Abstract Simulated hypobaric hypoxia (HBH), resembling high altitude hypoxia severely affects the CNS and results in several physiological changes. The hippocampus is closely associated with learning ...and memory and an insult to this region affects cognition. Previous studies suggest that rapid or prolonged exposures to HBH are associated with psychomotor and cognitive impairments. The defense personnel, mountain climbers and rescue teams are exposed to such harsh environment and thus it demands a systematic study emphasizing the subtle effects of such extreme environments on cognitive function. Accordingly, this study evaluated the effect of hypobaric hypoxia on structural changes in the principal neurons of the hippocampus and learning in eight-arm radial maze. Adult male Wistar rats, subjected to simulated hypobaric hypoxia equivalent to an altitude of 6000 m for a period of 2 or 7 days, in a hypoxic chamber served as hypoxic group (HY). Rats housed in a similar chamber for the same period of time, without hypoxic exposure served as sham control (SC), while normal control (NC) group of rats were housed in standard laboratory conditions. The dendritic morphology of neurons in cornu ammonis region 1 (CA1) and cornu ammonis region 3 (CA3) was studied in Golgi-impregnated hippocampal sections. Exposure for 2 days to hypobaric hypoxia had minimal deleterious effects on the CA1 pyramidal neurons, while exposure for 7 days resulted in a significant decrease in the number of branching points, intersections and dendritic length. Unlike the CA1 pyramidal neurons, the CA3 neurons exhibited dendritic atrophy following both 2 and 7 days of hypoxic exposure. Further, hippocampal-dependent spatial learning was affected marginally following 2 day exposure, while 7 day exposure severely affected learning of the partially baited radial arm maze task. Our study suggests that dendritic atrophy in the hippocampus on exposure to HBH could be one of the bases for the cognitive deficits exhibited under such conditions.
In a randomized, double-blind, crossover design, we compared the efficacy of sildenafil with placebo in patients with primary pulmonary hypertension (PPH). The primary end point was the change in ...exercise time on treadmill using the Naughton protocol. Secondary end points were change in cardiac index and pulmonary artery systolic pressure as assessed by Doppler echocardiography and quality of life (QOL) as assessed by a questionnaire.
Primary pulmonary hypertension is a disorder with limited treatment options. Uncontrolled studies had shown sildenafil to be beneficial in the treatment of PPH.
After initial clinical evaluation, including Doppler echocardiography and treadmill exercise test, patients were randomized to placebo or sildenafil with dosages ranging from 25 to 100 mg thrice daily on the basis of body weight. The evaluation was repeated after six weeks. Then patients were crossed over to alternate therapy. Final evaluation was performed after another six weeks of treatment.
Twenty-two patients completed the study. Exercise time increased by 44% from 475 +/- 168 s at the end of placebo phase to 686 +/- 224 s at the end of sildenafil phase (p < 0.0001). With sildenafil, cardiac index improved from 2.80 +/- 0.9 l/m2 to 3.45 +/- 1.1 l/m(2) (p < 0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 +/- 17.82 mm Hg to 98.50 +/- 24.38 mm Hg. There was significant improvement in the dyspnea and fatigue components of the QOL questionnaire. During the placebo phase, one patient died and another had syncope. There were no serious side effects with sildenafil.
Sildenafil significantly improves exercise tolerance, cardiac index, and QOL in patients with PPH.
Purpose
No systematic review has compared the clinical outcome of anterior stabilized ultra-congruent and standard cruciate-retaining inserts in fixed-bearing primary total knee arthroplasty. This ...study aimed to compare the outcomes and establish the superiority or equivalence of these inserts.
Methods
Pubmed, EMBASE, Medline, AMED, ERIC, and Proquest databases were searched electronically. PRISMA guidelines were followed in the conduct of the study. The clinical outcomes compared in the meta-analysis were overall knee score, WOMAC, score for knee function, score for knee pain, SF-12 PCS, knee flexion, manipulation under anaesthesia for postoperative knee stiffness, revision total knee arthroplasty or change of polyethylene insert for post-operative instability (relative risk RR) and survivorship. Study quality was evaluated using the Newcastle Ottawa Scale and the Modified Jadad scale.
