Hydrochemical Assessment of Groundwater from the Harrat Khyber Flood Basalts, Northwest Saudi Arabia.

The present study was carried out in the Harrat Khyber region of the Madinah province in Western Saudi Arabia. The objective of the study was to determine the main factors affecting groundwater chemistry and assess the impact of groundwater quality on human health with respect to nitrate, fluoride, and heavy metals (arsenic, chromium, copper, nickel, selenium, and zinc). Hydrochemical data for 70 groundwater samples from dug wells and bore wells from Harrat Khyber were interpreted to achieve the research objective. The groundwater chemistry is influenced by ion-exchange and the evaporation process. A wide variation in the concentration of various major ions is observed primarily due to the varied nature of the aquifer system which includes the unconsolidated wadi deposits, weathered-fractured basaltic aquifer system, and subbasaltic sedimentary aquifer system. The total hazard quotient (THQ) with respect to NO3 and F was determined. Although the F values are well within the limits of human consumption in water prescribed by WHO, the values of NO3 exceed the allowable limits in 50% of the groundwater samples. The average THQ values are 2.16, 2.92, and 2.34 for adults, children, and infants, respectively, which makes the water unsafe for human consumption. Six heavy metals (arsenic, chromium, copper, nickel, selenium, and zinc) were used to calculate the heavy-metal contamination index (HCI). The average HCI value is 19.505. Overall HCI calculation shows that the groundwater is unpolluted with respect to heavy metals. The heavy metals in water are mainly of geogenic origin.

Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells.

IMPORTANCE: Persistent human gastric infection with Helicobacter pylori is the single most important risk factor for development of gastric malignancy, which is one of the leading causes of cancer-related deaths worldwide. An important virulence factor for Hp colonization and severity of gastric disease is the protein exotoxin VacA, which is secreted by the bacterium and modulates functional properties of gastric cells. VacA acts by damaging mitochondria, which impairs host cell metabolism through impairment of energy production. Here, we demonstrate that intoxicated cells have the capacity to detect VacA-mediated damage, and orchestrate the repair of mitochondrial function, thereby restoring cellular health and vitality. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies.

Acute effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity and cardiorespiratory responses in dogs.

NEW FINDINGS: What is the central question of this study? What are the effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity in vivo and how do carotid body chemoreceptor stimulation-mediated cardiorespiratory responses in beagle dogs compare during euglycaemia and insulin-induced hypoglycaemia? What is the main finding and its importance? Intracarotid insulin administration leads to sustained increase in carotid body chemoreceptor activity and respiratory response with significant cardiovascular effects. Insulin-induced hypoglycaemia exacerbated NaCN-mediated carotid body chemoreceptor activity and respiratory response with enhanced cardiovascular reflex response. These findings suggest that insulin-induced hypoglycaemia augments the carotid body chemoreceptors to initiate the adaptive counter-regulatory responses to restore the normoglycaemic condition. ABSTRACT: The carotid body chemoreceptors (CBC) play an important role in the adaptive counter-regulatory response to hypoglycaemia by evoking the CBC-mediated sympathetic neuronal system to restore normoglycaemia. Ex vivo studies have shown varied responses of insulin-induced hypoglycaemia on CBC function, and several in vivo studies have indirectly established the role of CBCs in restoring normoglycaemia in both animals and humans. However, a direct effect of insulin and/or insulin-induced hypoglycaemia on CBC activity is not established in animal models. Therefore, the aim of this study was to evaluate in vivo effects of insulin and insulin-induced hypoglycaemia on CBC activity and cardiorespiration in a preclinical large animal model. The carotid sinus nerve (CSN) activity and cardiorespiratory responses to sodium cyanide (NaCN; 25 µg/kg) were compared before (euglycaemic) and after (hypoglycaemic) intracarotid administration of insulin (12.5-100 µU/dogs) in beagle dogs. Insulin administration increased CSN activity and minute ventilation ( V ̇ $\dot V$ E ) with significant (P < 0.0001) effects on heart rate and blood pressure. Insulin-mediated effects on CSN and cardiorespiration were sustained and the change in V ̇ $\dot V$ E was driven by tidal volume only. Insulin significantly (P < 0.0001) lowered blood glucose level. NaCN-mediated CSN activity and V ̇ $\dot V$ E were significantly (P < 0.0001) augmented during insulin-induced hypoglycaemia. The augmented V ̇ $\dot V$ E was primarily driven by respiratory frequency and partially by tidal volume. The cardiovascular reflex response mediated through CBC stimulation was significantly (P < 0.0001) exacerbated during insulin-induced hypoglycaemia. Collectively, these results demonstrate direct effects of insulin and insulin-induced hypoglycaemia on CBC chemosensitivity to potentiate CBC-mediated neuroregulatory pathways to initiate adaptive neuroendocrine and cardiorespiratory counter-regulatory responses to restore normoglycaemia.

