Penetrability of interleukin-1beta and its effect on the concentration of tumor necrosis factor-alpha and interleukin-6 in the aqueous humor of rabbits treated with interleukin-1beta.

BACKGROUND: Interleukin (IL)-1beta may effectively decrease introcular pressure (IOP) when administered by subconjunctival injection in normal rabbit. However, IL-1beta is a large molecular agent and an inflammation factor. The aim of this study was to evaluate the penetrability of IL-1beta, and the concentrations of both tumor necrosis factor (TNF)-alpha and IL-6 in the aqueous humor of normal rabbits treated with IL-1beta. METHODS: A total of 170 rabbits were used in the study and were assigned to several different treatment groups as follows: 125 of the rabbits were assigned to two groups. In one group, 33 rabbits were injected subconjunctivally with IL-1beta and 39 were injected with saline alone. In the other group, 27 rabbits were given eye drops containing IL-1beta (400 ng/ml) and 26 were given saline alone. Aqueous humor (AH) was drawn and the concentration of IL-1beta within the fluid measured. The IOP was measured in another six rabbits after administration of eye drops containing IL-1beta (400 ng/ml). A further 20 rabbits were assigned to 3 groups as follows: eight untreated normal controls; six injected subconjunctivally with IL-1beta; and six injected subconjunctivally with saline alone. AH was drawn and the concentration of TNF-alpha in the fluid was measured. Another 19 rabbits were assigned to 3 groups as follows: seven untreated normal controls; and six injected subconjunctivally with IL-1beta; and six injected subconjunctivally with saline alone. AH was drawn and the concentration of IL-6 in the fluid measured. Measurement of cytokine concentration was by radio-immunoassay in all cases. RESULTS: The IL-1beta concentration in the AH was higher in those animals in which it had been administered subconjunctivally (P < 0.01). The IL-1beta concentration in the AH of the animals given eye drops was almost the same as that in the controls (P > 0.05). The administration of IL-1beta in the form of eye drops had little effect upon IOP reduction. Lower TNF-alpha concentrations were seen in the AH after the subconjunctival administration of IL-1beta, but the concentration of IL-6 was the same as in the normal controls. CONCLUSIONS: IL-1beta shows good corneal penetrability after subconjunctival injection into normal rabbit eyes. The IOP reduction induced by IL-1beta is unlikely be associated with an inflammatory response.

Effects of MISA A on actin cytoskeleton of cultured HTM cells and intraocular pressure of rats and glaucomatous monkeys.

PURPOSE: To determine the effects of misakinolide (MISA) A, which leads to the disassembly of actin filaments, on the actin cytoskeleton of cultured human trabecular meshwork (HTM) cells and on intraocular pressure (IOP) in living rats and monkeys. METHODS: Cultured HTM cells were treated with MISA A, and the changes in the actin cytoskeleton were determined by immunofluorescence microscopy. Elevated IOP was induced in cynomolgus monkeys by unilateral laser photocoagulation of the trabecular meshwork (TM). The IOP response after topical administration of MISA A was determined in normotensive rats (Tonopen) and glaucomatous monkeys (pneumotonometer and Tonopen) at 0.5, 1, 2, 3, 4, 5, and 6 hr. RESULTS: MISA A caused dose- and time-dependent disruption of actin stress fibers in cultured HTM cells. Actin microfilaments and vinculin containing focal contacts deteriorated after 2 hr, 30 and 10 min of incubation with 5 nM, 10 nM, and 25 nM MISA A, respectively. Recovery was also dose- and time-dependent. The actin-disrupting effects were not reversible when the cells were incubated with MISA A at a low dose (10 nM) for 24 hr or a high dose (25 nM) for 30 min. Topical administration of MISA A significantly decreased IOP in rats by 5.8 +/- 0.5 (mean +/- SEM) (p < 0.05) Tonopen rat units. In monkeys, IOP was decreased by 3.8 +/- 0.5 mmHg (p < 0.001) in the normotensive eye and by 9.2 +/- 1.2 mmHg (p < 0.001) in the glaucomatous eye. CONCLUSIONS: MISA A greatly altered the actin cytoskeleton and cellular adhesions and reduced IOP, suggesting that MISA A may be a useful antiglaucoma strategy.

