Septic encephalopathy. Evidence for altered phenylalanine metabolism and comparison with hepatic encephalopathy

We elected to test the hypothesis that the metabolic encephalopathy associated with systemic sepsis may have a pathogenesis that is similar to hepatic encepathology, ie, as the consequence of hepatic dysfunction that induces alterations in synthesis of catecholic and noncatecholic neurotransmitters. Eleven patients with septic encephalopathy were compared with nine patients with septic encephalopathy and nine normal controls with respect to blood and cerebrospinal fluid (CSF) amino acid profile, phenylethylamine and its metabolite phenylacetic acid, and blood ammonia. Blood and CSF levels of phenylacetic acid increased markedly in septic and hepatic encephalopathy while CSF phenylethylamine levels were not increased in either condition, presumably due to rapid turnover. The CSF concentrations of all the aromatic amino acids were increased in hepatic encephalopathy, whereas in the patients with sepsis, only phenylalanine levels were increased. Evidence of stimulated neutral amino acid transport into brain was demonstrated in hepatic not septic encephalopathy and appeared to correlate with the CSF glutamine concentration. Blood ammonia levels were increased in hepatic but not in septic encephalopathy. Our data support the hypothesis that metabolites of phenylethylamine contribute to encephalopathy in systemic sepsis and hepatic failure; however, the entities differ in other respects.     

Tumor location and nature of lymphatic vessels are key determinants of cancer metastasis

Tumor metastasis to lymph nodes is a key indicator of patient survival, and is enhanced by the neo-lymphatics induced by tumor-secreted VEGF-C or VEGF-D, acting via VEGFR-3 signalling. These targets constitute important avenues for anti-metastatic treatment. Despite this new understanding, clinical observations linking metastasis with tumor depth or location suggest that lymphangiogenic growth factors are not the sole determinants of metastasis. Here we explored the influence of tumor proximity to lymphatics capable of responding to growth factors on nodal metastasis in a murine VEGF-D over-expression tumor model. We found that primary tumor location profoundly influenced VEGF-D-mediated lymph node metastasis: 89 % of tumors associated with the flank skin metastasised, in contrast with only 19 % of tumors located more deeply on the body wall (p < 0.01). Lymphatics in metastatic tumors arose from small lymphatics, and displayed distinct molecular and morphological profiles compared with those found in normal lymphatics. Smaller lymphatic subtypes were more abundant in skin (2.5-fold, p < 0.01) than in body wall, providing a richer source of lymphatics for VEGF-D⁺ skin tumors, a phenomenon also confirmed in human samples. This study shows that the proximity of a VEGF-D⁺ primary tumor to small lymphatics is an important determinant of metastasis. These observations may explain why tumor location relative to the lymphatic network is prognostically important for some human cancers.     

Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis

Metastasis to regional lymph nodes is an important and early event in many tumors. Vascular endothelial growth factor-C (VEGF-C), VEGF-D and their receptor VEGFR-3, play a role in tumor spread via the lymphatics, although the timing of their involvement is not understood. In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth. We demonstrate the critical role for VEGFR-3, but not VEGFR-2, in the early events of metastasis. In a tumor model exhibiting both VEGF-D-dependent angiogenesis and lymphangiogenesis, an antibody to VEGFR-2 (DC101) was capable of inhibiting angiogenesis (79 % reduction in PECAM + blood vessels) and growth (93 % reduction in tumor volume). However, unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). Early excision of the primary tumors demonstrated that VEGF-D-mediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm²) than size-matched (11.7) or larger non-metastatic tumors (12.4) thus supporting the importance of lymphatic vessels, as opposed to angiogenesis-mediated primary tumor growth, for nodal metastasis. These results suggest that lymphangiogenesis via VEGF-D is more critical than angiogenesis for nodal metastasis.     

