Endoscopic Therapy of Gastric Varices: Safety and Efficacy of N-Butyl-2-Cyanoacrylate Injection.

Background Upper gastrointestinal bleeding (UGIB) is a common medical emergency that results in significant morbidity, mortality, and socioeconomic burden. Both types of cardio-fundal varices, gastro-esophageal varix 2 (GOV2) and isolated gastric varices type 1 (IGV1), can cause massive bleeding and often are difficult to treat compared to the other types of gastric varices. Endoscopic variceal band ligation (EVBL) is a less effective treatment modality for gastric varices than esophageal varices and is associated with high re-bleeding rates. N-butyl-2-cyanoacrylate (Histoacryl) injection is an effective and potential treatment option for fundal varices. This study aims to evaluate the safety and efficacy of n-butyl-2-cyanoacrylate injection therapy in cardio-fundal varices. Objective To assess the efficacy and safety of n-butyl-2-cyanoacrylate injection therapy for fundal varices. Methods This retrospective observational cohort study was conducted at the Department of Gastroenterology, Allied Teaching Hospital, Gujranwala, over one year. All patients, irrespective of age and gender, presenting with UGIB and in whom fundal varices were diagnosed on gastroscopy followed by n-butyl 2-cyanoacrylate injection therapy were included in this study. The efficacy and safety of Histoacryl therapy were assessed by analyzing successful hemostasis, frequency of re-bleeding, obliteration, and regression of fundal varices on repeat endoscopy. Adverse events such as re-bleeding and mortality related to fundal variceal treatment were documented. Results A total of 60 patients were included in the study. Of these, 70% had IGV1, while the remaining 30% had GOV2. Hemostasis was achieved in 100% of patients following n-butyl-2-cyanoacrylate injection. Successful obliteration with regression of varices was observed in 91.3% of patients. Various adverse events were observed, with abdominal pain being the most common observed complication in 18.3% of participants. However, only 8.3% of participants developed re-bleeding due to ulcer formation at the injection site, and no death occurred directly due to fundal variceal treatment. Conclusion N-butyl-2-cyanoacrylate injection therapy is a lifesaving, effective, and safe intervention for controlling bleeding from cardio-fundal varices, leading to improved health status and a consequent decrease in episodes of recurrent bleeding. Its side effects are few and infrequent. However, larger-scale studies are needed to further evaluate the safety and effectiveness of n-butyl-2-cyanoacrylate injection therapy. These studies will be crucial in establishing comprehensive guidelines for the management of fundal varices.

Comparison Between Two Types Of Matrix Systems For Contact Tightness In Class-Ii Composite Restorations.

BACKGROUND: The reconstruction of proximal defects with tight contacts has always been a challenge for dental clinicians, especially with composite material. Recent literature shows that the most frequently used matrix systems for the restoration of proximal cavities are circumferential or sectional matrix band systems. The objective of this study was to compare the contact tightness that is achieved with these two matrix band systems when using composite material. METHODS: A total of 30 patients, i.e., 60 cavities were selected in this quasi-experimental study. Patients with two cavities in the posterior teeth were selected. Both the cavities were restored with the circumferential system, i.e., Tofflemire and sectional matrix band system, i.e., Palodent plus on the same appointment. Hence both systems were used in every patient and then contact tightness assess was ed based on an evaluation criterion, i.e., Fédération Dentaire Internationale clinical criteria for evaluation of contact in direct and indirect restorations. To make a comparison between the two systems Chi square test was used and p<0.05. RESULTS: The mean age of the patients in the study was 31 years (SD, 7.59 years) with a range from 18 to 45 years. Most of the contact tightness in the Palodent matrix system was score 1 (n=33, 55%) and score 2 (n=17, 28.3%) while in Tofflemire was score 4 (n=28, 46.7%) and score 5 (n=19, 31.7%). Statistical analysis showed significance (p=.037) between Palodent matrix system contact tightness and Tofflemire. Conclusion: The sectional matrix band system was statistically superior to the circumferential matrix band system in achieving a tighter contact for class II composite restorations.

Evaluation of Caralluma edulis for its Potential Against Obesity, Atherosclerosis and Hypertension.