Management of star fruit-induced neurotoxicity and seizures in a patient with chronic renal failure.

An 84-year-old Asian woman with hypertension and chronic renal failure was evaluated for incoherent speech, followed by intermittent interruptions of consciousness, and then status epilepticus after ingesting one star fruit (Averrhoa carambola) each day for 3 days. Conventional first-line anticonvulsants and hemodialysis were administered without significant control of the patient's seizures. Treatment was started with propofol, an intravenous agent that induces anesthesia with rapid onset and elimination from the central nervous system; this resulted in complete control of the seizures. Propofol may be an effective alternative when dialysis and conventional first-line anticonvulsants are unsuccessful in treating the symptoms of neurotoxicity.

Adult Acinetobacter meningitis and its comparison with non-Acinetobacter gram-negative bacterial meningitis.

Between January 1999 and December 2003, 81 cases of single pathogen-related culture-proven Gram-negative adult bacterial meningitis were identified at Chang Gung Memorial Hospital-Kaohsiung. Of these 81 cases, Acinetobacter infection was found in 13 cases. Clinical and laboratory data of these Acinetobacter meningitis patients were studied and were compared with those of other 68 non-Acinetobacter Gram-negative bacterial meningitis (GNBM) patients. Of the 13 implicated Acinetobacter strains, A. baumannii was the most common (12), and the other was A. lwoffii (1). Eleven of these 13 cases were due to a post-neurosurgical infection. The results of the antibiotic susceptibility test of the 13 Acinetobacter strains from cerebrospinal fluid included ceftriaxone, (1/13, 8%), ciprofloaxin (6/13, 46%), ceftazidime (6/13, 46%), cefepime (7/13, 54%), ampicillin-subtactam (7/13, 54%), imipenem (12/13, 92%) and meropenem (12/13, 92%). One strain with pan-drug resistant A. baumannii (PDRAB) emerged in 2003. A statistically significant difference between Acinetobacter meningitis and non-Acinetobacter GNBM included hydrocephalus and ceftazidime-resistance. A mortality rate was 30% (4/13), and 7 of the other 9 survivals had severe neurologic deficits. The emergence of Acinetobacter infections in adult post-neurosurgical infections, multiple antibiotic resistant characteristics, and the emergence of PDRAB strain remained a challenge of the initial management of this specific meningitis. Use of carbapenem, especially meropenem, could be considered as one of the initial empiric antibiotics chosen for the management of adult post-neurosurgical meningitis.

Clinical characteristics of adult Escherichia coli meningitis.

The clinical characteristics and therapeutic outcomes of adult meningitis due to Escherichia coli alone have not been examined adequately. In this study, we analyzed the clinical and laboratory data of 15 adult patients with monomicrobial E. coli meningitis. The 15 patients, collected over a period of 18 years (January 1986-December 2003), included 7 men and 8 women, aged 45-77 years. They accounted for 5% (15/306) of our adult bacterial meningitis with single pathogen infection. This study also revealed that a post-neurosurgical state is the most important factor predisposing adult patients to develop E. coli meningitis. In this study, all of the tested E. coli strains showed their susceptibility to imipenem and/or meropenem, however, E. coli strains that are not susceptible to third-generation cephalosporin have emerged since 2001. As to the therapeutic results of these 15 cases, all 4 patients without appropriate antibiotic treatment died and the other 11 patients with appropriate antibiotic treatment showed a mortality rate of 27%. The emergence of third-generation cephalosporin non-susceptible E. coli strains in adult bacterial meningitis, as shown in this study, has caused a therapeutic challenge in choosing initial empirical antibiotics for treating adult patients with post-neurosurgical meningitis. Our results emphasize that the timely use of appropriate antibiotics is essential for the management of this potentially fatal central nervous system infection. However, it should be noted that the number of cases examined in this study is too small to reach a therapeutic conclusion regarding adult E. coli meningitis, and further large-scale studies will be needed for this purpose.