Evaluation of heavy metal contamination and groundwater quality along the Red Sea coast, southern Saudi Arabia.

To evaluate the heavy metal contamination and groundwater quality in southern Saudi Arabia, 105 groundwater samples were analyzed for EC, pH, TDS, major ions (NO3-, Cl-, HCO3-, SO42-, F-, Ca2+, Mg2+, Na+, and K+), and heavy metals (Fe, Li, As, B, Al, Cr, Cu, Mo, Ni, Se, Sr, V, Zn, and Mn). Groundwater quality index (GWQI), degree of contamination (Cd), heavy metal pollution index (HPI), ecological risks of heavy metals (ERI), salinity hazard (EC), sodium adsorption ratio (SAR), sodium percentage (Na%), and Kelly's ratio (KR) were calculated and compared, and multivariate statistical techniques were applied. The results revealed that the major cations and anions followed the orders of Na+ > Ca2+ > Mg2+ > K+ and Cl- > SO42- > HCO3- > NO3- > F-, respectively. The maximum values of As, Mn, Cr, Ni, Se, and Zn were above the permissible limits for drinking water purposes. Pollution indices indicated that 20 to 52% of the groundwater samples were suitable for agricultural and domestic purposes. The unsuitable samples were distributed mostly in the western part along the Red Sea coast. Multivariate statistical analyses revealed that the dissolution of halite and gypsum (in sabkha deposits), carbonates, and the agricultural activities were the possible sources of the major cations and anions, and heavy metals in the study area.

Assessment of hydrological processes operating in a multi-layered sedimentary aquifer system in Saudi Arabia using integrated chemical and statistical approach.

Hydrochemical processes have a great influence on the groundwater quality especially in arid regions where groundwater is the single most important source of water supply. The present study was carried out in the Wadi Ad Dawasir region of Saudi Arabia. The objective of this study was to determine the processes influencing the groundwater composition in the region by integrated hydrochemical and statistical assessment. Hydrochemical data from 140 groundwater samples were interpreted using hydrochemical and statistical techniques. Evaporation, mineral dissolution, reverse ion exchange, and chloride/nitrate contamination from irrigation return flows were the main geogenic and anthropogenic sources influencing the groundwater composition. Principal component analysis was carried out to determine the component showing the maximum variability in the data. Two principal components were extracted. The first principal component representing gypsum dissolution and anthropogenic pollution (chloride and nitrate pollution from agricultural farms) was more pronounced in the western part of the study area whereas the second principal component representing silicate weathering process was more dominant in the eastern part. Total dissolved solid was found to be the single most important hydrochemical parameter showing the maximum variation in the analyzed data set. This study demonstrates that the loadings of the individual hydrochemical parameters in the extracted principal component and the component scores of the individual samples for each extracted principal component can be effectively used for determining the hydrochemical processes influencing the groundwater chemistry in an area.

Assessment of artificial groundwater recharge potential through estimation of permeability values from infiltration and aquifer tests in unconsolidated alluvial formations in coastal areas.

Twenty infiltration tests and 12 pumping tests were carried out in Wadi Baysh in southwestern Saudi Arabia. The objective of the study was to assess the soil and aquifer permeability from the point of view of artificial groundwater recharge. Infiltration tests showed that the soil permeability values ranged from 0.58 to 37.15 m/day and showed good recharge potential. The analysis of the pumping tests showed that the aquifer permeability values ranged from 2.6 to 57.4 m/day and were approximately within the same range as those obtained from infiltration tests. Monitoring of groundwater levels in a few wells before and 1 month after a heavy rainfall event in August 2016 shows an average increase of 2.25 m in the groundwater levels which substantiates the recharge rates obtained from infiltration and pumping tests. Average annual groundwater recharge for the area calculated from water table fluctuation method is 72.08 mm/year indicating that the lower reaches of Wadi Baysh catchment has good potential for groundwater recharge and if managed properly can help in tackling the problem of groundwater depletion due to excessive pumping.