Obesity, a chronic metabolic condition, is an increase in fat mass and blood lipid levels mainly causing atherosclerosis and hypertension, which further lead to cardiovascular complications. The objective of the study was to investigate the crude extract of Caralluma edulis (CE.Cr) for its potential against high-fat diet (HFD)-induced obesity and its related complications. Hyperlipidemia was induced in Wistar albino rats with HFD (1% cholesterol + 0.5% cholic acid) for 28 days. Treatment groups were administered with different doses of CE.Cr (100, 300 and 500 mg/Kg, p.o.) and the standard group received atorvastatin. At the end of study, sera were analyzed for biochemical markers and the aorta was dissected for microscopic examination. Antioxidant potential was evaluated and high-performance liquid chromatography (HPLC) analysis was performed. The hypotensive potential of CE.Cr was evaluated through an invasive technique. HPLC analysis of CE.Cr showed the presence of chlorogenic acid, caffeic acid, apigenin and naringenin. Histological examination of the aorta section showed anti-atherosclerotic effects which were also evident from decrease in serum total cholesterol, triglycerides and low-density lipoproteins levels. CE.Cr decreased mean arterial blood pressure and evoked significant hypotensive effects. The crude extract of C. edulis showed anti-obesity, antihypertensive, anti-atherosclerotic and antioxidant potential.

Effect Of Dental Proximal Restorations On Periodontal Health In Patients.

Background: The oral cavity is colonized by more than 700 species of bacteria and hundreds of those can be present within oral biofilms. Objective was to determine the frequency of periodontal attachment loss in patients with dental proximal restorations. Methods: This cross-sectional study included 100 patients with Class II (mesial /distal or mesio-occluso-distal composite and amalgam restorations. The minimum duration of pre-existing restoration for which periodontal attachment loss was assessed was more than 3 months. Patients wearing orthodontic appliances, pregnant women, patients having systemic health problems with well-established links to periodontal diseases such as diabetes mellitus and patients who had received periodontal treatment within the last 3 months were excluded. Periodontal Pocket depth and bleeding on probing was recorded using WHO periodontal probe. Pocket depth greater than 3 mm was considered pathologic. The data were analyzed using the SPSS, version 20. Descriptive statistics were computed. Chi square test was applied to compare the effects of duration of restoration and type of teeth on periodontal attachment loss. Results: Of total 100 participants 65 (65%) were males and 35 (35%) were females. The mean age was 30.74±9.21 years. In 14% cases having class II or Mesio occluso distal restorations normal pocket depth was recorded while 86% had pathologic pockets. Teeth where proximal restorations were present for more than one year were most commonly associated (29%) with pathologic pockets followed by proximal restorations which were present for three months (25%). As the duration of proximal restoration increased, the frequency of periodontal pathologic pockets increased (p<0.001). The prevalence of periodontal pocket was more in molars than premolars (p<0.001). Conclusion: Proximal restoration can be a significant risk factor for periodontal disease. Strict oral hygiene, proper design of restoration margin and supportive periodontal therapy is the utmost responsibility of the clinician.

Protein Kinase C Life Cycle: Explained Through Systems Biology Approach.

Protein kinase C (PKC) enzymes are a family of kinases that mediate signal transduction originating at the cell surface. Most cell membranes can contain functional PKC enzymes. Aberrations in the PKC life cycle may result in cellular damage and dysfunction. For example, some cancerous cells exhibit alterations in PKC activity. Here, we use a systems biology approach to describe a molecular model of the PKC life cycle. Understanding the PKC life cycle is necessary to identify new drug targets. The PKC life cycle is composed of three key regulatory processes: maturation, activation, and termination. These processes precisely control PKC enzyme levels. This model describes the fate of PKC during de novo synthesis and PKC's lipid-mediated activation cycle. We utilize a systems biology approach to show the PKC life cycle is controlled by multiple phosphorylation and dephosphorylation events. PKC processing events can be divided into two types: maturation via processing of newly synthesized enzyme and secondary messenger-dependent activation of dormant, but catalytically competent enzyme. Newly synthesized PKC enzyme is constitutively processed through three ordered phosphorylations and stored in the cytosol as a stable, signaling-competent inactive and autoinhibited molecule. Upon extracellular stimulation, diacylglycerol (DAG) and calcium ion (Ca2+) generated at the membrane bind PKC. PKC then undergoes cytosol-to-membrane translocation and subsequent activation. Our model shows that, once activated, PKC is prone to dephosphorylation and subsequent degradation. This model also describes the role of HSP70 in stabilization and re-phosphorylation of dephosphorylated PKC, replenishing the PKC pool. Our model shows how the PKC pool responds to different intensities of extracellular stimuli? We show that blocking PHLPP dephosphorylation replenishes the PKC pool in a dose-dependent manner. This model provides a comprehensive understanding of PKC life cycle regulation.