An adult case of Chryseobacterium meningosepticum meningitis.

Chryseobacterium meningosepticum is an uncommon pathogen causing adult bacterial meningitis. Herein, we report the case history of one 21-year-old woman with this uncommon central nervous system infection. A diagnosis of adult C. meningosepticum meningitis can only be confirmed by a positive cerebrospinal fluid (CSF) culture. The patient had insulin-dependent diabetes mellitus as the underlying condition associated with this infection. The clinical presentations were fever, headache, consciousness disturbance, and seizure. CSF analysis revealed a purulent inflammatory reaction. After a 21-day course of intravenous cefepime (6 g/day) treatment, this patient was discharged in a state of complete recovery.

Serotypes of clinical cerebrospinal fluid Cryptococcus neoformans isolates from southern Taiwan and their in vitro susceptibilities to amphotericin B, fluconazole, and voriconazole.

In this study, 34 clinical cerebrospinal fluid isolates of Cryptococcus neoformans were serotyped, and their in vitro susceptibilities to amphotericin B, fluconazole, and voriconazole were analyzed. Of these 34 isolates, serotype A was found in 29 isolates and serotype B in the other five. The voriconazole geometric mean MIC was significantly lower than the amphotericin B/antibiotic medium 3 geometric mean MIC (P < 0.0001 at both 48 and 72 h), as well as the fluconazole geometric mean MIC (P < 0.0001 at both 48 and 72 h). Of the three antifungal agents, only fluconazole, with geometric mean MICs at both 48 and 72 h, showed significant difference between the serotypes A and B of C. neoformans.

Bacterial meningitis in infants: the epidemiology, clinical features, and prognostic factors.

This 16-year (1986-2001) retrospective study enrolled 80 infantile patients (aged, 30-365 days old) with culture-proven bacterial meningitis. The most prevalent pathogens were Salmonellaspecies, Streptococcus (S.) agalactiae, Escherichia (E.) coli, and Haemophilus (H.) influenzae, accounting for about 59% of the episodes. Meningitis caused by Salmonella species, E. coli and H. influenzae occurs more often in the older infants, while that caused by S. agalactiae occurs more often in young infants. Our study revealed a decrease in the proportion of Salmonella meningitis from 27% in the first 8 years to 9% in the second 8 years with E. coli replacing Salmonella species as the leading pathogen of this disease during the second period. Overall mortality rate for both periods of time was 11%. However, if we take those with undesirable poor outcomes into account, 43% of patients could be considered treatment failures. The study also reveals a high prevalence of neurological complications when this disease is caused by H. influenzae, S. pneumoniae, and Salmonella species. Stepwise logistic regression analysis revealed that only initial changing levels of consciousness (P = 0.006) were independently associated with treatment failure. The most frequent neurological complications associated with this disease included subdural empyema, hydrocephalus, cerebral infarctions, and seizures. Because therapeutic regimens may require attention to the eradication of bacterial pathogen but also the neurological complications, early diagnosis and choice of appropriate antibiotics are essential to increasing the possibility of survival.

Long-term prognosis for Guillain-Barré syndrome: evaluation of prognostic factors and clinical experience of automated double filtration plasmapheresis.

Sixty patients with Guillain-Barré syndrome (GBS), aged 16-83 years, have been identified over a period of 7 years. Of 60 patients, 30 received the double filtration plasmapheresis (DFP), 4 received intravenous immunoglobulin, and the other 26 received supportive care only. Therapeutic outcomes at 1 year were determined using a modified Barthel index. At a follow-up of 1 year or longer, 31 patients (52%) had recovered, 24 (40%) had residua, and 5 (8%) had died. According to the statistical analysis, disability at the nadir and electrophysiological signs significantly influenced the long-term outcomes. Complications associated with DFP procedures included physiologic change, technique-related complications, and vascular access-related complications. None of our patients had fatal complications related to DFP treatment. Contrary to the established belief that the disease has a favorable outcome, several hospital-treated patients may still die or present residua even several months after the onset of symptoms. Because disability at the nadir influences the outcomes, early diagnosis and choice of appropriate treatment, which might include DFP, to prevent further neurological deficits, are essential to maximize the potential for survival.