Effect of coadministration of metformin with mirogabalin: Results from a phase 1, randomized, open-label, drug-drug interaction study
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Mirogabalin, a selective voltage-dependent calcium channel α2δ ligand under development for treatment of neuropathic pain, may be coadministered with metformin in patients with type 2 diabetes mellitus who have diabetic peripheral neuropathic pain. A randomized, open-label, single-dose, 3-treatment, 3-period crossover study evaluated the pharmacokinetics (PK) and safety of mirogabalin and metformin upon coadministration. Eligible subjects received 3 treatments separated by a 7-day washout period: 1 oral dose of mirogabalin 15 mg; 1 oral dose of metformin 850 mg; and coadministration of mirogabalin 15 mg with metformin 850 mg. PK assessments included maximum observed plasma concentration (Cmax); time of maximum plasma concentration; area under the concentration-time curve from time 0 to the last quantifiable concentration, and from 0 to infinity (AUClast and AUC0-inf, respectively). Safety assessments included adverse event (AE) monitoring and physical and clinical laboratory evaluations. 21 healthy men with a mean age of 30.4 years were enrolled and completed the study. Geometric least square means ratios (coadministration vs. alone; 90% confidence interval) for metformin Cmax, AUClast, and AUC0-inf were 1.00 (0.95 - 1.05), 1.04 (1.00 - 1.07), and 1.03 (1.00 - 1.07), respectively; ratios for mirogabalin were 0.94 (0.87 - 1.02), 0.99 (0.95 - 1.04), and 1.00 (0.96 - 1.04), respectively. Three subjects reported treatment-emergent AEs: dyspepsia, headache, and increased hepatic enzymes (resolved upon follow-up without sequelae). There were no deaths, serious AEs, or discontinuations due to AEs. Coadministration of mirogabalin and metformin is well tolerated in healthy subjects with no evidence of a drug-drug interaction.
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Innervation of taste buds revealed with Brainbow-labeling in mouse.

Nerve fibers that surround and innervate the taste bud were visualized with inherent fluorescence using Brainbow transgenic mice that were generated by mating the founder line L with nestin-cre mice. Multicolor fluorescence revealed perigemmal fibers as branched within the non-taste epithelium and ending in clusters of multiple rounded swellings surrounding the taste pore. Brainbow-labeling also revealed the morphology and branching pattern of single intragemmal fibers. These taste bud fibers frequently innervated both the peripheral bud, where immature gemmal cells are located, and the central bud, where mature, differentiated cells are located. The fibers typically bore preterminal and terminal swellings, growth cones with filopodia, swellings, and rounded retraction bulbs. These results establish an anatomical substrate for taste nerve fibers to contact and remodel among receptor cells at all stages of their differentiation, an interpretation that was supported by staining with GAP-43, a marker for growing fibers and growth cones.

Reverse ion exchange as a major process controlling the groundwater chemistry in an arid environment: a case study from northwestern Saudi Arabia.

Assessment of groundwater quality is of utmost significance in arid regions like Saudi Arabia where the lack of present-day recharge and high evaporation rates coupled with increasing groundwater withdrawal may restrict its usage for domestic or agricultural purposes. In the present study, groundwater samples collected from agricultural farms in Hail (15 samples), Al Jawf (15 samples), and Tabuk (30 samples) regions were analyzed for their major ion concentration. The objective of the study was to determine the groundwater facies, the main hydrochemical process governing the groundwater chemistry, the saturation index with respect to the principal mineral phases, and the suitability of the groundwater for irrigational use. The groundwater samples fall within the Ca-Cl type, mixed Ca-Mg-Cl type, and Na-Cl type. Evaporation and reverse ion exchange appear to be the major processes controlling the groundwater chemistry though reverse ion exchange process is the more dominating factor. The various ionic relationships confirmed the reverse ion exchange process where the Ca and Mg in the aquifer matrix have been replaced by Na at favorable exchange sites. This phenomenon has accounted for the dominance of Ca and Mg ions over Na ion at all the sites. The process of reverse ion exchange was further substantiated by the use of modified Piper diagram (Chadha's classification) and the chloro-alkaline indices. Evaporation as a result of extreme aridity has resulted in the groundwater being oversaturated with aragonite/calcite and dolomite as revealed by the saturation indices. The groundwater samples were classified as safe (less than 10) in terms of sodium adsorption ratio (SAR) values, good (less than 1.25) in terms of residual sodium carbonate (RSC) values, and safe to moderate (between 0 and 3) in terms of Mg hazard for irrigation purposes. Though the high salinity groundwater in the three regions coupled with low SAR values are good for the soil structure, it can have a negative impact on the crop production by adversely affecting the crop physiology. Cultivation of high-salinity-resistant varieties of crops is recommended for maximum agricultural productivity.

