Iron deficiency down-regulates the Akt/TSC1-TSC2/mammalian Target of Rapamycin signaling pathway in rats and in COS-1 cells

Iron deficiency (ID) is one of the most commonly known forms of nutritional deficiencies. Low body iron is thought to induce neurologic defects but may also play a protective role against cancer development by cell growth arrest. Thus, ID may affect cellular pathways controlling cell growth and proliferation, the mechanism of which is still not fully understood. The serine/threonine protein kinase Akt and its downstream target, the mammalian Target of Rapamycin (mTOR), is known to play a crucial role in the regulation of cell growth and survival. Therefore, we hypothesized that Akt/mTOR pathway could be influenced by ID. Three-week-old male Wistar-strain rats were divided into 3 groups and the 2 groups had free access to a control diet (C group) or an iron-deficient diet (D group). The third group (PF group) were pair-fed the control diet to the mean intake of the D group. After 4 weeks, rats were killed and their brains were sampled. In separate experiments, COS-1 cells were cultured with or without the iron chelator deferoxamine. Western blots of brain samples and COS-1 lysates were used to analyze the expression and phosphorylation state of Akt, TSC2, mTOR, and S6 kinase proteins implicated in the Akt/mTOR pathway. Using 2 different ID models, we show for the first time that iron deficiency depresses Akt activity in rats and in COS-1 cells, leading to a decrease in mTOR activity.     

Detailed Analysis of Mucosal Restoration of the Small Intestine After the Cavitary Two-Layer Cold Storage Method

Small bowel transplantation (SBT) is associated with a high incidence of infectious complications because of ischemia/reperfusion (I/R) mucosal injury concomitant with potent immunosuppression. In this study, we evaluated whether the cavitary two-layer method (cTLM) could reduce I/R injury and allow early mucosal restoration, particularly after prolonged preservation and transplantation. Canine heterotopic segmental SBT was performed immediately without preservation (group 1), after 24-h preservation in UW solution (group 2) or by the cTLM (group 3). The graft samples were taken 1 h after reperfusion and on days 1, 4 and 7. We assessed graft mucosa with detailed microscopic and electromicroscopic analyses. In Group 3, histological injury and cell apoptosis after transplantation were significantly alleviated and rapidly recovered to a similar level of group 1. The mucosal restoration was morphologically completed within 4 days. In contrast, in group 2, more pronounced mucosal injury and delayed recovery were noted. Crypt cell proliferation activity was well maintained in groups 1 and 3 throughout the experimental period. Our ultrastructural analysis suggested that mitochondrial integrity achieved by the cTLM was a basal mechanism under the prompt mucosal restoration. The cTLM could reduce I/R injury, facilitate mucosal regeneration and restore the nearly normal structure early after SBT.     

Surgical management of endocrine tumor of the pancreas in Japan

Endocrine tumor of the pancreas is potentially malignant. A multicenter analysis of these tumors was conducted to clarity the present status of their surgical management and the subsequent long-term surgical results. The Japan pancreatoduodenectomy (JPD) study group carried out the study; 368 patients were enrolled and variables related to tumor characteristics, surgery, and survival were retrospectively analyzed. There were 222 patients with functioning tumor and 143 patients with nonfunctioning tumor. Malignant tumor was found in 140 of 368 (38%) of the patients, and 63/140 (45%) of these patients had metastatic lesion; the most common site of the metastasis was liver 34/136 (25%), followed by regional lymph nodes 26/136 (19%). Pancreatic resection was performed in 91% of patients with nonfunctional tumor and in 83% of those with malignant tumor, and 73% of the pancreatic resections were done with lymph node dissection. The overall 5-year actuarial survival rate was 76% in patients with malignant tumor. The actuarial 5-year survival rate was 93% in the patients without metastasis and 83% in patients who received curative resection. Multivariate analysis showed that the presence or absence of synchronous metastasis was the sole significant prognostic factor. The results suggest that: (i) malignant endocrine tumor of the pancreas is a curable malignancy when pancreatic resection with lymph node dissection is adopted and (ii) that synchronous metastasis is the dominant prognostic factor. This study was carried out as a group project. The authors' institutions are as follows     

A case of corticobasal degeneration presenting with visual hallucination]

We report a case of corticobasal degeneration (CBD) presenting with visual hallucination. A 65-year-old woman showed clumsiness of the left hand. Clinical symptoms slowly progressed to include rigidity, which was left side dominant, limb-kinetic apraxia of the left hand, disorder of construction and dressing, unilateral spatial neglect, cortical sensory loss and alien limb phenomenon. Cranial MRI showed atrophy of the parietal and medial aspect of the frontal lobes, which was more severe on the right than on the left. SPECT images showed hypoperfusion in the parietal, frontal and temporal lobes, which were similarly more severe on the right than on the left. We diagnosed the patient as having CBD based on the clinical symptoms. Two years' later, she developed recurrent visual hallucinations that were typically well formed and detailed. Since patients with CBD generally do not experience visual hallucination, this case is considered the very rare and indicates the possibility that visual hallucination may be one of the clinical symptoms of CBD.     