TRPC3 Channel Activity and Viability of Purkinje Neurons can be Regulated by a Local Signalosome.

Canonical transient receptor potential channels (TRPC3) may play a pivotal role in the development and viability of dendritic arbor in Purkinje neurons. This is a novel postsynaptic channel for glutamatergic synaptic transmission. In the cerebellum, TRPC3 appears to regulate functions relating to motor coordination in a highly specific manner. Gain of TRPC3 function is linked to significant alterations in the density and connectivity of dendritic arbor in Purkinje neurons. TRPC3 signals downstream of class I metabotropic glutamate receptors (mGluR1). Moreover, diacylglycerol (DAG) can directly bind and activate TRPC3 molecules. Here, we investigate a key question: How can the activity of the TRPC3 channel be regulated in Purkinje neurons? We also explore how mGluR1 activation, Ca2+ influx, and DAG homeostasis in Purkinje neurons can be linked to TRPC3 activity modulation. Through systems biology approach, we show that TRPC3 activity can be modulated by a Purkinje cell (PC)-specific local signalosome. The assembly of this signalosome is coordinated by DAG generation after mGluR1 activation. Our results also suggest that purinergic receptor activation leads to the spatial and temporal organization of the TRPC3 signaling module and integration of its key effector molecules such as DAG, PKCγ, DGKγ, and Ca2+ into an organized local signalosome. This signaling machine can regulate the TRPC3 cycling between active, inactive, and desensitized states. Precise activity of the TRPC3 channel is essential for tightly regulating the Ca2+ entry into PCs and thus the balance of lipid and Ca2+ signaling in Purkinje neurons and hence their viability. Cell-type-specific understanding of mechanisms regulating TRPC3 channel activity could be key in identifying therapeutic targeting opportunities.

Gisekia pharnaceoides Restores Colonic Mucosal Homeostasis by Regulating Antioxidant Enzyme System and Cytokines Signaling in Ulcerative Colitis Mice Model.

BACKGROUND: Gisekia pharnaceoides Linn. (Aizoaceae), traditionally known as baluka saag or sareli is commonly found in the deep Cholistan region of Pakistan. It is used by the native community for the mitigation of a range of diseases, including inflammatory disorders and gastric ulcers. OBJECTIVE: This study is designed to evaluate the defensive impact of G. pharnaceoides in acetic acid-induced ulcerative colitis in mice and to discover the mechanism for anti-inflammatory action. METHODS: The ethanolic crude extract of G. pharnaceoides (Gp.Cr) was prepared and evaluated for phytochemical substances by preliminary screening and HPLC analysis. Anti-inflammatory activity of Gp.Cr (300 and 500 mg/kg) was examined by administration of 200 µl of 7.5% acetic acid intra- rectally to induce ulcerative colitis and colonic mucosal injury, while mucosal homeostasis was evaluated by disease activity index, colonic ulcer score, and hematological parameters. The anti-inflammatory potential was quantified by assessing antioxidant enzymes (SOD, CAT, GPX-1), lipid peroxides, nitric oxide, and cytokines (IL-1ß, IL-6, TNF-α) immunoassays and further analyzed by histological analysis of colon tissues. RESULTS: Phytochemical screening of Gp.Cr revealed the presence of alkaloids, phenols, flavonoids, steroids, tannins, and saponins, while HPLC analysis confirmed the presence of quercetin, gallic acid, coumaric and sinapic acid. In acetic acid-induced ulcerative colitis model, Gp.Cr (300 and 500 mg/kg) along with sulphasalazine (500 mg/kg) decreased disease activity index, ulcer scores, and hematological parameters. Gp.Cr showed a significant anti-inflammatory potential by increasing antioxidant enzymes and decreasing lipid peroxides, nitric oxide, and cytokines levels. Histopathological examination showed a significant decline in ulceration and tissue disruption. CONCLUSION: Hence, the findings confirmed the effectiveness of G. pharnaceoides crude extract in the treatment of ulcerative colitis and might be a promising remedy to manage inflammatory disorders.

Radiographic And Clinical Assessment Of Two Canals In The Maxillary Second Premolar.

