Pharmacokinetics of amikacin in children and neonates

To evaluate pharmacokinetics of amikacin (AMK), one of the aminoglycoside antibiotics, children with ages from 2 days to 11 years were treated with various doses by various administration routes, and both plasma and urinary levels of AMK were determined. The following is a summary of the results obtained: 1. Of 6 children, three were treated with 2.0 mg/kg of AMK by a 30-minute intravenous drip infusion, and the other 3 with 4.0 mg/kg by a 60-minute. Peaks of average plasma levels were observed at the ends of the infusions in both cases, and their levels were 9.23 and 13.67 micrograms/ml, respectively, showing a dose-dependency. Both half-lives and areas under plasma concentration-time curves (AUCs) were similar to those of adults. However, the volume of distribution (Vd) showed a lower value than that of adults. Peaks of average urine levels were 149.3 micrograms/ml with 2.0 mg/kg in 0-2 hours after the start of the infusion and 223.3 micrograms/ml with 4.0 mg/kg in 2-4 hours. Average urinary recovery rates within 6 hours after the start of the infusion were 95.4% with 2.0 mg/kg and 85.7% with 4.0 mg/kg. These recoveries were equal to or higher than that of adults. 2. When 3.0, 4.0 and 6.0 mg/kg of AMK were administered to 3 groups of mature or premature babies by intramuscular injection, average peak levels of AMK in plasma were 6.26, 8.61 and 12.60 micrograms/ml, respectively, at 30 minutes after the injection, showing dose-dependency. In these groups, the younger the day age after birth was, the longer the half-life became. The AUCs were larger as the half-life became longer. The Vd was larger than that in the intravenous drip infusion group, but, any particular was not observed. Average peak levels of AMK in urine were 78.83 micrograms/ml at 4-6 hours with a dose level of 3.0 mg/kg, 99.17 micrograms/ml at 2-4 hours with 4.0 mg/kg and 139.20 micrograms/ml at 0-2 hours with 6.0 mg/kg. Average urinary recovery rates within 6 hours were 36.57% with 3.0 mg/kg, 34.67% with 4.0 mg/kg and 43.77% with 6.0 mg/kg. These recovery rates were markedly lower than those observed in adults and children. One of the causes of this low recovery is that mature and premature babies have immature renal functions. 3. When 3.0 mg/kg of AMK was administered to three premature babies by a 30-minute intravenous drip infusion, the average peak plasma levels was 7.61 micrograms/ml at the end of the drip infusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

IgG Anti-GM1 antibody is associated with reversible conduction failure and axonal degeneration in guillain-barré syndrome

To investigate the pathophysiological role of anti-GM1 antibody in Gullain-Barre syndrome (GBS), we reviewed sequential nerve conduction studies of 345 nerves in 34 GBS patients. Statistically significant correlation between IgG anti-GM1 antibodies and electrodiagnoses was found. Sixteen IgG anti-GM1-positive patients were classified as having acute motor sensory axonal neuropathy (AMAN or AMSAN) (12 patients), as having acute inflammatory demyelinating polyneuropathy (AIDP) (3 patientsrpar;, or as undetermined (1 patient) by electrodiagnostic criteria. Besides axonal features, there was rapid resolution of conduction slowing and block. In 3 patients initially diagnosed as having AIDP, conduction slowing was resolved within days, and 1 of them and 3 AMAN patients showed markedly rapid increases in amplitudes of distal compound muscle action potentials that were not accompanied by prolonged duration and polyphasia. The time courses of conduction abnormalities were distinct from those in IgG anti-GM1-negative AIDP patients. Rapid resolution of conduction slowing and block, and the absence of remyelinating slow components, suggest that conduction failure may be caused by impaired physiological conduction at the nodes of Ranvier. Reversible conduction failure as well as axonal degeneration constitutes the pathopsiological mechanisms in IgG anti-GM1)positive GBS. In both cases, immune-mediated attack probably occurs on the axolemma of motor fibers.     

Respiratory complications associated with tracheal intubation and extubation

We conducted a prospective survey on the incidence of respiratory complications associated with tracheal intubation and extubation in 1005 patients who underwent elective general anaesthesia over a 4-month period. During induction of anaesthesia, respiratory complications occurred in 46 patients (4.6%; 95% confidence limits (CL): 3.3, 5.9%). The common complications were coughing (1.5%) and difficult ventilation through a facemask (1.4%). Tracheal intubation was difficult in eight patients (0.8%). Complications occurred immediately after tracheal extubation in 127 patients (12.6%; 95% CL: 10.6, 14.7) and in the recovery room in 95 patients (9.5%; 95% CL: 7.6, 11.3%). The common complications immediately after extubation were coughing (6.6%) and oxygen desaturation (SaO2 < 90%) (2.4%), and in the recovery room, airway obstruction (3.8%) and coughing (3.1%). The incidence of complications was significantly higher immediately after tracheal extubation than during induction of anaesthesia (P << 0.001). Even when all incidents of coughing that occurred after tracheal extubation were disregarded as a complication, the overall incidence was still higher immediately after extubation (7.4%) than during induction of anaesthesia (P < 0.01). We conclude that the incidence of respiratory complications associated with tracheal extubation may be higher than that during tracheal intubation.      

