recently transported nonhuman primates, especially chimpanzees, in biomedical research. In order to allow animals to adapt to their new surroundings and to prevent unwanted confounds from influencing experiments, sufficient time must be provided after transport for chimpanzees to acclimatize.

Spatial dynamics of meningococcal meningitis in Niger: observed patterns in comparison with measles.

Throughout the African meningitis belt, meningococcal meningitis outbreaks occur only during the dry season. Measles in Niger exhibits similar seasonality, where increased population density during the dry season probably escalates measles transmission. Because meningococcal meningitis and measles are both directly transmitted, we propose that host aggregation also impacts the transmission of meningococcal meningitis. Although climate affects broad meningococcal meningitis seasonality, we focus on the less examined role of human density at a finer spatial scale. By analysing spatial patterns of suspected cases of meningococcal meningitis, we show fewer absences of suspected cases in districts along primary roads, similar to measles fadeouts in the same Nigerien metapopulation. We further show that, following periods during no suspected cases, districts with high reappearance rates of meningococcal meningitis also have high measles reintroduction rates. Despite many biological and epidemiological differences, similar seasonal and spatial patterns emerge from the dynamics of both diseases. This analysis enhances our understanding of spatial patterns and disease transmission and suggests hotspots for infection and potential target areas for meningococcal meningitis surveillance and intervention.

Explaining seasonal fluctuations of measles in Niger using nighttime lights imagery.

Measles epidemics in West Africa cause a significant proportion of vaccine-preventable childhood mortality. Epidemics are strongly seasonal, but the drivers of these fluctuations are poorly understood, which limits the predictability of outbreaks and the dynamic response to immunization. We show that measles seasonality can be explained by spatiotemporal changes in population density, which we measure by quantifying anthropogenic light from satellite imagery. We find that measles transmission and population density are highly correlated for three cities in Niger. With dynamic epidemic models, we demonstrate that measures of population density are essential for predicting epidemic progression at the city level and improving intervention strategies. In addition to epidemiological applications, the ability to measure fine-scale changes in population density has implications for public health, crisis management, and economic development.

The epidemiology of rubella in Mexico: seasonality, stochasticity and regional variation.

The factors underlying the temporal dynamics of rubella outside of Europe and North America are not well known. Here we used 20 years of incidence reports from Mexico to identify variation in seasonal forcing and magnitude of transmission across the country and to explore determinants of inter-annual variability in epidemic magnitude in rubella. We found considerable regional variation in both magnitude of transmission and amplitude of seasonal variation in transmission. Several lines of evidence pointed to stochastic dynamics as an important driver of multi-annual cycles. Since average age of infection increased with the relative importance of stochastic dynamics, this conclusion has implications for the burden of congenital rubella syndrome. We discuss factors underlying regional variation, and implications of the importance of stochasticity for vaccination implementation.

Measles hotspots and epidemiological connectivity.

Though largely controlled in developed countries, measles remains a major global public health issue. Regional and local transmission patterns are rooted in human mixing behaviour across spatial scales. Identifying spatial interactions that contribute to recurring epidemics helps define and predict outbreak patterns. Using spatially explicit reported cases from measles outbreaks in Niger, we explored how regional variations in movement and contact patterns relate to patterns of measles incidence. Because we expected to see lower rates of re-introductions in small, compared to large, populations, we measured the population-size corrected proportion of weeks with zero cases across districts to understand relative rates of measles re-introductions. We found that critical elements of spatial disease dynamics in Niger are agricultural seasonality, transnational contact clusters, and roads networks that facilitate host movement and connectivity. These results highlight the need to understand local patterns of seasonality, demographic characteristics, and spatial heterogeneities to inform vaccination policy.

Intra-ocular pressure changes associated with intubation with the intubating laryngeal mask airway compared with conventional laryngoscopy.

This open, prospective, randomised study was designed to evaluate the changes in intra-ocular pressure and haemodynamics after tracheal intubation using either the intubating laryngeal mask airway (ILMA) or direct laryngoscopy. Sixty adult patients, ASA physical status 1 or 2 with normal intra-ocular pressure were randomly allocated to one of the two techniques. Anaesthesia was induced with propofol followed by rocuronium. Tracheal intubation was performed using either the ILMA or Macintosh laryngoscope. Intra-ocular pressure, heart rate and blood pressure were measured immediately before and after tracheal intubation and then minutely for five minutes. In the laryngoscopy group there was a significant increase in intra-ocular pressure (from 7.2+/-1.4 to 16.8+/-5.3 mmHg, P<0.01), which did not return to pre-intubation levels within five minutes, and also in mean arterial pressure after tracheal intubation, which returned to baseline levels after five minutes. In the ILMA group there were no significant changes in intra-ocular pressure (from 7.6+/-1.8 to 10.4+/-2.8 mmHg, P >0.05) or mean arterial pressure after tracheal intubation. Time to successful intubation was longer with the ILMA, 56.8+/-7.8 seconds, compared with the laryngoscopy group, 33+/-3.6 seconds (P<0.01). Mucosal trauma was more frequent with the ILMA (eight of 30) compared with the laryngoscopy group (three of 30) (P<0.01). The postoperative complications were comparable. In terms of minimising increases in intra-ocular pressure and blood pressure, we conclude that the ILMA has an advantage over direct laryngoscopy for tracheal intubation.

Oral immunization of rhesus macaques with adenoviral HIV vaccines using enteric-coated capsules.

Targeted delivery of vaccine candidates to the gastrointestinal (GI) tract holds potential for mucosal immunization, particularly against mucosal pathogens like the human immunodeficiency virus (HIV). Among the different strategies for achieving targeted release in the GI tract, namely the small intestine, pH sensitive enteric coating polymers have been shown to protect solid oral dosage forms from the harsh digestive environment of the stomach and dissolve relatively rapidly in the small intestine by taking advantage of the luminal pH gradient. We developed an enteric polymethacrylate formulation for coating hydroxy-propyl-methyl-cellulose (HPMC) capsules containing lyophilized Adenoviral type 5 (Ad5) vectors expressing HIV-1 gag and a string of six highly-conserved HIV-1 envelope peptides representing broadly cross-reactive CD4(+) and CD8(+) T cell epitopes. Oral immunization of rhesus macaques with these capsules primed antigen-specific mucosal and systemic immune responses and subsequent intranasal delivery of the envelope peptide cocktail using a mutant cholera toxin adjuvant boosted cellular immune responses including, antigen-specific intracellular IFN-gamma-producing CD4(+) and CD8(+) effector memory T cells in the intestine. These results suggest that the combination of oral adenoviral vector priming followed by intranasal protein/peptide boosting may be an effective mucosal HIV vaccination strategy for targeting viral antigens to the GI tract and priming systemic and mucosal immunity.