BACKGROUND: The second premolar is one of the teeth which are crucial both aesthetically as well as functionally and one of the most commonly endodontically treated tooth. Aim of the study was to assess the number of canals in maxillary second premolar by clinical and radiographic evaluation in Pakistani sub population. It was a cross sectional study conducted in Endodontic Department of Rehmat Memorial Dental Teaching Hospital, Abbottabad, from January 2019 to January 2020. METHODS: One hundred and five patients were selected for the study, based on nonprobability sampling technique. All patients were examined clinically by exploration of pulp chamber followed by intra oral peri-apical radiograph to verify the clinical exploration of canals. RESULTS: One hundred and five patients (46 males (43.8%) and 59 females (56.2%)} were selected for the study. Out of total 105 patients 47 (44.8%) had one canal and 58 (55.2%) had two canals. Out of 46 males 25 (54.3%) had two canals and out of 59 females 33 (56.9%) had two canals. Statistical analysis showed no significant difference (p=0.1871) of canals arrangements between genders. CONCLUSION: Clinicians should be careful whenever doing root canal treatment of maxillary second premolars because of the extreme variability of the anatomy of those teeth, there is always risk of missing the second canal. Frequency of two canals was high, which is not age or gender dependant.

Serotonin-release assay-positive but platelet factor 4-dependent enzyme-immunoassay negative: HIT or not HIT?

IgG-specific and polyspecific PF4-dependent enzyme-immunoassays (EIAs) have exceptionally high sensitivity (≥99%) for diagnosis of heparin-induced thrombocytopenia (HIT), a drug reaction caused by platelet-activating antibodies detectable by serotonin-release assay (SRA). The IgG-specific EIAs are recommended for screening, as their high sensitivity is accompanied by relatively high specificity vis-à-vis polyspecific EIAs. We investigated the frequency of SRA-positive/EIA-negative (SRA+/EIA-) HIT, prompted by referral to our reference HIT laboratory of serial blood samples from a patient ("index case") with false-negative IgG-specific EIAs. Despite initial clinical suspicion for HIT, repeat negative IgG-specific EIAs prompted heparin resumption, which triggered recurrent thrombocytopenia and near-fatal cardiac arrest, indicating likely post-heparin HIT-associated anaphylactoid reaction. Further investigations revealed a strong-positive SRA, whether performed with heparin alone, PF4 alone, or PF4/heparin, with inhibition by Fc receptor-blocking monoclonal antibody (indicating IgG-mediated platelet activation); however, five different IgG-specific immunoassays yielded primarily negative (or weak-positive) results. To investigate the frequency of SRA+/EIA- HIT, we reviewed the laboratory and clinical features of patients with this serological profile during a 6-year period in which our reference laboratory investigated for HIT using both SRA and IgG-specific EIA. Although ~0.2% of 8546 patients had an SRA+/EIA- profile, further review of 15 such cases indicated clerical/laboratory misclassification or false-positive SRA in all, with no SRA+/EIA- HIT case identified. We conclude that while SRA+/EIA- HIT is possible-as shown by our index case-this clinical picture is exceptionally uncommon. Moreover, the requirement for a positive EIA is a useful quality control maneuver that reduces risk of reporting a false-positive SRA result.

Pharmacological evaluation of analgesic, anti-inflammatory and antipyretic activities of ethanolic extract of Indigofera argentea Burm. f.

