PVN electrical stimulation prolongs withdrawal latencies and releases oxytocin in cerebrospinal fluid, plasma, and spinal cord tissue in intact and neuropathic rats

We are studying an endogenous, oxytocinergic analgesia system to obtain more information about normal and pathological pain processes. In the recent years, this oxytocinergic system has been shown to be involved in normal and pathological pain suppression. The paraventricular nucleus (PVN) of the hypothalamus is an important source of brain oxytocin (OT). A descending pathway reaching the dorsal horn in the spinal cord was postulated to mediate analgesic effects at the spinal cord level. However, the oxytocin concentration during pain conditions and during PVN electrical stimulation needs to be determined. We designed experiments to measure the OT concentration in cerebrospinal fluid (CSF), plasma, and OT protein in lumbar spinal cord tissue in control and neuropathic rats. Sciatic loose ligature was used as the experimental method to produce neuropathic pain. The main findings were (1) Chronic pain experiments in animals showed that the stimulation of the anterior part of the PVN increased OT concentration and produced analgesia states, as measured by von Frey, cold, and heat plantar tests. (2) Differential effects were produced by electrical stimulation of the anterior or posterior regions of the PVN; electrical stimulation of the anterior part of the PVN enhanced the OT concentration in CSF and plasma, and it also increased OT protein concentrations in the spinal cord tissue; in contrast, the stimulation of the posterior part of the PVN only increased OT concentrations in CSF. These results suggest the participation of an endogenous analgesia system mediated by OT.     

Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet

Dietary factors influence BDNF in animal studies, but there is no comparable data in clinical populations. We examined the effect of a dietary intervention on BDNF serum levels in 67 DSM-IV schizophrenic outpatients (51 males and 16 females). Two groups were assessed in a cross-sectional study: one on a hypocaloric diet (HD) and the other not on a hypocaloric diet. Weight, height and BMI data were collected concurrently with 5-ml blood sampling of each subject. BDNF levels were measured with a sandwich-ELISA. The blood sample was obtained a minimum of one month after the exposure to dietary intervention. Serum BDNF levels were significantly higher in patients on the HD (p=0.023). Additional research examining the interaction among patterns of nutritional food behavior and underlying physiopathology may result in insights upon which evidence-based decisions regarding dietary interventions can be made in people identified with major psychiatric disorders, such as schizophrenia.     

Transient 5-(4-phenylbutoxy)psoralen (PAP-1) treatment dissociates developing pathologies in autoimmune optic neuritis into two distinct pathology profiles

Discovery of treatments to protect axonal function of neurons and prevent permanent disability associated with progressive multiple sclerosis (MS) has faced the uphill challenge of assessing relatively small changes in accumulated axon damage within a background environment that is disorganized by CNS inflammation. We hypothesized that transient immunosuppression after initiation of MS-like autoimmune mechanisms would disassociate development of MS-like myelinated axon pathology from development of CNS inflammation in a rat model of autoimmune optic neuritis (AON). A rat model of myelin oligodendrocyte glycoprotein peptide-induced AON was transiently treated (on days 3-7 after antigen exposure) with 5-(4-phenylbutoxy)psoralen (PAP-1), an immunomodulatory drug previously shown specifically to suppress proliferation of effector memory T-cells and immunoglobulin class-switched B-cells. Thirteen days after antigen exposure, optic nerves were harvested for quantitative assessment of 12 MS-associated pathologies using microfluorimetry. With one exception, the immunoreactivities (-ir) for eight markers of MS-like neuroinflammation and immune infiltration were significantly reduced (P < 0.05) by transient PAP-1 treatment, often to levels significantly below those detected in normal control rat optic nerves. With one exception, four immunoreactive markers of MS-like myelinated axon pathology were detected at levels indicating increased axon/myelin pathology compared with vehicle-treated rats with AON (P < 0.05). These data suggest the conclusion that early causative mechanisms in CNS autoimmunity initiate signaling mechanisms that diverge into two separate pathways, one that is strongly associated with inflammatory responses and one that is associated predominantly with disturbed axon-myelin interactions and impaired fast axonal transport.     

