Transneuronal degeneration of thalamic neurons following deafferentation: quantitative studies using [3H]thymidine autoradiography.

Transneuronal degeneration of thalamic neurons following partial deafferentation was studied using [3H]thymidine autoradiography. Timed-pregnant female Sprague-Dawley rats received systemic injections of [3H]thymidine on embryonic day (E) 13, 14 and/or 15. On the day of birth, pups were anesthetized by hypothermia and subjected to unilateral enucleation, unilateral removal of the inferior colliculus or sham lesion. Animals were sacrificed on postnatal day 10 or 30 and the brains processed for autoradiography. Material from sham-lesioned animals demonstrates that neurons destined for the dorsal lateral geniculate nucleus (LGd) undergo final mitoses on E13, 14 and 15. Neurons in the ventral medial geniculate nucleus (MGv) undergo final mitoses on E13 and 14. Thirty days following neonatal unilateral eye removal, the contralateral LGd displays a loss of approximately 30-35% of [3H]thymidine labeled neurons. Neonatal unilateral removal of the inferior colliculus results in a loss of approximately 30-40% of labeled neurons in MGv. For both LGd and MGv, shorter survival times reveal less severe cell loss. Late generated (E15) LGd neurons show less severe loss following enucleation than do earlier generated neurons. These results document the degree of cell loss in sensory thalamic nuclei following deafferentation and demonstrate that [3H]thymidine autoradiography provides a useful quantitative method for assessing anterograde transneuronal cell loss in targeted populations of neurons in the developing central nervous system.     

Calcium, network activity, and the role of NMDA channels in synaptic plasticity in vitro.

Functionally effective neuronal circuits are constructed through a competitive process that requires patterned neuronal activity elicited by structured input from the environment. To explore the mechanisms of this activity-dependent synaptic restructuring, we have developed an in vitro preparation of mouse spinal cord neurons maintained in a 3-chambered cell-culture system. Sensory afferents that received chronic electrical stimulation for 3-5 d developed stronger synaptic connections than unstimulated afferents converging onto the same postsynaptic spinal cord neuron. Exposure to 100 microM DL-2-amino-5-phosphonovaleric acid (APV), an antagonist of the NMDA channel, during the stimulation period prevented the competitive advantage associated with electric stimulation. However, when APV was applied with a higher concentration of calcium (3 mM), activity-dependent synaptic plasticity was no longer inhibited by the NMDA receptor antagonist. This reversal of APV block of the plasticity was not impaired by reducing transmitter release with 3 mM magnesium (in addition to 3 mM calcium and APV). A suppressant effect of APV on spontaneous activity was observed, which was attributed to loss of the NMDA component of the EPSP. Activity-dependent plasticity was also blocked if spontaneous activity was suppressed with dilute tetrodotoxin (TTX; 5-10 nM), a dosage that reduces excitability of neurons but is insufficient to block sodium-dependent action potentials. These experiments bring into question how NMDA channel activation is involved in the processes of synaptic remodeling during development. The data suggest that postsynaptic activity is required for synaptic remodeling, but this activity need not involve NMDA receptor activation specifically for activity-evoked synaptic plasticity. Instead, the mechanism for plasticity appears to operate through calcium-dependent processes in general.     

Therapy of human cervical carcinoma with monoclonal antibody-Pseudomonas exotoxin conjugates.

Pseudomonas exotoxin A (PE) linked to the F(ab')2 fragment of 1H10, a murine monoclonal antibody recognizing a carbohydrate epitope of a glycoconjugate expressed on the surface of human cervical carcinoma tumor cells, was evaluated for in vitro and in vivo activity. PE can kill cells by ADP-ribosylating elongation factor 2 thus inhibiting protein synthesis. Disulfide- as well as thioether-linked immunotoxins (1H10-PE) killed cervical carcinoma cells in vitro and were 20-160 times more inhibitory to target than to control cells. Cell killing was antibody mediated as demonstrated by the reduction of 1H10-PE growth inhibition to target CaSki cells by free 1H10 F(ab')2. In addition, a control antibody immunotoxin was nontoxic to CaSki cells. Thioether-linked 1H10-PE administered either i.v. or i.p. suppressed the growth of established solid s.c. cervical carcinoma tumors xenografted in nude mice for over 30 days. Treatment with antibody alone or a control immunotoxin had no significant effect on tumor growth. Administration of immunotoxin i.p. was associated with less toxicity than administration i.v., but i.v. injections were more effective at suppressing the growth of established solid tumors.     

