Effect of Lithium on Rat Cerebrum Under Different Dietary Protein Regimens

This study was designed to investigate the effects of lithium in adult rat brain under different dietary protein regimens. Lithium as carbonate was given at a dose of 1.1 g/kg diet to female rats fed normal (18% protein), low protein (8% protein), and high protein (30% protein) diets for 30 days. Lithium treatment resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin in the cerebrum of the rat brain. Further, administration of lithium to rats fed low protein (LP) and high protein (HP) diets also showed a significant decrease in the levels of norepinephrine and dopamine but caused no significant change in the serotonin concentration. Lithium administration to normal diet, LP, and HP groups resulted in a significant increase in the activities of acetylcholinesterase and monoamine oxidase. Lithium treatment led to decrease in the activity of enzyme Na⁺ K⁺ ATPase in all groups. On the second day, the LP group showed enhanced transfer latency (TL), a dependent variable to study elevated plus-maze test, whereas HP diet went from 34% reduction to normal. On the other hand, lithium administration restored the already enhanced TL in the LP group. The study concludes that lithium treatment to protein-deficient cases may not further aggravate the effects of protein-deficient conditions, but it may afford protection.     

Effects of chronic plus acute prolonged stress on measures of coping style, anxiety, and evoked HPA-axis reactivity

Exposure to psychological trauma is the precipitating factor for PTSD. In addition, a history of chronic or traumatic stress exposure is a predisposing risk factor. We have developed a Chronic plus Acute Prolonged Stress (CAPS) treatment for rats that models some of the characteristics of stressful events that can lead to PTSD in humans. We have previously shown that CAPS enhances acute fear responses and impairs extinction of conditioned fear. Further, CAPS reduced the expression of glucocorticoid receptors in the medial prefrontal cortex. In this study we examined the effects of CAPS exposure on behavioral stress coping style, anxiety-like behaviors, and acute stress reactivity of the hypothalamic–pituitary–adrenal (HPA) axis. Male Sprague-Dawley rats were exposed to CAPS treatment, consisting of chronic intermittent cold stress (4 °C, 6 h/day, 14 days) followed on day 15 by a single 1-h session of sequential acute stressors (social defeat, immobilization, swim). After CAPS or control treatment, different groups were tested for shock probe defensive burying, novelty suppressed feeding, or evoked activation of adrenocorticotropic hormone (ACTH) and corticosterone release by an acute immobilization stress. CAPS resulted in a decrease in active burying behavior and an increase in immobility in the shock probe test. Further, CAPS-treated rats displayed increases in the latency to feed in the novelty suppressed feeding test, despite an increase in food intake in the home cage. CAPS treatment also reduced the HPA response to a subsequent acute immobilization stress. These results further validate CAPS treatment as a rat model of relevance to PTSD, and together with results reported previously, suggest that CAPS impairs fear extinction, shifts coping behavior from an active to a more passive strategy, increases anxiety, and alters HPA reactivity, resembling many aspects of human PTSD.     

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Objective: Report efficacy findings from three clinical trials (one phase 2 and two phase 3 [OPUS-1, OPUS-2]) of lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease (DED).

Research design and methods: Three 84-day, randomized, double-masked, placebo-controlled trials. Adults (≥18 years) with DED were randomized (1:1) to lifitegrast 5.0% or matching placebo. Changes from baseline to day 84 in signs and symptoms of DED were analyzed.

Main outcome measures: Phase 2, pre-specified endpoint: inferior corneal staining score (ICSS; 0–4); OPUS-1, coprimary endpoints: ICSS and visual-related function subscale (0–4 scale); OPUS-2, coprimary endpoints: ICSS and eye dryness score (EDS, VAS; 0–100).

Results: Fifty-eight participants were randomized to lifitegrast 5.0% and 58 to placebo in the phase 2 trial; 293 to lifitegrast and 295 to placebo in OPUS-1; 358 to lifitegrast and 360 to placebo in OPUS-2. In participants with mild-to-moderate baseline DED symptomatology, lifitegrast improved ICSS versus placebo in the phase 2 study (treatment effect, 0.35; 95% CI, 0.05–0.65; p?=?0.0209) and OPUS-1 (effect, 0.24; 95% CI, 0.10–0.38; p?=?0.0007). Among more symptomatic participants (baseline EDS ≥40, recent artificial tear use), lifitegrast improved EDS versus placebo in a post hoc analysis of OPUS-1 (effect, 13.34; 95% CI, 2.35–24.33; nominal p?=?0.0178) and in OPUS-2 (effect, 12.61; 95% CI, 8.51–16.70; p?<?0.0001).

Limitations: Trials were conducted over 12 weeks; efficacy beyond this period was not assessed.