Results
Fourteen studies comprising 9989 knees (three RCTs and 11 comparative case-cohort studies) were included for qualitative and quantitative analysis. The pooled analysis of the ultracongruent insert and the standard cruciate retaining insert was based on a cohort of 2860 and 7129 TKA, respectively. Knee pain was significantly better in patients that had standard inserts (
p
= 0.02; 95% CI − 1.06 to − 0.10), and the physical component of health-related quality of life was also significantly better in patients that had standard inserts (
p
= 0.02; 95% CI − 6.43 to − 0.64). There was a 72% lesser chance of revision TKA or change of insert for postoperative instability in knees that had been implanted with ultracongruent inserts (RR = 0.28;
p
= 0.0002; 95% CI 0.15–0.55). There was no difference in the otheroutcome measures. There was no significant difference between the two inserts, considering the minimal clinically important difference or absolute ratio.
Conclusion
Differences observed between the two types of inserts were not clinically significant. Therefore, based on current evidence, arthroplasty surgeons can use either of these inserts with cruciate-retaining knee prosthesis.
Level of evidence
Therapeutic study, Level II.
In the present paper an attempt is made to evaluate the axial pullout and oblique pullout capacity of hollow aluminum belled piles embedded in sand. A series of model tests were conducted on a model ...piles with different length of piles of 240 mm, 360 mm and 480 mm respectively and length of the pile to diameter of pile (L/D) ratios employed are 5, 7.5 and 10 respectively. A pile of shaft diameter 48 mm is used and the ratio of diameter of bell to diameter of shaft (D
b
/D
s
) is varied as 1.5 and 2 respectively. The bell angle is varied as 30°, 45
o
and 60° respectively. It is further extended to study the influence of oblique pull out capacity by varying the inclination angle as 0°, 30°, and 45° with vertical axis of the piles. The present experimental investigation is conducted in a model box of size equal to 1.2 m × 0.75 m × 1.5 m. All the model tests are conducted at a relative density of 60% corresponding to medium dense state of sand. It is found that as L/D ratio, D
b
/D
s
ratio and bell angle increases, the uplift capacity was found to increase. Also as the oblique angle increases the pullout capacity was found to decrease in belled pile and in case of monopile the pullout capacity was found to increase. The percentage of vertical and horizontal movement reported was found to vary between 1to8% of length of pile and 2 to 50% of diameter of the pile respectively.
Major depressive disorder (MDD) is associated with enhanced anxiety and reduced reward processing leading to impaired cognitive flexibility. These pathological changes during depression are ...accompanied by dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its impaired regulation by the amygdala. Notably, the electrical stimulation of brain reward areas produces an antidepressant effect in both MDD patients and animal models of depression. However, the effects of chronic electrical self-stimulation of lateral hypothalamus - medial forebrain bundle (LH-MFB) on depression-associated anxiety and accompanying changes in plasma corticosterone levels, structural, and neurochemical alterations in the amygdala are unknown. Here, we used the neonatal clomipramine (CLI) model of depression. During adulthood, neonatal CLI and vehicle administered rats were subjected to bilateral electrode implantation at LH-MFB and trained to receive intracranial self-stimulation (ICSS) for 14 days. Rats were then tested for anhedonic and anxiety-like behaviors, followed by estimation of plasma corticosterone levels, assessment of amygdalar volumes and neuronal/glial numbers, levels of monoamines and their metabolites in the amygdala. We found that chronic ICSS of LH-MFB reverses CLI-induced anhedonia and anxiety. Interestingly, amelioration of CLI-induced enhanced anhedonia and anxiety in ICSS rats was associated with partial reversal of enhanced plasma corticosterone levels, hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. We suggest that beneficial effects of ICSS on CLI-induced anxiety at least in part mediated by the restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that brain stimulation rewarding experience might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.
•ICSS of LH-MFB reverses CLI-induced anxiety-like behavior.•Chronic ICSS treatment ameliorates HPA axis dysfunctions in CLI rats.•CLI-induced hypertrophy of BLA was reversed by ICSS treatment.•Neither CLI nor ICSS alters the neuronal or glial numbers in the amygdalar complex.•ICSS reverses altered metabolism of NA in the amygdalar complex of CLI rats.