后SARS时期对公共卫生与健康的再思考

在人们印象中“公共卫生”是一个很模糊的领域，它比较形象的载体可能就是爱国卫生运动或预防接种。美国1932年提出的公共卫生的定义，对现在依然有指导意义：公共卫生就是预防疾病，延长寿命，通过有组织的社会共同努力来改变环境卫生，从而促进身体的健康，提高工作效率，控制社区传染病的流行，教育个人形成良好的卫生习惯，组织医护人员对疾病进行早期的诊断和预防性治疗。简而言之，“公共卫生”就是关注公众健康的科学。公共卫生学不能脱离临床医学，后是对某种疾病的个体的治疗，而前则着眼对某种疾病做群体防护。     

In vivo PET imaging of cardiac presynaptic sympathoneuronal mechanisms in the rat.

The sympathetic nervous system of the heart plays a key role in the pathophysiology of various cardiac diseases. Small-animal models are valuable for obtaining further insight into mechanisms of cardiac disease and therapy. To determine the translational potential of cardiac neuronal imaging from rodents to humans, we characterized the rat sympathetic nervous system using 3 radiotracers that reflect different subcellular mechanisms: (11)C-meta-hydroxyephedrine (HED), a tracer of neuronal transport showing stable uptake and no washout in healthy humans; (11)C-phenylephrine (PHEN), a tracer of vesicular leakage and intraneuronal metabolic degradation with initial uptake and subsequent washout in humans; and (11)C-epinephrine (EPI), a tracer of vesicular storage with stable uptake and no washout in humans. METHODS: We used a small-animal PET system to study healthy male Wistar rats at baseline, after desipramine (DMI) pretreatment (DMI block), and with DMI injection 15 min after tracer delivery (DMI chase). The rats were kept under general isoflurane anesthesia while dynamic emission scans of the heart were recorded for 60 min after radiotracer injection. A myocardial retention index was determined by normalizing uptake at 40 min to the integral under the arterial input curve. Washout rates were determined by monoexponential fitting of myocardial time-activity curves. RESULTS: At baseline, HED showed high myocardial uptake and sustained retention, EPI showed moderate uptake and significant biphasic washout, and PHEN showed moderate uptake and monoexponential washout. The average (+/- SD) left ventricular retention index for HED, PHEN, and EPI was 7.38% +/- 0.82%/min, 3.43% +/- 0.45%/min, and 4.24% +/- 0.59%/min, respectively; the washout rate for HED, PHEN, and EPI was 0.13% +/- 0.23%/min, 1.13% +/- 0.35%/min, and 0.50% +/- 0.24%/min, respectively. The DMI chase resulted in increased washout only for HED. DMI block decreased myocardial uptake of all tracers by less than 90%. CONCLUSION: Kinetic profiles of HED in the rat myocardium were similar to those of HED in humans, suggesting comparable neuronal transport density. Unlike in humans, however, significant washout of EPI and faster washout of PHEN were encountered, consistent with high intraneuronal metabolic activity, high catecholamine turnover, and reduced vesicular storage. This evidence of increased neuronal activity in rodents has implications for translational studies of cardiac neuronal biology in humans.     

The role of neck dissection in the eradication of salivary carcinomas]

From 1955 to 1984, radical neck dissection (RND) had been done in 300 salivary carcinoma patients, 114 of which had regional lymph node metastasis, with a 38% metastatic rate. Respective 3, 5, 10, 15, 20 year survival rates were 76, 64, 47, 35, 35% in a 3 to 20 years follow-up study in 283 patients (94.33%). The following four points are concluded: 1. The metastatic rate is determined not only on tumor staging, but more to its typing (pathologic behaviour). 2. Elective RND gave a better prognosis than therapeutic and negative metastasis has a better survival chance than positive where the low level metastasis is the worst. 3. According to pathologic typing, Elective RND is indicated for undifferentiated adenocarcinoma, high malignant mucoepidermoid carcinoma, squamous cell carcinoma, adenocarcinoma and papillary cystic adenocarcinoma, therapeutic RND for malignant pleomorphic adenoma, acinic cell carcinoma and mucoepidermoid carcinoma. 4. Unilateral RND is indicated for all but sublingual and buccal tumors.     

