Oxytocin receptor antagonist reverses the blunting effect of pair bonding on fear learning in monogamous prairie voles.

Social relationships among spouses, family members, and friends are known to affect physical and mental health. In particular, long-lasting bonds between socio-sexual partners have profound effects on cognitive, social, emotional, and physical well-being. We have previously reported that pair bonding in monogamous prairie voles (Microtus ochrogaster) is prevented by a single prolonged stress (SPS) paradigm, which causes behavioral and endocrine symptoms resembling post-traumatic stress disorder (PTSD) patients in rats (Arai et al., 2016). Since fear memory function is crucial for anxiety-related disorders such as PTSD, we investigated the effects of pair bonding on fear learning in prairie voles. We applied an SPS paradigm to male prairie voles after the cohabitation with a male (cage-mate group) or female (pair-bonded group). The cage-mate group, but not the pair-bonded group, showed enhanced fear response in a contextual fear conditioning test following the SPS treatment. Immunohistochemical analyses revealed that cFos-positive cells in the central amygdala were increased in the pair-bonded group after the contextual fear conditioning test and that oxytocin immunoreactivity in the paraventricular nucleus of the hypothalamus was significantly higher in the pair-bonded group than the cage-mate group. This pair-bonding dependent blunting of fear memory response was confirmed by a passive avoidance test, another fear-based learning test. Interestingly, intracerebroventricular injection of an oxytocin receptor antagonist 30 min before the passive avoidance test blocked the blunting effect of pair bonding on fear learning. Thus, pair bonding between socio-sexual partners results in social buffering in the absence of the partner, blunting fear learning, which may be mediated by oxytocin signaling.

A single prolonged stress paradigm produces enduring impairments in social bonding in monogamous prairie voles.

Traumatic events such as natural disasters, violent crimes, tragic accidents, and war, can have devastating impacts on social relationships, including marital partnerships. We developed a single prolonged stress (SPS) paradigm, which consisted of restraint, forced swimming, and ether anesthesia, to establish an animal model relevant to post-traumatic stress disorder. We applied a SPS paradigm to a monogamous rodent, the prairie vole (Microtus ochrogaster) in order to determine whether a traumatic event affects the establishment of pair bonds. We did not detect effects of the SPS treatment on anhedonic or anxiety-like behavior. Sham-treated male voles huddled with their partner females, following a 6day cohabitation, for a longer duration than with a novel female, indicative of a pair bond. In contrast, SPS-treated voles indiscriminately huddled with the novel and partner females. Interestingly, the impairment of pair bonding was rescued by oral administration of paroxetine, a selective serotonin reuptake inhibitor (SSRI), after the SPS treatment. Immunohistochemical analyses revealed that oxytocin immunoreactivity (IR) was significantly decreased in the supraoptic nucleus (SON), but not in the paraventricular nucleus (PVN), 7days after SPS treatment, and recovered 14days after SPS treatment. After the presentation of a partner female, oxytocin neurons labeled with Fos IR was significantly increased in SPS-treated voles compared with sham-treated voles regardless of paroxetine administration. Our results suggest that traumatic events disturb the formation of pair bond possibly through an interaction with the serotonergic system, and that SSRIs are candidates for the treatment of social problems caused by traumatic events. Further, a vole SPS model may be useful for understanding mechanisms underlying the impairment of social bonding by traumatic events.

[Acute encephalopathy among patients with renal dysfunction after ingestion of "sugihiratake", angel's wing mushroom--study on the incipient cases in the northern area of Niigata Prefecture].

An outbreak of acute encephalopathy among 6 patients with renal dysfunction after eating "Sugihiratake" mushroom in the northern area of Niigata Prefecture was reported. All of the patients had varying degrees of renal dysfunction, and 3 of them were on dialysis treatment. Patients initially presented with shaking limbs and difficulty in walking. Several days later, disturbances in consciousness developed, which were followed by status epileptics. Four patients were put on mechanical ventilation for seizure control. Two of the 6 cases died. CSF examination showed elevated protein without pleocytosis; bacterial, rickettsial and viral screenings was negative. Brain CT and MRI studies showed edema in the claustrum and external capsule, and in the white matter of the base of the frontal, parietal, and temporal lobes. No common drug administration was recognized. All of the patients had a history to have ingested "Sugihitarake" mushroom (angels' wing mushroom, pleurocybella porrigens) in varying quantities and frequencies prior to the onset of the illness. This mushroom may have induced toxic encephalopathy although no similar case have been reported in the past.