Depression is highly comorbid with anxiety disorders and associated with profound cognitive impairment. Moreover, cognitive deficits associated with hippocampal dysfunction are central in depression ...and anxiety disorders. Furthermore, depression is accompanied by glutamatergic dysfunction which can further impair the functioning of the hippocampus. Recent studies have shown that N-acetyl cysteine (NAC), a glutamate modulator produces an antidepressant-like effect by normalization of the periterminal release of glutamate and/or antioxidant effects. However, the effects of repeated NAC treatment on depression-induced anxiety, cognitive deficits, and associated neurochemical and structural alterations are relatively unknown. Accordingly, we investigated whether chronic NAC treatment could reverse cognitive deficits, and associated hippocampal volume loss and monoaminergic alterations in the neonatal clomipramine (CLI) model of depression. We found that chronic NAC treatment produces antidepressive and antianhedonic-like effects. NAC treatment also reversed CLI-induced anxiety. Interestingly, repeated NAC treatment improved the performance of CLI rats in rewarded alternation task in T-maze. The antidepressive-like and procognitive effects of NAC was associated with normalization of volume loss in CA1, dentate gyrus (DG) and hilar subfields of the hippocampus. Furthermore, NAC restored CLI-induced decrease in levels of monoamines and normalized enhanced metabolism in the hippocampus. Taken together, chronic NAC treatment ameliorates depressive and anxiety-like behavior, spatial learning deficits, and reverses CLI-induced pathological alterations at structural and neurochemical levels in the hippocampus. Our findings might help in evolving NAC as a viable pharmacotherapy for reversal of cognitive deficits in depression and associated disorders.
•Chronic NAC treatment reverses depressive-like behavior in CLI model of depression.•NAC reverses the CLI-induced anxiety-like behavior.•Repeated NAC treatment ameliorates CLI-induced cognitive deficits.•NAC reverses the CLI-induced volume loss in CA1, DG and hilus.•NAC normalizes the CLI-induced alterations in metabolism of hippocampal monoamines.
Chronic stress decreases neurogenesis in the adult brain, while exposure to enriched environment (EE) increases it. Recent studies demonstrate the ability of EE to ameliorate stress-induced ...behavioral deficits. Whether a restored neurogenesis contributes to these effects of EE is unknown. Recently, we demonstrated that EE following restraint stress restores cell proliferation in the dentate gyrus (DG), hippocampal volume and learning. In the current study, we examine the effects of EE following stress on survival and differentiation of the progenitor cells in the DG and behavioral depression using the forced swim test (FST) and sucrose consumption test (SCT). Adult male Wistar rats were subjected to 21 days of restraint stress followed by housing in either standard or enriched conditions (10 days, 6
h/day). Survival and differentiation of BrdU-labeled cells were evaluated 31 days post-BrdU administration. Stress decreased the survival and differentiation of progenitor cells, which was ameliorated by EE. Also the percentage of BrdU-ir cells that did not co-localize with NeuN or S100β was significantly greater in the stressed rats and was restored by EE. Stress increased immobility in FST and decreased sucrose preference in the SCT, and these behaviors were ameliorated by EE. Adult neurogenesis is thought to be linked to learning and memory and in mediating antidepressant effect. Taken together with our earlier report that EE restores stress-induced impairment in learning and cytogenesis, the current results indicate that the reversal of adult neurogenesis could be one of the mechanisms involved in the amelioration of stress-induced deficits.
Chronic exposure to stress causes cognitive deficits, anxiety and depression. Earlier studies have suggested that the prefrontal cortex (PFC) and basolateral amygdala (BLA) can differentially ...modulate the stress-induced alterations either by their action on HPA axis or via direct reciprocal connections between them. The PFC dysfunction and BLA hypertrophy following stress are known to cause anxiety and affective symptoms. Recent studies indicate that inactivation of BLA projections to PFC remarkably decreases anxiety. However, the effect of BLA inactivation on stress-induced anxiety and associated volume loss in prelimbic (PrL) and anterior cingulate (ACC) subregions of PFC is not known. Accordingly, we evaluated the effect of BLA lesion or inactivation during chronic immobilization stress (CIS) on an approach-avoidance task and associated volume loss in the PFC. The stressed rats showed a significant volumetric reduction in layer I and II of the PrL and ACC. Interestingly, BLA lesion prior to stress prevented the volume loss in PrL and ACC. Further, BLA lesion blocked the anxiety-like behavior in stressed rats. However, in the absence of stress, BLA lesion increased the number of shocks as compared to controls. As BLA lesion produced an anticonflict effect, we performed temporary inactivation of BLA specifically during stress. Similar to BLA lesion, lidocaine-induced inactivation prevented the stress-induced volume loss and anxiety-like behavior. We demonstrate that inactivation of BLA during stress prevents CIS-induced anxiety and associated structural correlates in the PFC. The present study extends the hypothesis of amygdalar silencing as a possible management strategy for stress and associated disorders.
•Chronic immobilization stress (CIS) precipitates anxiety and volume loss in PFC.•CIS-induced volume loss was specific to layer I and II of PFC.•Inactivation of BLA during CIS prevents volume loss in PFC and associated anxiety.•BLA inactivation might prevent CIS-induced emotional deficits via restoration of PFC functions.
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