Choice and administration sequence of antiepileptic agents for status epilepticus and frequent seizures in children

We investigated the sequence of the administration, the efficacy and the safety of antiepileptic drugs (AED) given intravenously for the treatment of status epilepticus and frequent seizures in children. Our institute has a recommended sequence of AED administration for treatment of status epilepticus: the first-line agent is diazepam (0.3 - 0.5 mg/kg administered intravenously, once or twice). The second-line drugs include midazolam (0.15 - 0.4 mg/kg intravenously, once or twice, and if necessary, followed by continuous infusion at 0.06 - 0.18 mg/kg/hour), lidocaine (1 - 2 mg/kg intravenously, once or twice, and if necessary, followed by continuous infusion at 2 - 4 mg/kg/hour) and phenytoin (10 - 20 mg/kg, infused slowly). For those patients who previously experienced a seizure which was refractory to diazepam but responsive to the second-line agent, it was recommended to use the second-line agent as a first-line agent. When seizures were refractory to the first and second-line agents, thiopental was administered (3 - 10 mg/kg intravenously, and if necessary, followed by continuous infusion at 2 -5 mg/kg/hour). The etiologies of 177 occasions of status epilepticus and frequent seizures were categorized into two groups:epilepsy (n = 95) and situation-related seizures (n = 82). Situation-related seizures included febrile seizures (n = 44), acute encephalopathy/encephalitis (n = 31) and benign infantile convulsions (n = 7). The ages of the patients ranged from 0.1 to 18.4 years (average +/- SD:3.69 +/- 3.15 years). Diazepam was administered as the first-line drug on 157 of 177 occasions (88.7%). On 116 occasions the second-line agents were administered. Midazolam and lidocaine were injected as the second-line agent on 54 (46.6%), and on 33 (28.4%) occasions, respectively, although both midazolam and lidocaine injections were off-label use for seizure control in Japan. Thiopental was used as the third to fifth-line agent. Effective ratios (effective occasions/total occasions) of each drug were the following: thiopental 19/21 (90.4%), midazolam 57/99 (57.6%), lidocaine 25/60 (41.7%), phenytoin 16/41 (39.0%), diazepam 59/164 (36.0%). Thiopental was statistically more effective than midazolam, lidocaine, diazepam or phenytoin (p < 0.01), and midazolam was statistically more effective than diazepam (p < 0.01) or phenytoin (p < 0.05). Administration of thiopental caused complications more frequently than the other agents (p < 0.01): The complications by thiopental were severe in some cases requiring intratracheal intubations and artificial ventilation. From the viewpoint of both efficacy and safety, midazolam should be recommended as one of the first-line agents for status epilepticus.     

Premature ovarian failure in a female with proximal symphalangism and Noggin mutation

OBJECTIVE: To report a case of premature ovarian failure (POF) and a mutation of the gene for Noggin (NOG). DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 33-year-old Japanese female with POF and proximal symphalangism. INTERVENTION(S): Direct sequence analysis of the NOG gene. MAIN OUTCOME MEASURE(S): Occurrence of POF. RESULT(S): A novel heterozygous G to A transition was identified at the nucleotide position 142 (142 G>A), which is predicted to cause an amino acid substitution of glutamic acid by lysine (E48K). CONCLUSION(S): Because NOG is expressed in the ovary and interacts with bone morphogenetic proteins, which play an important role in the ovarian function, a NOG mutation may constitute one of the multiple susceptibility genes for the development of POF.     

Alendronate inhibits urinary calcium microlith formation in a three-dimensional culture model