Synaptic organization of thalamocortical axon collaterals in the perigeniculate nucleus and dorsal lateral geniculate nucleus

We examined the synaptic targets of large non-gamma-aminobutyric acid (GABA)-ergic profiles that contain round vesicles and dark mitochondria (RLD profiles) in the perigeniculate nucleus (PGN) and the dorsal lateral geniculate nucleus (dLGN). RLD profiles can provisionally be identified as the collaterals of thalamocortical axons, because their ultrastrucure is distinct from all other previously described dLGN inputs. We also found that RLD profiles are larger than cholinergic terminals and contain the type 2 vesicular glutamate transporter. RLD profiles are distributed throughout the PGN and are concentrated within the interlaminar zones (IZs) of the dLGN, regions distinguished by dense binding of Wisteria floribunda agglutinin (WFA). To determine the synaptic targets of thalamocortical axon collaterals, we examined RLD profiles in the PGN and dLGN in tissue stained for GABA. For the PGN, we found that all RLD profiles make synaptic contacts with GABAergic PGN somata, dendrites, and spines. In the dLGN, RLD profiles primarily synapse with GABAergic dendrites that contain vesicles (F2 profiles) and non-GABAergic dendrites in glomerular arrangements that include triads. Occasional synapses on GABAergic somata and proximal dendrites were also observed in the dLGN. These results suggest that correlated dLGN activity may be enhanced via direct synaptic contacts between thalamocortical cells, whereas noncorrelated activity (such as that occurring during binocular rivalry) could be suppressed via thalamocortical collateral input to PGN cells and dLGN interneurons.     

Gastric fundoplication is effective in promoting weight gain in children with severe congenital heart defects

Aim

The aim of this study was to determine outcomes, including weight gain, morbidity, and mortality, of children with severe congenital heart disease who underwent fundoplication (FP) for gastroesophageal reflux disease.

Methods

An institutional review board-approved retrospective review was conducted on all children with congenital heart disease who underwent FP from 1999 to 2005. Preoperative age, weight, cardiac procedures, postoperative weight, and mortality were extracted from medical records. The Wilcoxon signed rank, Wilcoxon rank sum, and log-rank tests were used; P value less than .05 was significant. All procedures were performed with dedicated cardiac anesthesia personnel with recovery in a cardiac intensive care unit.

Results

Of 112 subjects identified, 37 (33%) had single ventricle (SV) physiology. The most frequent cardiac procedures performed were Norwood (33), pulmonary artery band (11), and systemic pulmonary artery shunt (11). A total of 104 laparoscopic FPs (with 2 conversions to open) and 8 open FPs were performed. The median preoperative age was 3 months, and weight percentile was 1.5%. From baseline, postoperative median weight percentiles increased to 4% at 3 months (P < .001) and to 20% at 5 years postoperatively (P = .004). Single ventricle physiology had no significant effect on outcomes. Postoperative mortality (≤30 days) was 4.5% (5/112); 5-year survival was 74% (83/112). Five-year survival of SV subjects (59%) was significantly lower (P = .03) than that of the other subjects (81%). No significant difference in survival was seen between SV subjects with FP and all SV patients seen at our center during the study period. Only one death was directly related to antireflux surgery (SV subject). There were 8 patients who had recurrent gastroesophageal reflux disease: 4 were treated with reoperation, and 4 were treated medically.

Conclusion

Weight gain in this high-risk population can be expected after antireflux surgery. Mortality is high because of intrinsic disease, especially in the SV population. Fundoplications performed with the assistance of dedicated pediatric cardiac anesthesia personnel followed by recovery in a cardiac intensive care unit is possible with acceptable postoperative morbidity and mortality.     

Improving state pain policies: recent progress and continuing opportunities

The National Institutes of Health reports that 100 million Americans suffer from chronic pain, including pain associated with the disease of cancer. Painful conditions can strike anyone, including cancer patients and cancer survivors. Unrelieved severe pain can limit a person's functioning and sometimes even destroy the will to live. When the quality of pain relief provided is inadequate, it is usually the result of failures to apply existing knowledge about pain and its treatment, including the appropriate use of opioids. But pain relief also can be affected by the regulatory environment and fear of being investigated for excessive prescribing. The importance of evaluating and improving policies governing pain management has been recognized by national and international authorities, including the Institute of Medicine and the World Health Organization. A pilot examination of state laws and regulatory policies demonstrated that they contained a number of outdated medical concepts and prescribing restrictions and did not contain key elements of law that can make pain management a priority for licensed medical practitioners. The Pain & Policy Studies Group developed a research program to evaluate US federal and state policy governing the medical use of pain medication. This article describes 3 national policy evaluations and how the results are being used to document improvements in state pain policies. An emerging role for clinicians and their professional organizations to improve their state's pain policies is discussed.