Effects of targeted activation of tongue muscles on oropharyngeal patency in the rat.

Laboratory rats were acutely implanted with an electrode array composed of eight independently controllable contacts applied to ventral and dorsal aspects of the left and right hypoglossal nerves (HGNs) and their branches. Bipolar intramuscular electromyographic (EMG) electrodes were implanted into the left and right genioglossus, hyoglossus and styloglossus muscles to identify which muscles were activated during stimulation via the contacts. Elicited movements, including changes in the position of the tongue and in the size and the shape of the airway, were documented video-graphically through a surgery microscope and an endoscope. Constant current electrical stimulation activated various combinations of electrode contacts and the stimulation patterns were correlated with corresponding oral movements, airway sizes, and EMG activities. Results demonstrate that graded responses and differential activation of the various tongue muscles are achievable by stimulation of specific contacts in the electrode array. These effects are interpreted to result from the targeted activation of regions of the nerve lying under and between the electrodes. Further testing established that the muscle responses elicited by unilateral electrical stimulation with the present approach can be smoothly graded, that the muscle responses resulted in opening of the airway and could be reliably maintained for long durations.

A pragmatic approach to study the groundwater quality suitability for domestic and agricultural usage, Saq aquifer, northwest of Saudi Arabia.

The present study deals with detailed hydrochemical assessment of groundwater within the Saq aquifer. The Saq aquifer which extends through the NW part of Saudi Arabia is one of the major sources of groundwater supply. Groundwater samples were collected from about 295 groundwater wells and analyzed for various physico-chemical parameters such as electrical conductivity (EC), pH, temperature, total dissolved solids (TDS), Na(+), K(+), Ca(2+), Mg(2+), CO3 (-), HCO3 (-), Cl(-), SO4 (2-), and NO3 (-). Groundwater in the area is slightly alkaline and hard in nature. Electrical conductivity (EC) varies between 284 and 9,902 µS/cm with an average value of 1,599.4 µS/cm. The groundwater is highly mineralized with approximately 30 % of the samples having major ion concentrations above the WHO permissible limits. The NO3 (-) concentration varies between 0.4 and 318.2 mg/l. The depth distribution of NO3 (-) concentration shows higher concentration at shallow depths with a gradual decrease at deeper depths. As far as drinking water quality criteria are concerned, study shows that about 33 % of samples are unfit for use. A detailed assessment of groundwater quality in relation to agriculture use reveals that 21 % samples are unsuitable for irrigation. Using Piper's classification, groundwater was classified into five different groups. Majority of the samples show Mix-Cl-SO4- and Na-Cl-types water. The abundances of Ca(2+) and Mg(2+) over alkalis infer mixed type of groundwater facies and reverse exchange reactions. The groundwater has acquired unique chemical characteristics through prolonged rock-water interactions, percolation of irrigation return water, and reactions at vadose zone.

Tongue anatomy and physiology, the scientific basis for a novel targeted neurostimulation system designed for the treatment of obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) is a chronic condition that affects millions adults. The effective standard treatment is positive airway pressure (PAP). However, approximately half of the patients that are prescribed PAP are unable or unwilling to comply with this therapy. Untreated OSA ultimately leads to very serious comorbidities. An alternative therapy for this patient population, therefore, is desirable. Hypoglossal nerve (HGN) stimulation is under investigation by multiple groups as a possible alternative therapy for OSA. OBJECTIVE: To understand the underlying mechanisms of actions related to HGN stimulation, and the implication of this knowledge for specifying and designing a neurostimulation system for the treatment of OSA. RESULTS: Loss of lingual and pharyngeal tone within a narrow airway is the primary mechanism for OSA. Posterior and anterior tongues are different in their anatomy and physiology. Muscle fibers in the posterior tongue are predominantly fatigue resistant that are responsible for the long sustained tonic activities required for maintaining the tongue's position and preventing its mass from falling into the retroglossal airway. The human tongue is a muscular hydrostat and hence would benefit from a sophisticated HGN stimulation system that is capable of achieving a concerted spatio-temporal interplay of multiple lingual muscles, including retrusors. CONCLUSION: Targeted neurostimulation of the proximal HGN presents as a viable system approach that is far more versatile and physiologic and quite different than prior systems.

Types of taste circuits synaptically linked to a few geniculate ganglion neurons.