ETHNOPHARMACOLOGICAL RELEVANCE: Indigofera argentea Burm. f.; commonly known as neel, jantari, hathio; is traditionally used for the treatment of headache, fever, inflammation and body pain. Local communities also used this plant for the treatment of malaria, jaundice, vertigo and gastric disorders. AIM OF THE STUDY: This study is aimed to evaluate the toxicity and possible analgesic, anti-inflammatory and antipyretic activities of the ethanolic crude extract of Indigofera argentea (IaCr) to support its use in folk medicine and to screen the phytochemical constituents and antioxidant activity. MATERIALS AND METHODS: Aqueous ethanolic (30:70) extract of whole plant of Indigofera argentea (IaCr) was prepared and phytochemical study was performed by preliminary methods followed by HPLC and DPPH method. In vivo experiments were performed in Wistar albino rats including hot plate, tail immersion, formalin and capsaicin-induced pain tests in rats and acetic acid-induced writhing test in mice. Anti-inflammatory activity was assessed by using in vitro human red blood cell (HRBC) membrane stabilization and carrageenan-induced rat paw edema test, while antipyretic activity was evaluated by Brewer's yeast-induced pyrexia test. RESULTS: The crude extract of Indigofera argentea confirmed the presence of flavonoids, glycosides, alkaloids, saponins and tannins as soluble ethanolic constituents in preliminary study. The maximum quantity of gallic acid equivalent (GAE) phenolics, and quercetin equivalent (QE) flavonoid content found was 81 ± 2 mg GAE/g and 56 ± 1.4 mg QE/g of extract respectively. Quantification based on HPLC exposed the presence of phenols and flavonoids, quercetin, gallic acid, caffeic acid, chlorogenic acid, benzoic acid, ferulic acid and coumaric acid. In vivo experiments revealed significant P < 0.05) dose-dependent inhibition in hot plate, tail immersion and capsaicin-induced pain test. IaCr showed significant inhibition of pain latency against both phases in formalin test and considerably decreased the number of writhes caused by acetic acid at the doses of 30, 100 and 300 mg/kg. In the in vitro anti-inflammatory (HRBC) assay, IaCr showed good membrane stability with maximum percentage hemolysis inhibition of 49.29% while in carrageenan-induced paw edema test in rats the IaCr showed significant anti-inflammatory action in a dose-dependent fashion. Statistical significant reduction in rectal temperature was observed at the doses of 100 and 300 mg/kg in yeast-induced pyrexia test in rats. CONCLUSION: The results of the experimental studies proved the analgesic, anti-inflammatory and antipyretic activities of Indigofera argentea and supported the traditional use of this plant.

Increase in PKCα Activity during Heart Failure Despite the Stimulation of PKCα Braking Mechanism.

Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the ß-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C α (PKCα) activity may fit the criteria of a therapeutic target with milder systemic effects that still boosts contractility in HF patients. PKCα activity has been observed to increase during HF. This increase in PKCα activity is perplexing because it is also accompanied by up-regulation of a molecular braking mechanism. Objective: I aim to explore how PKCα activity can be increased and maintained during HF despite the presence of a molecular braking mechanism. Methods and Results: Using a computational approach, I show that the local diacylglycerol (DAG) signaling is regulated through a two-compartment signaling system in cardiomyocytes. These results imply that after massive myocardial infarction (MI), local homeostasis of DAG signaling is disrupted. The loss of this balance leads to prolonged activation of PKCα, a key molecular target linked to LV remodeling and dysfunctional filling and ejection in the mammalian heart. This study also proposes an explanation for how DAG homeostasis is regulated during normal systolic and diastolic cardiac function. Conclusions: I developed a novel two-compartment computational model for regulating DAG homeostasis during Ang II-induced heart failure. This model provides a promising tool with which to study mechanisms of DAG signaling regulation during heart failure. The model can also aid in identification of novel therapeutic targets with the aim of improving the quality of life for heart failure patients.

Studies on antidiarrheal and laxative activities of aqueous-ethanol extract of Asphodelus tenuifolius and underlying mechanisms.

BACKGROUND: Asphodelus tenuifolius Cav. (Asphodelaceae) has traditional reputability in treatment of diarrhea and constipation but no scientific study has been reported for its gastrointestinal effects. Present study was conducted to evaluate antidiarrheal and laxative activities of the plant. METHODS: Aqueous-ethanol crude extract of Asphodelus tenuifolius (At.Cr) was subjected to phytochemical screening and liquid-liquid fractionation. In vivo studies of charcoal meal intestinal transit test, antidiarrheal activity against castor oil induced diarrhea and laxative activity were performed in mice. In vitro experiments were conducted upon rabbit jejunum preparations using standard tissue bath techniques. RESULTS: Phytochemical screening indicated presence of alkaloids, anthraquinones, flavonoids, saponins, steroids, tannins and phenols in At.Cr. In charcoal meal intestinal transit test, At.Cr increased (p < 0.001) intestinal motility at 100 mg/kg dose, but decreased (p < 0.001) it at 500 mg/kg dose, when compared to the control group. At.Cr (300-700 mg/kg) provided protection from castor oil induced diarrhea in mice, which was significant (p < 0.001) at 500 and 700 mg/kg doses, as compared to the saline treated control group. At.Cr (50 and 100 mg/kg) enhanced total and wet feces counts in normal mice, as compared to saline treated control. In jejunum preparations, At.Cr inhibited spontaneous, K+ (80 mM) and K+ (25 mM) mediated contractions, similar to verapamil. Pre-incubation of jejunum preparations with At.Cr resulted in rightward nonparallel shift in Ca+ 2 concentration response curves, similar to verapamil. The spasmolytic activity was concentrated in ethylacetate fraction. Aqueous fraction exhibited spasmogenicity upon spontaneous contractions, which was blocked in presence of verapamil, but remained unaffected by other tested antagonists. CONCLUSION: The Asphodelus tenuifolius crude extract possesses gut modulatory activity, which may normalize gut functions in diarrhea and constipation. The spasmolytic activity of the extract was found to be mediated through Ca+ 2 channel blocking action. The spasmogenic activity, found partitioned in aqueous fraction, possibly involves Ca+ 2 influx through voltage gated Ca+ 2 channels. The study supports ethnic uses of the plant in diarrhea and constipation.