Successful balloon pulmonary valvuloplasty for congenital valvular pulmonary stenosis in an octogenarian.

While balloon valvuloplasty has been widely used for the treatment of congenital valvular pulmonary stenosis (PS) in children and adults, its use in elderly patients is less common. An 80-year-old woman with congenital valvular PS received valvuloplasty with double-balloon technique. Right ventricle systolic pressure and pulmonary valve systolic pressure gradient decreased from 95 to 44 mm Hg and from 75 to 35 mm Hg, respectively. Follow-up Doppler echocardiography 2 months later showed further decrease in the transvalvular systolic pressure gradient to 29 mm Hg. The patient had symptomatic relief, and no major complication was noted. Balloon pulmonary valvuloplasty can be an effective treatment for elderly patients with congenital valvular PS.     

Recurrent acalculous cholecystitis and sclerosing cholangitis in a patient with X-linked hyper-immunoglobulin M syndrome.

X-linked hyper-immunoglobulin M (IgM) syndrome (XHIGM) is a rare genetic primary immunodeficiency disease caused by mutations of the CD40 ligand (CD40L) gene with normal or elevated levels of IgM and markedly decreased serum IgG, IgA, and IgE. Liver disease may occur as a clinical manifestation in XHIGM. This complication appears to increase with age. We report an 18-year-old male patient who had recurrent episodes of acalculous cholecystitis (AC) and sclerosing cholangitis (SC). The diagnosis of XHIGM was confirmed by the finding of CD40L expression < 1% of normal and a tyrosine 169 asparaginase (t526a) mutation in exon 5 (the tumor necrosis factor domain) of the CD40L gene. The patient had direct hyperbilirubinemia (direct bilirubin 5.5 mg/dL, total bilirubin 8.7 mg/dL), cholestasis (alkaline phosphatase 1133 U/L, gamma-glutamyl transferase 1019 U/L) and elevated transaminases (aspartate aminotransferase 70 U/L, alanine aminotransferase 101 U/L). Findings on abdominal ultrasound and abdominal computed tomography were compatible with AC. After the fourth episode of cholecystitis, cholecystectomy and liver biopsy were performed. Operative cholangiography revealed poor opacification of the hepatic duct and proximal common bile duct; the upstream intrahepatic bile ducts were not visualized. The biopsy specimen showed marked fibrosis of the portal areas. Enterococcus species was cultured from the bile. Children or adolescents with recurrent AC and SC should be evaluated for an underlying immunodeficiency syndrome such as XHIGM.     

Matched-unrelated-donor bone marrow transplantation for children with leukemia.

BACKGROUND AND PURPOSE: This report describes the results of matched-unrelated-donor transplant for leukemia or myelodysplasia in the first 23 recipient children at a single medical center in Taiwan. METHODS: Between August 1994 and February 2003, 23 consecutive children with leukemia or myelodysplasia underwent matched-unrelated-donor bone marrow transplantation (BMT). The preparative regimen consisted of fractionated total body irradiation and cyclophosphamide in 6 patients; busulfan in combination with etoposide and cyclophosphamide in 4 patients who received cranial irradiation before transplantation; and busulfan and cyclophosphamide in 13 patients. RESULTS: Engraftment was achieved in 91.3% of cases. Acute graft-versus-host disease (GVHD) occurred in 18 of 21 patients who engrafted (85.7%). Event-free survival for all patients was 24.46 +/- 9.24%. The 12 children with standard-risk disease had better event-free survival than the 11 children with high-risk disease (46.88 +/- 15.03% vs 0%, p < or = 0.001). CONCLUSIONS: The major obstacles to successful matched-unrelated-donor BMT are acute GVHD, relapse and infection. Early transplantation and patient selection, prophylactic and therapeutic maneuvers for GVHD, as well as appropriate donor selection and virus prophylaxis may improve the results.