The present study evaluates the central circuits that are synaptically engaged by very small subsets of the total population of geniculate ganglion cells to test the hypothesis that taste ganglion cells are heterogeneous in terms of their central connections. We used transsynaptic anterograde pseudorabies virus labeling of fungiform taste papillae to infect single or small numbers of geniculate ganglion cells, together with the central neurons with which they connect, to define differential patterns of synaptically linked neurons in the taste pathway. Labeled brain cells were localized within known gustatory regions, including the rostral central subdivision (RC) of the nucleus of the solitary tract (NST), the principal site where geniculate axons synapse, and the site containing most of the cells that project to the parabrachial nucleus (PBN) of the pons. Cells were also located in the rostral lateral NST subdivision (RL), a site of trigeminal and sparse geniculate input, and the ventral NST (V) and medullary reticular formation (RF), a caudal brainstem pathway leading to reflexive oromotor functions. Comparisons among cases, each with a random, very small subset of labeled geniculate neurons, revealed "types" of central neural circuits consistent with a differential engagement of either the ascending or the local, intramedullary pathway by different classes of ganglion cells. We conclude that taste ganglion cells are heterogeneous in terms of their central connectivity, some engaging, predominantly, the ascending "lemniscal," taste pathway, a circuit associated with higher order discriminative and homeostatic functions, others engaging the "local," intramedullary "reflex" circuit that mediates ingestion and rejection oromotor behaviors.

Exuberant neuronal convergence onto reduced taste bud targets with preservation of neural specificity in mice overexpressing neurotrophin in the tongue epithelium.

A mouse fungiform taste bud is innervated by only four to five geniculate ganglion neurons; their peripheral fibers do not branch to other buds. We examined whether the degree or specificity of this exclusive innervation pattern is influenced by brain-derived neurotrophic factor (BDNF), a prominent lingual neurotrophin implicated in taste receptoneural development. Labeled ganglion cells were counted after injecting single buds with different color markers in BDNF-lingual-overexpressing (OE) mice. To evaluate the end-organs, taste buds and a class of putative taste receptor cells were counted from progeny of BDNF-OE mice crossbred with green fluorescent protein (GFP) (gustducin) transgenic mice. Fungiform bud numbers in BDNF-OE mice are 35%, yet geniculate neuron numbers are 195%, of wild-type mice. Neurons labeled by single-bud injections in BDNF-OE animals were increased fourfold versus controls. Injecting three buds, each with different color markers, resulted in predominantly single-labeled ganglion cells, a discrete innervation pattern similar to controls. Thus, hyper-innervation of BDNF-OE buds involves many neurons innervating single buds, not increased fiber branching. Therefore, both wild-type and BDNF-OE mice exhibit, in fungiform buds, the same, "discrete" receptoneural pattern, this despite dramatic neurotrophin overexpression-related decreases in bud numbers and increases in innervation density. Hyperinnervation did not affect GFP positive cell numbers; proportions of GFP cells in BDNF-OE buds were the same as in wild-type mice. Total numbers of ganglion cells innervating buds in transgenic mice are similar to controls; the density of taste input to the brain appears maintained despite dramatically reduced receptor organs and increased ganglion cells.

Discrete innervation of murine taste buds by peripheral taste neurons.

The peripheral taste system likely maintains a specific relationship between ganglion cells that signal a particular taste quality and taste bud cells responsive to that quality. We have explored a measure of the receptoneural relationship in the mouse. By injecting single fungiform taste buds with lipophilic retrograde neuroanatomical markers, the number of labeled geniculate ganglion cells innervating single buds on the tongue were identified. We found that three to five ganglion cells innervate a single bud. Injecting neighboring buds with different color markers showed that the buds are primarily innervated by separate populations of geniculate cells (i.e., multiply labeled ganglion cells are rare). In other words, each taste bud is innervated by a population of neurons that only connects with that bud. Palate bud injections revealed a similar, relatively exclusive receptoneural relationship. Injecting buds in different regions of the tongue did not reveal a topographic representation of buds in the geniculate ganglion, despite a stereotyped patterned arrangement of fungiform buds as rows and columns on the tongue. However, ganglion cells innervating the tongue and palate were differentially concentrated in lateral and rostral regions of the ganglion, respectively. The principal finding that small groups of ganglion cells send sensory fibers that converge selectively on a single bud is a new-found measure of specific matching between the two principal cellular elements of the mouse peripheral taste system. Repetition of the experiments in the hamster showed a more divergent innervation of buds in this species. The results indicate that whatever taste quality is signaled by a murine geniculate ganglion neuron, that signal reflects the activity of cells in a single taste bud.