The coexistence of Alzheimer's disease and Creutzfeldt-Jakob disease in a patient with dementia of long duration

Summary We report here a 75-year-old-male with a slowly progressive dementia of 5-year duration along with a rapid exacerbation of symptoms in the terminal 3 months. Neuropathological examinations revealed findings consistent with conspicuous Alzheimer's disease and mild Creutzfeldt-Jakob disease (CJD). The plaque amyloid was exclusively composed of -protein. The immunohistochemistry of prion protein using hydrolytic autoclaving pretreatment showed diffuse gray matter stainings in the sections of both the cerebral and cerebellar cortices. This method was thus considered useful in confirming the diagnosis of CJD for this case.     

Permeation and deposition of fibrinogen and low-density lipoprotein in the aorta and cerebral artery of rabbits--immuno-electron microscopic study.

The localization of fibrinogen and low-density lipoprotein (LDL) in the arterial wall has been studied to determine whether they mediate the effects of hypertension and/or hypercholesteraemia on atherogenesis. In untreated control rabbits, fibrinogen was localized in the caveolae and vesicles of the endothelial cells and in the subendothelial spaces of the aorta. No fibrinogen was found in the subendothelial spaces of the cerebral artery. Hypertension or hypercholesteraemia was accompanied by enhanced insudation of fibrinogen into the subendothelial spaces of the aorta and cerebral artery, and fibrinogen deposition was most prominent in the hypercholesteraemic rabbits with induced renovascular hypertension. The insudation of fibrinogen appeared to occur by way of vesicular transport, and to some extent by junctional transport. In the untreated control rabbits, LDL was localized only in the caveolae and vesicles of endothelial cells in both aorta and cerebral artery. LDL was deposited in the subendothelial space of the aorta of hypercholesteraemic rabbits with or without hypertension, and in the cerebral artery of hypercholesteraemic rabbits with hypertension. These findings suggest that fibrinogen insudates into the intima of the aorta and cerebral artery both during hypertension and hypercholesteraemia, and that LDL insudation into the intima of the aorta in hypercholesteraemia is accentuated by hypertension. LDL insudated into the intima of the cerebral artery in the presence of hypercholesteraemia linked to hypertension. Thus, hypertension plays a significant role in the pathogenesis of cerebral atherosclerosis.     

Expression of inhibin alpha, glial cell line-derived neurotrophic factor and stem cell factor in Sertoli cell-only syndrome: relation to successful sperm retrieval by microdissection testicular sperm extraction

BACKGROUND: Microdissection testicular sperm extraction (TESE) has provided new hope for successful sperm retrieval to patients with Sertoli cell-only syndrome (SCO). We determined expression of the inhibin alpha subunit, glial cell line-derived neurotrophic factor (GDNF) and stem cell factor (SCF) in Sertoli cells obtained from patients with SCO immunohistochemically and compared expression rates with rates of microdissection TESE sperm retrieval. METHODS: Testicular biopsy specimens were obtained from 52 men with non-obstructive azoospermia who underwent microdissection TESE and were diagnosed with SCO by histological analysis. RESULTS: All specimens showed intense staining for the inhibin alpha subunit. Moderate or intense staining for GDNF was observed in 65.8% of specimens. All but one showed moderate or intense staining for SCF. Among specimens negative for GDNF, the sperm retrieval rate was significantly higher (100%) for specimens with intense staining for SCF than for specimens with no or moderate staining (30.7%) (P<0.05) for SCF. CONCLUSION: GDNF expression differs among patients with SCO. The sperm retrieval rate was high in cases of no staining for GDNF and intense staining for SCF.     

Activation of protease-activated receptor 2 stimulates proliferation and interleukin (IL)-6 and IL-8 secretion of endometriotic stromal cells

BACKGROUND: Inflammation has been proposed to play essential roles in the pathophysiology of endometriosis, in which neutrophils and mast cells have been suggested to be involved. We studied whether the protease-activated receptor 2 (PAR2), which is activated by enzymes from neutrophils and mast cells, in endometriotic stromal cells (ESC) has any implication in the development of the disease. METHODS: Cultured ESC were stimulated with various concentrations of a specific PAR2 agonist peptide. Proliferating activity of the cells was determined using immunostaining of proliferating cell nuclear antigen (a cell proliferation marker), 5-bromo-2'-deoxyuridine incorporation into DNA and cell count. The concentrations of interleukin (IL)-6 and IL-8 were measured using specific enzyme-linked immunosorbent assay kits. The phosphorylation of three mitogen-activated protein kinases (MAPK), i.e. p38 MAPK, p42/44 MAPK and stress-activated protein Kinase/c-jun N terminal Kinase, in ESC was examined with Western blot analysis. RESULTS: Activation of PAR2 stimulated the proliferation of ESC and the secretion of IL-6 and IL-8 from ESC in a dose-dependent manner. Activation of PAR2 stimulated the phosphorylation of all three MAPK, and inhibitors of each MAPK suppressed the PAR2 activation-induced proliferation of ESC. CONCLUSIONS: The activation of PAR2 in ESC may be involved in the pathophysiology of endometriosis by inducing the growth and inflammation of endometriotic lesions.     