Effects of pulsatile cardiopulmonary bypass on the renin-angiotensin-aldosterone system following open heart surgery

The effects of pulsatile cardiopulmonary bypass on the renin-angiotensin-aldosterone system and tissue metabolism, especially those which occur soon after surgery, were studied in 26 patients who required total cardiopulmonary bypass for longer than 60 minutes. These patients comprised 11 who underwent open heart surgery utilizing nonpulsatile cardiopulmonary bypass (Group I) and 15 who underwent open heart surgery utilizing pulsatile cardiopulmonary bypass (Group II). Plasma angiotensin II and serum aldosterene levels were significantly increased one and 5 hours postoperatively in Group I when compared with the preoperative values, whereas no significant elevations were observed in Group II. Plasma angiotensin II and serum aldosterone levels one hour postoperatively in Group II were significantly lower than those in Group I. Lactate levels in the arterial blood were significantly elevated, one and 5 hours postoperatively in both Groups I and II. Moreover, no significant difference was observed in the lactate levels between Groups I and II, one hour postoperatively. In the nonpulsatile group (Group I), plasma angiotensin II levels one hour postoperatively were correlated significantly with the duration of total cardiopulmonary bypass. In conclusion, pulsatile cardiopulmonary bypass offers significant advantages in terms of lower plasma angiotensin II and serum aldosterone levels, when compared with nonpulsatile cardiopulmonary bypass soon after open heart surgery requiring total cardiopulmonary bypass for longer than 60 minutes, however, it does not offer a definite advantage for tissue metabolism.     

Curative resection of gastric cancer: Limitation of peritoneal lavage cytology in predicting the outcome

Patients with stage T3N0～2M0 gastric carcinoma (n = 108) were studied for relevant prognostic factors. Peritoneal lavage cytology (PLC) was performed in all. In univariate analysis, 5-year survival rates were better with smaller serosal invasion (diameter <3.0 cm vs. ≥3.0 cm, 61% vs. 37%, P < 0.05) and fewer metastatic nodes (≤5 vs. ≥6, 57% vs. 29%, P < 0.05). In multivariate analyses, only these two factors were significant. The predictive value of PLC was not shown in both univariate and multivariate analyses. Peritoneal recurrence occured in 14 (22%) of 77 patients with negative PLC, and in 3 (18%) of 17 with positive PLC, the difference being not significant. Our results indicate that PLC is insensitive in predicting the development of peritoneal recurrence. Its role in the estimation of survival is limited, as many will die of visceral or locoregional recurrence if not of peritoneal dissemination.     

Bilateral symmetric tonic posturing suggesting propagation to the supplementary motor area in a patient with precuneate cortical dysplasia.

We report a patient manifesting seizures with bilateral symmetric tonic posturing, which were markedly reduced after resection of the left precuneus. A 16-year-old man had sudden onset, complex partial seizures with bilateral symmetric tonic posturing since the age of eight years. Magnetic resonance fluid-attenuated inversion-recovery imaging revealed a hyperintense lesion in left precuneus. In almost all focal seizures recorded during an invasive EEG evaluation, ictal onset was detected from the inferomesial aspect of the lesion, but fast paroxysmal discharges from the ipsilateral supplementary motor area (SMA) were observed just before the clinical onset. After surgical excision of the EEG onset zone, including the lesion, seizure frequency was markedly (> 95%) reduced. By the 20th month after surgery, there were only brief nocturnal seizures involving slight elevation of both shoulders and slight abduction of both arms, with preservation of consciousness occurring once every few days. Invasive EEG findings and surgical outcome suggested that the epileptic activity originating from the epileptogenic zone may have propagated to the symptomatogenic zone including mainly the ipsilateral SMA. In summary, we report an interesting case of bilateral symmetric tonic posturing suggesting propagation to the SMA. MRI and invasive EEG confirmed the epileptogenic focus as a precuneate cortical dysplasia lesion.[Published with video sequences].     

Changes in Glucose Metabolism in Cerebral Cortex and Cerebellum Correlate With Tremor and Rigidity Control by Subthalamic Nucleus Stimulation in Parkinson's Disease: A Positron Emission Tomography Study

Objective. Employing [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) to assess the correlation between the effect of deep brain stimulation (DBS) on the subthalamic nucleus (STN) and the regional cerebral metabolic rate of glucose (rCMRGlc) in advanced Parkinson's disease patients (N = 8). Materials and Methods. On the basis of patients’ diary records, we performed FDG‐PET during the off‐period of motor activity with on‐ or off‐stimulation by STN‐DBS on separate days and analyzed the correlation between changes in motor symptoms and alterations in the rCMRGlc. Result. When FDG‐PET was performed, the motor score on the unified Parkinson's disease rating scale (UPDRS) was 64% lower with on‐stimulation than with off‐stimulation (p < 0.001, Wilcoxon single‐rank test). STN‐DBS increased the rCMRGlc in the posterior part of the right middle frontal gyrus, which corresponded to the premotor area, and the right anterior lobe of the cerebellum (p < 0.005, paired t‐test). No region exhibited a decrease in rCMRGlc. Among the items of the UPDRS motor score, the changes in resting tremor and rigidity of the left extremities showed a significant correlation with the changes in rCMRGlc observed in the right premotor area (p < 0.02 and p < 0.05, respectively, Spearman's rank correlation). Conclusions. STN‐DBS either activates the premotor area or normalizes the deactivation of the premotor area. These FDG‐PET findings obtained are consistent with the idea that STN‐DBS modifies the activities of neural circuits involved in motor control.