Conclusions: Across three trials, lifitegrast improved ICSS in participants with mild-to-moderate baseline symptomatology in two studies, and EDS in participants with moderate-to-severe baseline symptomatology in two studies. Based on the overall findings from these trials, lifitegrast shows promise as a new treatment option for signs and symptoms of DED.     

The impact of functional constipation on quality of life of middle-aged Black Americans: a prospective case–control study

Purpose

To quantify the impact of constipation on health-related quality of life (HRQoL) in Black Americans.

Methods

Case?Ccontrol design. Black subjects referred for colon cancer screening with a Bristol Stool Score of 3?C5 for >75% of bowel movements served as controls. Frequency-matched functional constipation subjects had to fulfill Rome III criteria. Both groups completed demographic and health surveys. Short Form-36 assessed HRQoL.

Results

We recruited 102 constipated patients and 100 controls. The groups were well matched demographically. After adjustment for comorbidities, SF-36 scores for vitality, bodily pain, social functioning, and role-emotional were significantly lower in constipated patients. Unadjusted physical and mental component summary scores (PCS and MCS) were significantly higher in the control group (47.1?±?10.6 vs. 43.3?±?8.6; P?=?0.005 and 50.6?±?12.4 vs. 43.4?±?11.8; P?<?0.001, respectively). After adjustment for comorbidities, PCS differences were no longer significant (P?=?0.54); however, MCS differences were significant (P?=?0.004). Marginal mean scores for the MCS for controls and constipated subjects were 49.9?±?1.2 and 43.6?±?1.2, respectively. The presence of a comorbidity was independently associated with PCS (P?<?0.001) and MCS (P?=?0.026) results.

Conclusions

Functional constipation has a significant impact on HRQoL in middle-aged Black Americans, particularly in regard to mental well-being.     

Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune-prone NZB/W female mice

OBJECTIVE: Cyclophosphamide (CTX), an alkylating agent, is extensively used in the treatment of lupus nephritis, but its administration has been associated with free radical mediated oxidative stress. The present study was designed to investigate the effect of dietary corn oil (CO), fish oil (FO) and food restriction (FR) on the activities of hepatic antioxidant enzymes, fatty acid composition and lipid peroxidation following CTX administration in autoimmune-prone NZB/W female mice. METHODS: Autoimmune-prone NZB/W female mice were fed either ad libitum (AL) or food restricted (60% of AL intake), semipurified diets containing 5% CO or 5% FO supplemented with equal levels of antioxidants and injected with either phosphate buffered saline (PBS), or CTX (50 mg/kg body weight) every 10 days. Proteinuria was measured biweekly. The treatment was stopped at 10 months and diets were continued until the mice were killed at 12 months. Fatty acid composition, activity of antioxidant enzymes and lipid peroxidation were analyzed in liver homogenates, and anti-DNA antibodies were analyzed in the serum. RESULTS: Mice in the FO/AL dietary group exhibited significantly higher liver catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities compared to the CO/AL dietary group. CTX significantly decreased SOD and GSH-Px activity in the FO/AL group and CAT and GSH-Px in the CO/AL group. In AL fed mice given CTX, activities of CAT, GSH-Px and GST were significantly higher in mice fed FO diets than in mice fed CO diets. FR increased the activity of enzymes in both the CO and FO diet groups. In FR mice, CTX decreased CAT and GSH-Px activity in both the CO and FO dietary groups, but glutathione S-transferase (GST) only in the CO group. The decrease in SOD activity was not significant in either of the restricted groups. CTX significantly increased generation of thiobarbituric acid reactive substances (TBARS) in both AL groups. FR significantly decreased lipid peroxidation in both the CO and FO groups, with or without CTX. CTX decreased serum anti-DNA antibody levels in both the CO and FO dietary groups. FR also decreased antibody titer in both the CO and FO dietary groups, and it was decreased further with CTX treatment. FO fed animals had higher levels of n-3 fatty acids, whereas CO fed animals had high levels of n-6 fatty acids. CTX significantly increased 20:4 and decreased 18:1 in CO/AL fed animals, whereas it increased 18:1 and decreased 22:6 in FO/AL fed animals. CONCLUSIONS: Results obtained in the present study suggests that FO and, more significantly, FO combined with FR can have a beneficial effect in hepatic tissues subjected to CTX induced oxidative stress by regulating the activity of antioxidant enzymes. In addition, the study also indicates that n-3 and n-6 dietary lipids are susceptible to lipid peroxidation, particularly in the presence of a prooxidant like CTX, and that FR is beneficial in decreasing lipid peroxidation. The study also suggests that FO and CTX can have additive effects in preventing kidney disease in NZB/W mice.     

