Factors pivotal for designing of nanoantimicrobials: an exposition

Understanding the interplay between bacterial pathogens and antimicrobials is a key to realize the control over infections causing morbidity and mortality. An important current issue of contemporary medicine and microbiology is the search for new strategies for adequate therapy of infectious diseases associated with rapidly emerging multidrug-resistant (MDR) pathogens. Recently, a great deal of progress has been made in the field of nanobiotechnology towards the development of various nanoantimicrobials (NAMs) as novel therapeutic solution. Current microbiological studies, employing either synthetic antibiotics or natural antimicrobial, have demonstrated the ability of NAMs to tackle the issue of MDR by reverting the mechanisms of resistance. The present review critically discusses the various factors that can contribute to modulate the effects of NAMs on microbes. It includes essential features of NAMs including but not limited to composition, surface charge, loading capacity, size, hydrophobicity/philicity, controlled release and functionalization. In contrast, how microbial structural differences, biofilm formation, persister cells and intracellular pathogens contribute towards sensitivity or resistance towards antimicrobials is comprehensively analysed. These multilateral factors should be considered earnestly in order to make NAMs a successful alternative of the conventional antibiotics.     

A new pepsin assay to detect pulmonary aspiration of gastric contents among newly intubated patients

Aspiration of gastric contents by endotracheally intubated patients is associated with significant morbidity and mortality. Previous studies suggest that pepsin in tracheal aspirates may be a valuable marker of occult aspiration. We sought to show the sensitivity and specificity of a new, pepsin-specific assay in humans. A prospective, case-controlled study was conducted with subjects serving as their own controls. After planned endotracheal and nasogastric intubation for elective surgery, 20 participants had tracheal and gastric aspirates withdrawn. A blinded investigator tested samples for the presence of pepsin using the assay. Positive samples were then tested with pepstatin, a specific pepsin inhibitor, to ensure that positive results were due to pepsin. All tracheal aspirates tested negative and all gastric aspirates tested positive for pepsin. Pepstatin halted pepsin activity in all positive samples, ensuring that positive results were due to pepsin. A pepsin-specific assay is extremely reliable for detecting gastric contents in humans.     

Coordinated regulation of polycomb group complexes through microRNAs in cancer

Polycomb Repressive Complexes (PRC1 and PRC2)-mediated epigenetic regulation is critical for maintaining cellular homeostasis. Members of Polycomb Group (PcG) proteins including EZH2, a PRC2 component, are upregulated in various cancer types, implicating their role in tumorigenesis. Here, we have identified several microRNAs (miRNAs) that are repressed by EZH2. These miRNAs, in turn, regulate the expression of PRC1 proteins BMI1 and RING2. We found that ectopic overexpression of EZH2-regulated miRNAs attenuated cancer cell growth and invasiveness, and abrogated cancer stem cell properties. Importantly, expression analysis revealed an inverse correlation between miRNA and PRC protein levels in cell culture and prostate cancer tissues. Taken together, our data have uncovered a coordinate regulation of PRC1 and PRC2 activities that is mediated by miRNAs.     

Typhoid fever from water desalinized using reverse osmosis.

In May 1992, 81 bacteriologically confirmed cases of typhoid fever (TF) were identified in all districts of Tabuk City in northwestern Saudi Arabia. Attack rates (AR) in residential districts ranged from 0.9-10.3 per 10,000. Confirmed cases included 9 workers in the city''s referral hospital, King Khalid Hospital (AR 140/10,000), 2 in families of medical staff, 57 in the community (AR 4.4/10,000) and 13 in a local military cantonment (AR 0.8/10,000). The outbreak began with the onset of TF in the three areas within 5 days, continued for 7 weeks, and ended 2 weeks after chlorination began. Among water sources, the odds ratio (OR) was highest (2.6; 95% confidence interval [CI] 1.25-5.39) for water purchased from reverse osmosis (RO) plants, especially RO plants supplied by one well (ASUW) (OR = 7.05; 95% CI 2.51-20.7). The aquifer for ASUW lay partially beneath a depression where city sewage collected. Unchlorinated water samples from ASUW 1 month after the outbreak ended yielded coliforms. ASUW probably became contaminated with Salmonella typhi when KKH demand overtaxed the aquifer and drew in surface water. Membranes in RO plants using this unchlorinated well water could then become fouled with S. typhi. RO plants, which are common throughout Saudi Arabia, need close monitoring. Water for RO must be prechlorinated to prevent microbiologic fouling of the membranes.     