The effect of acute and repeated ischemic preconditioning on recovery following exercise-induced muscle damage

ObjectivesThe aim of this investigation was to determine if acute or repeated applications of ischemic preconditioning (IPC) could enhance the recovery process, following exercise induced muscle damage (EIMD).DesignRandomized control trial.MethodsTwenty-three healthy males were familiarised with the muscle damaging protocol (five sets of 20 drop jumps from a 0.6 m box) and randomly allocated to one of three groups: SHAM (3 × 5 min at 20 mmHg), Acute IPC (3 × 5 min at 220 mmHg) and Repeated IPC (3 days x 3 × 5 min at 220 mmHg). The indices of muscle damage measured included creatine kinase concentration ([CK]), thigh swelling, delayed onset muscle soreness, counter movement jumps (CMJ) and maximal voluntary isometric contraction (MVIC).ResultsBoth acute and repeated IPC improved recovery in MVIC versus SHAM. Repeated IPC led to a faster MVIC recovery at 48 h (101.5%) relative to acute IPC (92.6%) and SHAM (84.4%) (P < 0.05). Less swelling was found for both acute and repeated IPC vs. SHAM (P < 0.05) but no group effects were found for CMJ, soreness or [CK] responses (P > 0.05).ConclusionTaken together, repeated IPC can enhance recovery time of MVIC more than an acute application, and both reduce swelling following EIMD, relative to a SHAM condition.     

A Basomedial Amygdala to Intercalated Cells Microcircuit Expressing PACAP and Its Receptor PAC1 Regulates Contextual Fear

Trauma can cause dysfunctional fear regulation leading some people to develop disorders, such as post-traumatic stress disorder (PTSD). The amygdala regulates fear, whereas PACAP (pituitary adenylate activating peptide) and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs) in adult mice. In vivo optogenetic stimulation of this pathway increased CFOS expression in mICCs, decreased fear recall, and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICC PACAPergic pathway produced EPSCs in mICC neurons, which were enhanced by the PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via a microcircuit containing the BMA and mICCs, and in a manner that was dependent on behavioral state.SIGNIFICANCE STATEMENT Traumatic stress can affect different aspects of fear behaviors, including fear learning, generalization of learned fear to novel contexts, how the fear of the original context is recalled, and how fear is reduced over time. While the amygdala has been studied for its role in regulation of different aspects of fear, the molecular circuitry of this structure is quite complex. In addition, aspects of fear can be modulated differently in males and females. Our findings show that a specific circuitry containing the neuropeptide PACAP and its receptor, PAC1, regulates various aspects of fear, including acquisition, generalization, recall, and extinction in a sexually dimorphic manner, characterizing a novel pathway that modulates traumatic fear.     

Progression of sleep disturbances in Parkinson’s disease: a 5-year longitudinal study

Journal of Neurology - Sleep disorders can occur in early Parkinson’s disease (PD). However, the relationship between different sleep disturbances and their longitudinal evolution has not...     

Magnitude and time course of changes in maximal oxygen uptake in response to distinct regimens of chronic interval training in sedentary women

Purpose

This study aimed to compare changes in maximal oxygen uptake (VO_2max) in response to two regimens of chronic interval training.

Methods

Twenty healthy sedentary women (mean ± SD age and VO_2max = 23.0 ± 5.7 years and 30.1 ± 4.4 mL kg^?1 min^?1, respectively) were randomized to complete 12 weeks of one of two interval training regimes, while an additional seven women served as controls. Training was performed 3 days week^?1 on a cycle ergometer and consisted of 6–10 bouts of 1 min duration at lower (60–80 % W _max = LO, n = 10) or more intense (80–90 % W _max = HI, n = 10) workloads separated by a brief recovery. Every 3 weeks, measures of VO_2max and W _max were repeated to assign new training intensities. Changes in blood pressure and body composition were also examined.

Results

Data revealed significant (p < 0.001) improvements in VO_2max in LO (22.3 ± 6.9 %) and HI (21.9 ± 11.6 %) that were similar (p > 0.05) between groups. Approximately 60 % of the increase in VO_2max in HI was observed in the initial 3 weeks, compared to only 20 % in LO. No change (p > 0.05) in body weight or body composition was revealed in response to training. Results demonstrate that a relatively prolonged regimen of moderate or more intense interval training induces similar improvements in cardiorespiratory fitness, although HI induced greater increases in VO_2max early on in training than LO. Completion of more intense interval training may be an effective means to expedite increases in VO₂max soon after initiation of exercise training.