Neonatal bacterial meningitis in southern Taiwan.

To determine the epidemiologic trends, prognostic factors, and therapeutic results of neonatal bacterial meningitis, 60 neonatal patients with culture-proven neonatal bacterial meningitis were enrolled in this study. To compare changes over time, the appearance of disease among the patients was divided into two equal periods (1986-1993 and 1994-2001). Group B streptococci were the most common causative pathogens, accounting for approximately 32% of the episodes. Escherichia coli, the next most common pathogen, was more frequently observed in the second period. Seventy-seven percent of gram-negative bacilli isolates were resistant to ampicillin. Moreover, oxacillin-resistant Staphylococcus and ampicillin-resistant group B streptococci strains occurred in the second periods as late-onset neonatal bacterial meningitis. The overall mortality rates for the first and second study period were 17% and 8%, respectively. However, if individuals with poor outcomes were taken into account, 38% of patients were considered treatment failures. Significant prognostic factors included the presence of seizures, thrombocytopenia, and high cerebrospinal fluid protein and low cerebrospinal fluid glucose concentration. Although the mortality rate was significantly reduced in the second period, there has been increasing incidence of the emergence of resistant strains presenting a therapeutic challenge. The presentation in neonatal bacterial meningitis might be nonspecific, and blood culture results were negative in 45% of the episodes. Early diagnosis, choice of appropriate antibiotics, and correction of metabolic derangement are essential to improving outcomes.

Treatment of pediatric idiopathic pulmonary hemosiderosis with low-dose cyclophosphamide.

OBJECTIVE: To report the safety and efficacy of long-term, low-dose cyclophosphamide therapy in a child with idiopathic pulmonary hemosiderosis (IPH). CASE SUMMARY: A 7-year-old boy diagnosed with IPH 4 years previously was initially prescribed prednisolone. Because he only had a transient response to prednisolone, oral cyclophosphamide 2 mg/kg/d was later added. A dramatic improvement was noted during the subsequent follow-up. One year after cyclophosphamide therapy, the patient suddenly developed thrombocytopenia (platelet count 75 x 10(3)/mm(3)), with the platelet count decreasing to 10 x 10(3)/mm(3) over the following 10 months. Cyclophosphamide was tapered to an alternating daily dosage of 1 mg/kg. The tapering resulted in a subsequent increase in the platelet count, which was maintained between 20 and 50 x 10(3)/mm(3) without occurrence of petechiae or spontaneous bleeding. Under this reduced dosing regimen, the disease has remained in remission for >1 year. DISCUSSION: Due to the low prevalence of IPH, only limited data document the safety and efficacy of immunosuppressive therapy in treating this disease. Although our patient showed a good response to low-dose cyclophosphamide, he developed thrombocytopenia with its use. The mechanism is unclear, but it may be similar to that of high-dose cyclophosphamide-induced myelosuppression. Due to the development of thrombocytopenia, the use of cyclophosphamide was maintained under a reduced dosing regimen. The benefit of long-term immunosuppressive therapy is controversial, and more clinical evidence is required to support its continued usage. CONCLUSIONS: Long-term, low-dose cyclophosphamide is effective in treating childhood IPH, but caution should be exercised due to the possible development of thrombocytopenia. Periodic monitoring of the platelet count in long-term treatment is recommended.

Clinical features and in vitro antimicrobial susceptibilities of community-acquired Klebsiella pneumoniae meningitis in Taiwan.