IGF-I enhances cortisol secretion from guinea-pig adrenal gland: in vivo and in vitro study

Insulin-like growth factor (IGF)-I is a ubiquitously synthesized peptide that, along with IGF-II, acts via the IGF-R type I receptor. IGF-I and its receptor are expressed in the adrenal gland of humans and bovines, the secretion of which they seem to stimulate. As in humans and cows, the main glucocorticoid hormone secreted by guinea-pig adrenals is cortisol, and hence we have studied the adrenocortical effects of IGF-I in this species. In vivo experiments showed that prolonged IGF-I administration raised the plasma concentration of cortisol in both normal and dexamethasone/captopril-treated guinea pigs, thereby ruling out the possibility that IGF-I may act by activating the hypothalamic-pituitary-adrenal axis and the renin-angiotensin system. In vitro experiments demonstrated that IGF-I enhanced basal, but not maximally agonist [ACTH and angiotensin-II (Ang-II)]-stimulated, cortisol secretion from freshly dispersed guinea-pig inner adrenocortical cells. The IGF-I immuno-neutralization suppressed the IGF-I secretagogue effect, without altering the cortisol response to both ACTH and Ang-II. IGF-I raised cyclic-AMP and inositol triphosphate release from dispersed guinea-pig cells, and the effect was reversed by the adenylate cyclase inhibitor SQ-22536 and the phospholipase-C (PLC) inhibitor U-73122. SQ-22536, U-73122, the protein kinase (PK) A inhibitor H-89 and the PKC inhibitor calphostin-C decreased by approximately 50% the cortisol response of dispersed cells to IGF-I, and the combined exposure to SQ-22536 and U-73122 abolished it. We conclude that IGF-I stimulates glucocorticoid secretion from guinea-pig adrenocortical cells, acting via selective receptors coupled to both the adenylate cyclase/PKA- and PLC/PKC-dependent signaling cascades.     

A coupled human–natural system analysis of freshwater security under climate and population change

Limited water availability, population growth, and climate change have resulted in freshwater crises in many countries. Jordan’s situation is emblematic, compounded by conflict-induced population shocks. Integrating knowledge across hydrology, climatology, agriculture, political science, geography, and economics, we present the Jordan Water Model, a nationwide coupled human–natural-engineered systems model that is used to evaluate Jordan’s freshwater security under climate and socioeconomic changes. The complex systems model simulates the trajectory of Jordan’s water system, representing dynamic interactions between a hierarchy of actors and the natural and engineered water environment. A multiagent modeling approach enables the quantification of impacts at the level of thousands of representative agents across sectors, allowing for the evaluation of both systemwide and distributional outcomes translated into a suite of water-security metrics (vulnerability, equity, shortage duration, and economic well-being). Model results indicate severe, potentially destabilizing, declines in freshwater security. Per capita water availability decreases by approximately 50% by the end of the century. Without intervening measures, >90% of the low-income household population experiences critical insecurity by the end of the century, receiving <40 L per capita per day. Widening disparity in freshwater use, lengthening shortage durations, and declining economic welfare are prevalent across narratives. To gain a foothold on its freshwater future, Jordan must enact a sweeping portfolio of ambitious interventions that include large-scale desalinization and comprehensive water sector reform, with model results revealing exponential improvements in water security through the coordination of supply- and demand-side measures.