[An autopsy case of systemic vasculitis associated with hepatitis C virus-related mixed cryoglobulinemia presenting severe peripheral neuropathy].

A 75-year-old man, previously diagnosed as having chronic hepatitis C virus (HCV) infection, suddenly developed left foot drop, followed by progressive motor weakness and sensory disturbance in all of the extremities. Because of an elevated level of the rheumatoid factor (RF), he had been treated with antirheumatic drugs three years before the onset of his neurological symptoms. Within two months, he became unable to walk any more, and was transferred to our hospital. Neurologic examination showed asymmetrical severe muscular weakness and atrophy of all the limbs, and a sensory deficit under the level of the wrists and knees. Livedo reticularis was also noted in bilateral legs. Nerve conduction study revealed severe sensorimotor axonal neuropathy, and muscle biopsy specimens showed necrotizing vasculitis of small arteries in the perimysium. Serological tests indicated type II cryoglobulinemia (monoclonal IgAkappa + polyclonal IgG). A diagnosis of vasculitic neuropathy associated with HCV-related mixed cryoglobulinemia was made. A high-dose intravenous immunoglobulin therapy (IVIg) and a high-dose steroid therapy were not effective, and he died of alveolar hemorrhage probably due to pulmonary vasculitis. Postmortem pathological examination revealed severe vasculitis, accompanied by fibrinoid degeneration and the infiltration of predominant mononuclear cells into the small and medium-sized vascular walls of multiple organs such as the liver, kidney, pancreas and intestine as well as the peripheral nerves and skeletal muscles. A severe loss of myelinated fibers were also observed in the multiple peripheral nerves examined. We emphasize that patients with HCV infection and mixed cryoglobulinemia may develop severe systemic vasculitis resembling polyarteritis nodosa leading to often life-threatening polyvisceral failure, particularly in patients showing progressive mononeuropathy multiplex.

[Two cases of generalized tetanus presenting with dysphagia as an initial symptom].

We describe two patients with generalized tetanus, a 60-year-old man and a 76-year-old woman, presenting with dysphagia as an initial symptom of the disease. Eighty percent of patients with generalized tetanus manifest dysphagia on admission to a hospital. However, dysphagia is rare as an initial symptom. Both our patients had dysphagia as their initial symptom, followed by neck stiffness and trismus. We made a diagnosis of generalized tetanus based on these neurological findings in the absence of an apparent episode of trauma. After the administration of tetanus immunoglobulin on admission, they recovered without exhibiting generalized convulsion, autonomic storm, or any other serious complications. The vaccination of tetanus toxoid cannot maintain sufficient antibody titers more than ten years. Therefore, elderly people are considered susceptible to tetanus. We suggest that tetanus should be considered in the differential diagnosis of dysphagia particularly in elderly patients. We also suggest that treatment of tetanus should be initiated immediately, because tetanus still has a high mortality rate at present.

A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees.

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive muscular disorder characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood and sparing of the quadricep muscles. The UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene was recently identified as the causative gene for hereditary inclusion body myopathy (HIBM). To investigate whether DMRV and HIBM are allelic diseases, we conducted mutational analysis of the GNE gene of six Japanese DMRV pedigrees and found that all the pedigrees share a homozygous mutation (V572L) associated with a strong linkage disequilibrium, suggesting a strong founder effect in Japanese DMRV pedigrees.

[A case of Hashimoto's encephalopathy associated with Graves' disease].

A 23-year-old woman with Graves' disease was first admitted to a hospital because of generalized convulsion, consciousness disturbance, and tachycardia. Investigations showed biochemical hyperthyroidism and positive thyroid binding inhibitory immunoglobulin (TBII). She was treated with anticonvulsant and antithyroid therapy. One month later the patient developed the second episode of generalized convulsion, followed by cognitive deficits especially concerning short-term memory, when she was transferred to our hospital. Although thyroid function was normalized at that time, anti-thyroid peroxidase (TPO) antibodies level were elevated to 5,850 U/ml in the serum, and 4.9 IU/ml in CSF. CSF protein was elevated to 133 mg/dl. Brain SPECT showed global decrease of cerebral perfusion, and EEG demonstrated diffuse slowing of the background rhythm without any signs of epileptic activity, although brain MRI was normal. Based on a diagnosis of Hashimoto's encephalopathy associated with Graves' disease, therapy with steroids was started, which definitely improved her clinical symptoms. Anti-TPO antibodies disappeared in CSF and decreased in the serum after the treatment. Hashimoto's encephalopathy should always be kept in mind in patients with Hashimoto's disease and Graves' disease.