Antidiabetic and antidyslipidemic potential of Echinops echinatus in rat models of type I and type II diabetes.

Echinops echinatus is traditionally an important plant that finds its extensive use as a diuretic, anti-inflammatory, anti-pyretic, nerve tonic, abortifacient, aphrodisiac, antiasthmatic, and antidiabetic agent. The current study investigates protection against the hyperglycemia and dyslipidemia in alloxan-induced (type I diabetes) and fructose-fed insulin resistance (type II diabetes) models of diabetes treated with aqueous methanolic root extract of E. echinatus (Ee.Cr). Albino rats were treated orally with Ee.Cr at doses 100, 300 and 500mg/kg. The fasting blood glucose was measured by glucometer, while standard kits were used to determine the levels of serum total cholesterol, triglycerides and HDL. The administration of Ee.Cr significantly (P<0.001) reduced the FBG concentration in a dose-dependent pattern in alloxan-induced and fructose-fed diabetic rats. The Ee.Cr also corrected the dyslipidemia associated with fructose and alloxan-induced diabetes by significantly (P<0.001) decreasing the concentration of serum total cholesterol, triglycerides, and LDL and by increasing HDL concentration. Ee.Cr also significantly (P<0.001) improved the glucose tolerance in fructose-fed rats. We conclude that Ee.Cr has antidiabetic and antidyslipidemic effects in both insulin-dependent alloxan-induced diabetes and fructose-induced insulin resistance diabetes rat models.

Prospective nonrandomized study with early steroid withdrawal (Day 5) postrenal transplant in low immunological risk patients: A singlecenter experience at prince sultan military medical city Riyadh.

Steroids remain an essential part of immunosuppressive therapy for renal transplant patients since the start of transplant era. Different immunosuppressive regimens are prescribed so as to minimize the side effects. The purpose of our study is to compare the outcome of early steroid withdrawal with steroid maintenance protocol. It is a prospective nonrandomized study. All patients that received renal transplants from January 2011 to December 2013 were included in the study. Early steroid withdrawal at day 5 was done in low immunological risk patients, and the results were compared with the steroid maintenance group, at one-year, posttransplant. Outcome measures included acute rejection (AR), slow graft function and delayed graft function (SGF and DGF), patient and graft survival, and new-onset diabetes after transplant (NODAT), dyslipidemia, hypertension, and obesity. A total of 249 patients were divided into two groups - 105 patients had early steroid withdrawal and 144 patients were maintained on steroid therapy. Outcome measures were compared one-year posttransplant. There was no significant difference in AR, patient and graft survival, creatinine level, and weight gain. However, a significant difference in systolic and diastolic blood pressure, lipid profile, NODAT, SGF, and DGF was found in the steroid group. Our study shows that early steroid withdrawal is a safe standard of care in low immunological risk patients.

Simplified Model of PKCγ Signaling Dysregulation and Cytosol-to-Membrane Translocation Kinetics During Neurodegenerative Spinocerebellar Ataxia Type 14 (SCA14).