Osteoporosis is associated with the pathogenesis of urinary stone formation. Urinary stones are similar to bone diseases such as osteoporosis and bone metabolism in terms of pathogenesis. Bisphosphonates are potent inhibitors of bone resorption, and are used in the management of bone disease. Furthermore, bisphosphonates have a strong affinity for calcium, and a reported inhibitory effect on calcium oxalate crystallization in vitro. Thus, bisphosphonates might also inhibit urinary stone formation. Madin-Darby canine kidney (MDCK) cells form calcium phosphate microliths at the basolateral side in vitro. We investigated the inhibitory effects of new generation bisphosphonates (alendronate and incadronate) on calcium phosphate microlith formation and on the expression of osteopontin, which is an important urinary stone matrix. MDCK cells formed two types of colonies in three-dimensional soft agar culture; dark colonies containing calcium phosphate microliths and clear colonies free from microliths. We applied purified alendronate and incadronate at concentrations of 10^–11, 10^–9, 10^–7 and 10^–5 M to MDCK cells cultured in three-dimensional soft agar and investigated the efficiency of colony formation and the dark colony ratio (number of dark colonies relative to the total number of colonies). The administration of 10^–9 and 10^–7 M alendronate decreased the dark colony ratio compared with controls, whereas incadronate did not significantly alter this colony ratio compared with controls. The expression of osteopontin in cultured cells was inhibited by the 10^–7 M alendronate administration. The present findings show that alendronate inhibits calcium stone formation, suggesting that it is effective in the prevention of urolithiasis.     

Secondary nephrotic syndrome due to cardiovascular disease

Cardiovascular diseases ralely evoke nephrotic syndrome. Especially hypertensive renal disease (nephroscrelosis) and renovascular hypertension occasionally may lead to nephrotic syndrome. We reported a case of nephrotic syndrome with renovascular hypertension successfully treated with candesartan. In eldery patients cardiovascular diseases are appeared. It is very important for clinicians to detect the mechanism of nephrotic syndrome caused by cardiovascular diseases.     

Optimum pain relief with continuous epidural infusion of local anesthetics shortens the duration of zoster-associated pain

OBJECTIVE: To investigate effects of continuous epidural infusion (CEI) of 0.5% bupivacaine added to intermittent epidural boluses (IEB) on the duration of zoster-associated pain (ZAP), as compared with continuous infusion of normal saline placebo added to IEB. DESIGN: A prospective, double-blind, randomized, placebo-controlled study. SETTING: A university hospital and an affiliated clinic in Japan from 1996 through 1999. PATIENTS: 56 immunocompetent herpes zoster (HZ) patients, 50 years or older, within 10 days of rash onset and with severe pain and eruption. INTERVENTIONS: Patients were hospitalized and randomly allocated into 2 groups. CEI group given CEI of 0.5% bupivacaine (0.5-1.0 mL/h) plus IEB of 0.5% bupivacaine 4 times daily (n = 29). IEB group given normal saline infusion plus IEB of 0.5% bupivacaine 4 times daily (n = 27). All patients received oral acyclovir 800 mg, 5 times daily, for 7 days. OUTCOME MEASURES: The number of days required for complete cessation of ZAP and the proportion of subjects with allodynia beyond 30 days. RESULTS: The median time to cessation of ZAP was significantly shorter in the CEI group than in the IEB group (29 days vs. 40 days, P = 0.002). The number of patients whose allodynia persisted beyond 30 days of treatment was significantly lower in the CEI group than in the IEB group (10% vs. 37%, P = 0.027). CONCLUSIONS: CEI of 0.5% bupivacaine plus IEB was associated with a shorter duration of ZAP and fewer patients with allodynia beyond 30 days, compared with IEB plus normal saline infusion. Patients at high risk for developing postherpetic neuralgia (PHN) can be managed with intensive therapies at the early stage of disease, such as CEI, which maintains effective analgesia and may reduce the burden of PHN.     

Dietary canola and soybean oil fed to SHRSP rat dams differently affect the growth and survival of their male pups

Canola oil (Can), as well as some other oils, shortens the survival of SHRSP rats compared with soybean oil (Soy). Although detrimental factors other than phytosterols have not been identified, they are likely to be hydrophobic and transmissible to pups. To test this possibility, female SHRSP rats (F0) were fed a diet supplemented with Can or Soy and mated at 11 wk of age. The growth of suckling pups (F1) from the Can-fed dams was significantly retarded compared with that of pups from the Soy-fed dams. Half of the male pups (F1) were weaned to the same diet as their dams (Can-->Can and Soy-->Soy groups) and the rest were weaned to the other diet (Can-->Soy and Soy-->Can groups). The survival rate of the male pups (F1) was significantly lower in the Can-->Can group than in the Soy-->Can group, and in the Can-->Soy group than in the Soy-->Soy group, indicating that the oils fed to dams differently affected the growth and survival of pups. There were fewer pups per dam in the Can-fed dams (F0) than in the Soy-fed dams, and in the dams (F1) of the Can-->Can and Soy-->Can groups than in those of the Can-->Soy and Soy-->Soy groups. Although Can is nutritionally detrimental to SHRSP rats compared with Soy, no direct evidence has been obtained thus far relating these observations to human nutrition.     

EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma

Lines of evidence have recently indicated a relationship between mutations in the P63 gene and ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome type 3 (EEC3). The p63 gene (P63) has homology to P53 known as a tumor-suppressor gene, but biological function of its protein has not yet been known well. There have been two reported patients who had EEC syndrome associated with malignant lymphoma. However, they did not undergo sequencing analysis of P63. Here, we present with a Japanese girl who had EEC3 and developed diffuse large B-cell type non-Hodgkin lymphoma. In this patient, we documented a heterozygous germline mutation, Asp312Gly, in P63. We speculated that p63 may exert a biological function as a tumor suppressor. Malignant lymphoma should be considered as an important complication of EEC3.     

Reduction of infarct volume and apoptosis by grafting of encapsulated basic fibroblast growth factor-secreting cells in a model of middle cerebral artery occlusion in rats

OBJECT: This study was conducted to evaluate the effects of grafting encapsulated basic fibroblast growth factor (bFGF)-secreting cells in rat brains subjected to ischemic injury. METHODS: Two cell lines were used for encapsulated grafting in this experiment, namely, a bFGF-secreting cell line established by genetic manipulation of baby hamster kidney (BHK) cells, and a naive BHK cell line. Forty-seven Sprague-Dawley rats were used in this experiment. The animals were divided into the following three groups: those receiving grafts of encapsulated bFGF-secreting cells (BHK-bFGF group); those with grafts of encapsulated naive BHK cells (naive BHK group); and those with no grafts (control group). The authors implanted encapsulated cells into the right striatum of host rats in the BHK-bFGF and naive BHK groups. Six days after grafting, the host and control animals underwent permanent right middle cerebral artery occlusion (MCAO) with an intraluminal suture procedure. The infarct volume was evaluated using 2,3,5-triphenyltetrazolium chloride staining and computerized image analysis 24 hours after MCAO. Fragmentations of DNA in the host brains were analyzed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling 12 hours after MCAO. The authors found that the infarct volume in the BHK-bFGF group was reduced by approximately 30% compared with that in the naive BHK and control groups. In the ischemic penumbral area, the number of apoptotic cells in the BHK-bFGF group was significantly decreased compared with that in the other groups. CONCLUSIONS: The grafting of encapsulated BHK bFGF-secreting cells protected the brain from ischemic injury. Encapsulation and grafting of genetically engineered cells such as bFGF-secreting cells is thus thought to be a useful method for protection against cerebral ischemia.     

Myopic choroidal neovascularization: a 10-year follow-up

PURPOSE: To clarify the long-term visual outcome of choroidal neovascularization (CNV) in eyes with high myopia in Asian patients. DESIGN: We reviewed the medical records of 25 consecutive patients (27 eyes) with myopic CNV who were followed up for at least 10 years after the onset of CNV. Visual acuity was examined 10 years after CNV onset. INTERVENTION: Demographic and clinical data were obtained from the patients' medical records. MAIN OUTCOME MEASURES: Visual acuity readings during the 10 years after CNV onset. RESULTS: At the onset of CNV, 19 eyes (70.4%) had a visual acuity better than 20/200, and six eyes (22.2%) had a visual acuity better than 20/40. Three years after the onset of CNV, 15 eyes (55.5%) retained a visual acuity of better than 20/200. At 5 and 10 years after the onset, however, visual acuity dropped to 20/200 or less in 24 eyes (88.9%) and in 26 eyes (96.3%), respectively. The logarithm of the minimum angle of resolution (logMAR) visual acuity was significantly worse at 5 and 10 years after onset as compared with that at CNV onset. Chorioretinal atrophy developed around the regressed CNV in 26 eyes (96.3%) at 5 and 10 years after the onset of CNV. CONCLUSIONS: Long-term visual outcome of myopic CNV is extremely poor. The visual acuity of almost all of the patients dropped to 20/200 or less within 5 to 10 years after the onset of CNV, secondary to the development of chorioretinal atrophy around the regressed CNV. These findings indicate that active treatments should be recommended to prevent long-term visual impairment in Asian patients with myopic CNV.