Replacement-fed infants born to HIV-infected mothers in India have a high early postpartum rate of hospitalization

Access to safe breast-feeding alternatives for HIV-infected mothers and their infants in many settings is limited. We compared the rates of early postpartum hospitalization of infants born to HIV-infected mothers using different infant-feeding practices in a large government hospital in Pune, India. From March 1, 2000 to November 30, 2001, infants born to HIV-infected mothers were followed in a postpartum clinic. All mothers had received a standard short course of antenatal zidovudine. Infant-feeding practices were assessed within 3 d of delivery, prior to postpartum hospital discharge. Sixty-two of 148 mothers (42%) were breast-feeding their infants. Eighty-six of the mothers (58%) were providing replacement feeding, primarily diluted cow, goat or buffalo milk (top feeding). Twenty-one of the 148 participating infants (14.2%) born during the study period required hospitalization within the 1st 6 mo of life and 6 infants required repeat hospitalization. All hospitalized infants were receiving replacement feeding with a rate of 0.093 hospitalizations per 100 person-days (95% CI, 0.062 to 0.136). The reasons for hospitalization included acute gastroenteritis (48.1%), pneumonia (18.5%), septicemia (11.1%) and jaundice (11.1%). A high risk for early postpartum hospitalization was seen in replacement-fed infants born to HIV-infected mothers in Pune, India. In settings such as India, where access to safe replacement feeding is limited, interventions making exclusive breast-feeding safer for HIV-infected mothers and infants are needed. Such interventions would be valuable additions to the very effective national prevention programs that currently rely on the provision of short-course zidovudine and nevirapine.     

Role of dietary phenols in mitigating microglia-mediated neuroinflammation

Chronic neuroinflammation is a pathological feature of a number of central nervous system (CNS) diseases and is mediated by sustained activation of microglial cells, the innate immune cells of the CNS. Studies have mainly focused on identifying the molecular and epigenetic mechanisms of microglial activation. This is crucial in designing therapeutic strategies for neuropathologies in which prolonged microglial activation is known to exacerbate disease condition. In recent years, increasing evidence show that naturally occurring compounds present in regular diet could function as “nutraceuticals,” arresting microglial activation, and thus conferring neuroprotection. This review summarizes our understanding of the role of dietary phenolic nutraceuticals in mitigating microglia-mediated neuroinflammation. Studies show that these natural phenols inhibit key signaling pathways in activated microglia such as the NFκB, MAPK and JAK-STAT that trigger microglia-mediated inflammation in various neuropathological conditions such as injury, infection, stroke, autism and neurodegenerative diseases, i.e., Alzheimer’s disease and Parkinson’s disease. The anti-inflammatory and antioxidant effect exerted by these natural phenols have shown considerable success in improving disease condition in animal models of neuropathologies, and thus seem to be suitable candidates for developing therapeutic strategies.     

Antimicrobial Resistance in Salmonella in the United States from 1948 to 1995

We conducted a retrospective study of 2,149 clinical Salmonella strains to help document the historical emergence of antimicrobial resistance. There were significant increases in resistance to older drugs, including ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline, which were most common in Salmonella enterica serotype Typhimurium. An increase in multidrug resistance was observed for each decade since the 1950s. These data help show how Salmonella evolved over the past 6 decades, after the introduction of new antimicrobial agents.     

Anti-inflammatory property of n-hexadecanoic acid: structural evidence and kinetic assessment

Ester bond hydrolysis of membrane phospholipids by Phospholipase A₂ and consequent release of fatty acids are the initiating steps of inflammation. It is proposed in this study that the inhibition of phospholipase A₂ is one of the ways to control inflammation. Investigations are carried out to identify the mode of inhibition of phospholipase A₂ by the n‐hexadecanoic acid. It may help in designing of specific inhibitors of phospholipase A₂ as anti‐inflammatory agents. The enzyme kinetics study proved that n‐hexadecanoic acid inhibits phospholipase A₂ in a competitive manner. It was identified from the crystal structure at 2.5 Å resolution that the position of n‐hexadecanoic acid is in the active site of the phospholipase A₂. The binding constant and binding energy have also been calculated using Isothermal Titration Calorimetry. Also, the binding energy of n‐hexadecanoic acid to phospholipase A₂ was calculated by in silico method and compared with known inhibitors. It may be concluded from the structural and kinetics studies that the fatty acid, n‐hexadecanoic acid, is an inhibitor of phospholipase A₂, hence, an anti‐inflammatory compound. The inferences from the present study validate the rigorous use of medicated oils rich in n‐hexadecanoic acid for the treatment of rheumatic symptoms in the traditional medical system of India, Ayurveda.