Spinocerebellar ataxia type 14 (SCA14) is an autosomal neurodegenerative disease clinically characterized by progressive ataxia in the patient's gait, accompanied by slurred speech and abnormal eye movements. These symptoms are linked to the loss of Purkinje cells (PCs), which leads to cerebellar neurodegeneration. PC observations link the mutations in PRKCG gene encoding protein kinase C γ (PKCγ) to SCA14. Observations also show that the link between PKCγ and SCA14 relies on a gain-of-function mechanism, and, in fact, both positive and negative regulation of PKCγ expression and activity may result in changes in cellular number, size, and complexity of the dendritic arbors in PCs. Here, through a systems biology approach, we investigate a key question relating to this system: why is PKCγ membrane residence time reduced in SCA14 mutant PCs compared to wild-type (WT) PCs? In this study, we investigate this question through two contrasting PKCγ signaling models in PCs. The first model proposed in this study describes the mechanism through which PKCγ signaling activity may be regulated in WT PCs. In contrast, the second model explores how mutations in PKCγ signaling affect the state of SCA14 in PCs. Numerical simulations of both models show that, in response to extracellular stimuli-induced depolarization of the membrane compartment, PKCγ and diacylglycerol kinase γ (DGKγ) translocate to the membrane. Results from our computational approach indicate that, for the same set of parameters, PKCγ membrane residence time is shorter in the SCA14 mutant model compared to the WT model. These results show how PKCγ membrane residence time is regulated by diacylglycerol (DAG), causing translocated PKCγ to return to the cytosol as DAG levels drop. This study shows that, when the strength of the extracellular signal is held constant, the membrane lifetime of mutant PKCγ is reduced. This reduction is due to the presence of constitutively active mutant PKCγ in the cytosol. Cytosolic PKCγ, in turn, leads to phosphorylation and activation of DGKγ while it is still residing in the cytosol. This effect occurs even during the resting conditions. Thus, the SCA14 mutant model explains that, when both DAG effector molecules are active in the cytosol, their interactions in the membrane compartment are reduced, critically influencing PKCγ membrane residence time.

The Nutritional and Phytochemical Composition of the Indigenous Australian Pindan Walnut (Terminalia cunninghamii) Kernels.

Nutritional composition of the kernels of two types of Pindan walnut (Terminalia cunninghamii), a native nut consumed traditionally by Australian Indigenous peoples, is reported for the first time. Results showed that Pindan walnut kernels contained high levels of fat, protein and ash, approximately 50, 30 and 5% fresh basis, respectively. The levels of minerals in the kernels were much higher than common walnuts and macadamia nuts, especially those of phosphorus, magnesium and zinc. The high amounts of polyphenols in the kernels provided strong hydrophilic antioxidant capacities, of up to 2004 mg Trolox equivalents/100 g fresh basis using the hydrophilic oxygen radical absorbance capacity assay. Both free polyphenol content and hydrophilic antioxidant capacities of the kernels were higher than those of macadamia nuts, although the lipophilic oxygen radical absorbance capacity was lower. These preliminary studies indicate high potential for wider use of the Pindan walnut as a novel, nutritious and health-promoting food.

Antispasmodic and bronchorelaxant activities of Salsola imbricata are mediated through dual Ca+2 antagonistic and ß-adrenergic agonistic effects.

CONTEXT: Salsola imbricata Forssk. (Chenopodiaceae) has folkloric repute for the treatment of various gastrointestinal and respiratory ailments. OBJECTIVE: The present study investigates spasmolytic and bronchorelaxant effects of S. imbricata. MATERIALS AND METHODS: The crude aqueous-ethanol extract of the aerial parts of S. imbricata and its fractions, in cumulative concentrations (0.01-10 mg/mL), were tested on contractions of isolated rabbit jejunum and tracheal preparations. Furthermore, concentration response curves (CRCs) of Ca+2 and carbachol were constructed in the absence and presence of the extract. Standard organ bath methods were used. RESULTS: The crude extract relaxed spontaneous, K+ (80 mM) and carbachol (1 µM)-induced contractions in jejunum preparations with respective EC50 values of 0.40 (0.35-0.46), 0.69 (0.60-0.79) and 0.66 (0.57-0.75) mg/mL. It shifted Ca+2 CRCs rightward in nonparallel manner. In isolated tracheal preparations, the crude extract caused relaxation of K+ (80 mM) and carbachol (1 µM)-induced contractions with EC50 values of 0.86 (0.75-0.98) and 0.74 (0.66-0.84) mg/mL, respectively. It displaced carbachol CRCs rightward with suppression of maximal response. In both tissues, pretreatment with propranolol (1 µM) caused rightward shift in inhibitory CRCs of the extract against carbachol-induced contractions. The ethyl acetate fraction was found more potent in relaxing smooth muscle contractions than the parent extract and its aqueous fraction. DISCUSSION AND CONCLUSION: The results suggest that the spasmolytic and bronchorelaxant activities of S. imbricata are related to Ca+2 antagonistic and ß-adrenergic agonistic effects, thus justifying some of the traditional uses of the plant.

Higher Levels of Aflatoxin M1 Contamination and Poorer Composition of Milk Supplied by Informal Milk Marketing Chains in Pakistan.