Saliva-binding region of Streptococcus mutans surface protein antigen.

A 190-kDa surface protein antigen (PAc) of Streptococcus mutans binds to human salivary components. For detection of specific binding of the PAc protein to human salivary components, a simple sandwich assay was used. Microtiter plates precoated with recombinant PAc (rPAc), PAc fragments, or S. mutans whole cells were allowed to react with human whole saliva and then were incubated with biotinylated rPAc. The biotinylated rPAc bound to salivary components was detected by use of alkaline phosphatase-conjugated streptavidin and p-nitrophenylphosphate. In this assay, the binding of whole cells of S. mutans and purified rPAc to salivary components was confirmed. For determination of a saliva-binding region of the PAc molecule, 14 truncated PAc fragments were constructed by use of the polymerase chain reaction and an expression vector, pAX4a+. The binding of these truncated PAc fragments to human salivary components was determined by the sandwich assay. Among the truncated PAc fragments, fragments corresponding to residues 39 to 864 and residues 39 to 1000 of PAc showed a high ability to bind to salivary components. Shorter recombinant fragments corresponding to residues 39 to 217, residues 200 to 481, residues 470 to 749, and residues 688 to 864 did not exhibit any binding ability. The fragment that corresponds to a proline-rich repeating region (residues 828 to 1000) bound directly to the PAc protein. These results suggest that residues 39 864 of the PAc molecule are important in the binding of the surface protein to human salivary components, and the proline-rich repeating region of the PAc protein may contribute to spontaneous self-aggregation of the PAc protein.     

Analysis of wild-type and e antigen-defective hepatitis B viruses during the course of a short-term corticosteroid therapy in chronic hepatitis B

Hepatitis B virus (HBV), with a G-to-A point mutation at nucleotide 83 in the precore region (mutant HBV83), accounts for most cases of hepatitis B e antigen (HBeAg)-defective HBV. However, it is still not clear how mutant HBV83 is associated with HBe seroconversion. Twenty-six HBeAgpositive patients with chronic hepatitis B who received oral prednisolone (30 mg/day) for 3 weeks were studied to clarify the prevalence of mutant HBV83 during the treatment using polymerase chain reaction with a restriction fragment length polymorphism assay. Twelve (46%) patients seroconverted to anti-HBe 1 year after treatment, whereas 14 (54%) did not. The proportion of mutant HBV83 to whole HBV remained unchanged in both groups during an acute exacerbation induced by withdrawal of corticosteroids. Among 12 anti-HBe-0seroconverted patients, five (56%) of nine patients with only wild-type HBV at baseline developed detectable levels of mutant HBV83 while all three patients with a mixed viral population of wild-type HBV and mu tant HBV83 at baseline developed a higher pro portion of mutant HBV83 one year after treat ment. In contrast, these changes were observed in only one (14%) of seven who failed to seroconvert. The results indicate that a flare-up of hepa titis precedes emergence or selection of mutant HBV83, followed by HBe seroconversion in patients with chronic hepatitis B. © 1995 WiIey-Liss, Inc.     

A case report of idiopathic myxedema with secondary amenorrhoea and hyperprolactinemia: effect of thyroid hormone replacement on reduction of pituitary enlargement and restoration of fertility

A 37-year old housewife was admitted to our department because of long-standing amenorrhoea and galactorrhoea. After several hormonal examinations, she was proved to be suffered from primary hypothyroidism with hyperprolactinemia. In addition, brain computed tomography (CT) showed the finding of enhanced pituitary enlargement, suggesting pituitary hypertrophy or pituitary adenoma. Based on some therapeutic experiences in similar cases in several reports, we have performed only thyroid hormone replacement and followed up the patient. Plasma thyroid stimulating hormone (TSH) and prolactin concentrations returned to normal range in a few months after starting thyroid hormone replacement. Furthermore, the finding of pituitary enlargement has completely disappeared on brain CT and come to pregnancy during the course. Thus, it seems that the finding of pituitary enlargement might be due to pituitary hypertrophy. Therefore, we think that thyroid hormone replacement should be a first choice therapy preceding the pituitary surgery or bromocriptine therapy in such a case.