Jordan, a nearly land-locked nation, has a tenuous freshwater future. The country’s water challenges stem from having extremely limited natural water availability with few alternatives for generating new supply and dependence on transboundary rivers and groundwater (Fig. 1A). Flows in the lower Jordan River, which marks Jordan’s western border with Israel and the West Bank, are estimated to have declined by nearly 90% since predevelopment conditions (1), mostly due to the diversion of the upper Jordan River into the National Water Carrier by Israel (2). The Yarmouk River tributary, currently Jordan’s primary surface-water source, is also largely captured by upstream Syria (3–6). Throughout the country, groundwater is being rapidly depleted, with observed groundwater-level declines of 0.9 to 3.5 m/y since 1995 in the country’s most highly productive aquifer (7, 8). To the south, Jordan competes with Saudi Arabia for shared groundwater from the fossil Disi regional aquifer (9). Jordan has long sought construction of the Red Sea–Dead Sea conveyance project, which would desalinate Red Sea water, transport the freshwater north to Amman, and dispose of the saline brine to the Dead Sea. Although first conceived of in the 1960s, project costs and fragile international cooperation have stood in the way.Open in a separate windowFig. 1.Map of Jordan and conceptual model. (A) Jordan relies on surface-water sources (primarily the Yarmouk River) and groundwater wells for water supply. The most recent record of total freshwater use from Jordan’s MWI is 1,054 MCM for 2017, with groundwater contributing 59% of the total supply, surface water 27%, and treated wastewater 14%. The domestic sector uses 45% of all water, agriculture 52%, and industry 3%. Groundwater is the primary source for the domestic sector, constituting over 70% of its supply. For the agricultural sector, groundwater constitutes 46% of the supply for irrigation, surface water 28%, and treated wastewater 26%. (B) The JWM consists of two types of modules: human modules (white rectangles) and biophysical modules (gray rectangles) of natural and engineered physical phenomena. The systems model includes interactions between modules, distinguished by endogenous human decisions (blue lines), endogenous physical flows and production (green lines), and exogenous scenarios (pink lines) and human interventions (yellow lines).Climate change and population growth further threaten Jordan’s tenuous situation (10). Rainfall decline in Jordan is already evident over the past century (11, 12), while climate models predict further increased temperatures with doubling in the frequency, duration, and intensity of droughts by 2100 (13). Jordan’s growing population has been punctuated by sudden, large refugee influxes (10, 14). In 2010, Jordan’s population was 7.2 million, growing to over 10.8 million by 2020, a period when at least 1.1 million Syrian refugees fled Syria’s 2011 war to Jordan (2, 15). In response to water shortage, Jordan has implemented significant water-supply efficiencies. In Amman, the largest city and capital, over 95% of wastewater is treated and recycled. However, Jordan’s water-distribution system is inefficient and intermittent. Approximately 50% of Jordan’s piped supply is lost as “nonrevenue water” (NRW), due to either physical factors (e.g., pipeline leaks) or administrative issues (e.g., water theft, incorrect meter readings, or underbilling). On average, households in the capital of Amman receive piped water for only 36 h per week (16), with lower-income neighborhoods receiving as low as 24 h of municipal supply, while higher-income households receive up to 5 d of uninterrupted supply per week (17). As a result, urban users purchase expensive water delivered by tanker trucks that obtain water from private agricultural wells through both formal and informal tanker-water markets (17, 18). Ecological impacts related to both groundwater and surface-water withdrawals by Jordan and upstream riparian nations in the Jordan River Basin have been severe, with notable examples including the drying of the Azraq Oasis, a Ramsar wetland (19, 20), and the shrinking of the Dead Sea, whose shoreline is receding by ∼1 m/y (21).The situation in Jordan is emblematic of water crises around the world, in which rapid population growth, intensifying water use, sudden demographic shocks, climate change, transboundary water competition, and institutional challenges pose serious threats to freshwater security (22–28). In the face of such global changes, an overarching sustainability goal is the long-term provision of freshwater as formalized in the 2015 Sustainable Development Goals (29). Given the complex and interacting physical and socioeconomic facets of such a challenge, there has been a growing call for analytic frameworks to evaluate freshwater systems that account for both the physical processes that govern freshwater supply and the human institutions and behaviors that influence the management, allocation, and consumption of water (30–36). Here, we present such a coupled human–natural-engineered system framework to explore the long-term impacts of a suite of policy interventions aimed at achieving freshwater security in Jordan in the face of anticipated changes in climate, population, and the economy.     

A Comparative Study of the Beneficial Effects of Ipratropium and Beclomethasone against Insulin-Induced Tracheal Tissue Contraction in a Guinea Pig Model

Objective

To evaluate the acute effects of insulin on airway reactivity and the protective effects of beclomethasone and ipratropium against insulin-induced airway hyperresponsiveness on isolated tracheal smooth muscle in a guinea pig model.

Materials and Methods

The trachea of each guinea pig was excised; one end of the tracheal strip was attached to the hook of the oxygen tube of a tissue bath and the other end was connected to a research-grade isometric force displacement transducer. The effects of varying concentrations of insulin (10⁻⁷ to 10⁻³M) and insulin pretreated with a fixed concentration of beclomethasone (10⁻⁶M) and ipratropium (10⁻⁶M) on the isolated tracheal tissue were studied by constructing cumulative concentration-response curves. Changes in tracheal smooth muscle contractions were recorded on a 4-channel oscillograph.

Results

The means ± standard error of the mean of the maximum amplitude of contraction with increasing concentrations of insulin and of insulin pretreated with fixed concentrations of beclomethasone and ipratropium were 35 ± 1.13, 22 ± 1.15 and 27.8 ± 1.27 mm, respectively.

Conclusion

The data showed that beclomethasone inhibited the contractile response of insulin to a greater extent than ipratropium. Thus we suggest that inhalational insulin pretreated with beclomethasone may be more efficacious than with ipratropium for the amelioration of potential respiratory adverse effects such as bronchoconstriction.Key Words: Airway hyper-reactivity, Inhaled insulin, Beclomethasone, Ipratropium, Tracheal muscle     

Posterior reversible encephalopathy syndrome (PRES)

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity. Neurotoxicity with characteristic watershed CT/MR imaging features characterize this condition. This case report describes PRES syndrome in a 35-year-old patient admitted with eclampsia. On the first postpartum day; she developed severe headache, generalized tonic-clonic seizures and visual symptoms including transient visual loss. MRI scan of the brain showed symmetric areas of hyperintense signal on T2-weighted images in the occipital lobes bilaterally. Patient improved symptomatically. Repeat MRI of the brain 4 months after initial admission showed resolution of the previous abnormalities.