The present study was conducted to observe the seasonal variation in aflatoxin M1 and nutritional quality of milk along informal marketing chains. Milk samples (485) were collected from three different chains over a period of one year. The average concentrations of aflatoxin M1 during the autumn and monsoon seasons (2.60 and 2.59 ppb) were found to be significantly higher (standard error of the difference, SED = 0.21: p = 0.003) than in the summer (1.93 ppb). The percentage of added water in milk was significantly lower (SED = 1.54: p < 0.001) in summer (18.59%) than in the monsoon season (26.39%). There was a significantly different (SED = 2.38: p < 0.001) mean percentage of water added by farmers (6.23%), small collectors (14.97%), large collectors (27.96%) and retailers (34.52%). This was reflected in changes in milk quality along the marketing chain. There was no difference (p = 0.178) in concentration of aflatoxin M1 in milk collected from the farmers (2.12 ppb), small collectors (2.23 ppb), large collectors (2.36 ppb) and retailers (2.58 ppb). The high levels of contamination found in this study, which exceed the standards set by European Union (0.05 ppb) and USFDA (0.5 ppb), demand radical intervention by regulatory authorities and mass awareness of the consequences for consumer health and safety.

Sharp Central Venous Recanalization in Hemodialysis Patients: A Single-Institution Experience.

PURPOSE: We report our institutional experience with sharp central venous recanalization in chronic hemodialysis patients who failed standard techniques. MATERIALS AND METHODS: Since January 2014, a series of seven consecutive patients (four males and three females), mean age 35 years (18-65 years), underwent sharp central venous recanalization. Indications included obtaining hemodialysis access (n = 6) and restoration of superior vena cava (SVC) patency to alleviate occlusion symptoms and restore fistula function (n = 1). The transseptal needle was used for sharp recanalization in six patients, while it could not be introduced in one patient due to total occlusion of the inferior vena cava. Instead, transmediastinal SVC access using Chiba needle was obtained. RESULTS: Technical success was achieved in all cases. SVC recanalization achieved symptoms' relief and restored fistula function in the symptomatic patient. One patient underwent arteriovenous fistula creation on the recanalized side 3 months after the procedure. The remaining catheters were functional at median follow-up time of 9 months (1-14 months). Two major complications occurred including a right hemothorax and a small hemopericardium, which were managed by covered stent placement across the perforated SVC. CONCLUSION: Sharp central venous recanalization using the transseptal needle is feasible technique in patients who failed standard recanalization procedures. The potential high risk of complications necessitates thorough awareness of anatomy and proper technical preparedness.

ANTIDIABETIC AND ANTIDYSLIPIDEMIC EFFECTS OF HELIOTROPIUM STRIGOSUM IN RAT MODELS OF TYPE I AND TYPE II DIABETES.

Heliotropiumz stnigosum Wilid. (Boraginaceae) is used traditionally as a laxative, diuretic, and as a treatment for snake bites and stings of nettles. Recent investigations have shown anti-inflammatory and antioxidant activity of H. sorigosum. However, antihyperglycemic and antidyslipidemic activity of H. strigosum has not been investigated to date and we aimed to explore these activities of the crude aqueous methanolic extract of thEaerial parts of H. strigosum (Hs.Cr). Hs.Cr was administered orally at doses of 100, 300, and 500 mg/kg in alloxan-induced diabetic rats (type I diabetes) and fructose-fed rats (type II diabetes). The fasting blood glucose (FBG) concentration was assessed by glucometer, while semum total cholesterol, triglycerides and HDL were estimated by using standard kits. The FBG concentration significantly (p < 0.05) decreased in dose-dependent pattern in both alloxan-induced diabetic and fructose-fed rats on Hs.Cr administration. The percentage glucose reductions in alloxanized rats with glibenclamide, Hs.Cr 100, 300, and 500 mg/kg were obeserved to be 67, 36, 56 and 62%, respectively. In fructose-fed rats, the percentage glucose redutions associated with metformin, Hs.Cr 100, 300, and 500 mg/kg were 23, 5, 11 and 12%, respectively. The extract also corrected the dyslipidemia associated with fructose and alloxan-induced diabetes by significantly (p < 0.00 1) decreasing the concentration of serum total cholesterol, triglycerides and LDL and by increasing HDL concentration. Our data demonstrate that the H. stigosum has antidiabetic and antidyslipidemic effects, thus encouraging further studies.