Twenty-seven adult patients were identified as having community-acquired Klebsiella pneumoniae meningitis. The K. pneumoniae isolates, collected from cerebrospinal fluid samples, were tested for in vitro antimicrobial susceptibilities. The prognostic factors of these 27 patients were also analysed. All of the third- and fourth-generation cephalosporins tested, as well as monobactam, carbapenem and ciprofloxacin, had good activities against the isolated K. pneumoniae strains. None of the clinical isolates was detected as being an extended-spectrum beta-lactamase-producing pathogen. Among the third- and fourth-generation cephalosporins, ceftizoxime, cefepime, ceftriaxone and cefotaxime had superior activities, with MIC90s about four- to eight-fold lower than those of ceftazidime and moxalactam. Mortality rates of patients classified by different antimicrobial agents were as follows: ceftazidime 38% (8/21) and cefepime 16.7% (1/6). The presence of septic shock and the initial level of consciousness at the start of appropriate antimicrobial therapy were the major determinants of survival and neurological outcomes in these 27 patients. Early diagnosis and choice of appropriate antibiotics according to antimicrobial susceptibilities may improve therapeutic outcomes.

Brain abscess caused by aerobic Gram-negative bacilli: clinical features and therapeutic outcomes.

Thirty-three patients (24 males and nine females) with brain abscesses resulting from infection by aerobic Gram-negative bacilli were identified at Kaohsiung Chang Gung Memorial Hospital over a period of 14 years. Of these, 23 cases developed spontaneously, with the remaining ten postneurosurgery. The organisms most frequently involved were Klebsiella (K.) pneumoniae, Pseudomonas aeruginosa, Escherichia coli and Proteus species and included some rare pathogens, such as Salmonella and Enterobacter species, K. oxytoca, Vibrio and Morganella morganii. Apart from one exception, the locations of the abscess were supratentorial. Twenty-four patients presented with a single abscess, while nine revealed multiple abscesses, with 26 treated surgically and seven with antibiotics exclusively. In total, seven patients died, representing an overall mortality rate of 21%. This study demonstrates that brain abscesses associated with neurosurgical procedures are not rare, accounting for 30% of cases in this study, with K. pneumoniae, Proteus and Enterobacter species the most prevalent of the revealed pathogens. Further, Proteus species were the most prevalent pathogens demonstrated for cases of both otogenic and polymicrobial infections. If brain abscesses are diagnosed for diabetic patients or have a gas-forming appearance, a diagnosis of K. pneumoniae infection should be considered, with particular attention paid to detection of other metastatic septic abscesses. In light of the high mortality rate, early treatment is essential to maximize the chances of survival.

Adult spinal epidural abscess: clinical features and prognostic factors.

Twenty-nine adult patients with spinal epidural abscess (SEA), aged 31-73 years, have been identified over a period of 8 years. The 29 SEA patients included 21 men and eight women with a mean age of 54 years. Initial diagnosis of SEA was made in only 17% of our patients and another 48% of patients were initially suggested of having infection or mass of the spine. Spinal pain and fever were the two most common clinical features shared among our patients. The two most common pathogens were Staphylococcus aureus and Mycobacterium tuberculosis, which were found in 62% of patients. Twenty-seven patients received surgical intervention and antibiotic treatment for SEAs, one of which succumbed to meningitis. Two patients without neurological abnormalities received conservative treatment alone and survived. The number of patients, which showed improvement of symptoms, included all seven patients with neck/back pain without neurologic deficits, all 15 patients with paraparesis, 10 of 13 patients with bladder/bowel dysfunction with or without motor deficits, and none of the five with plegia. Preoperative plegia was identified as a poor prognostic factor, and patients with SEA continue to show high rates of morbidity and mortality. Thus, in order to improve the therapeutic outcome of patients with SEA, early diagnosis and management are mandatory to treat the patients before the deterioration of neurologic deficit occurs.

Community-acquired bacterial meningitis in adults: the epidemiology, timing of appropriate antimicrobial therapy, and prognostic factors.

Between January 1986 and December 1999, 109 adult patients with culture-proven community-acquired bacterial meningitis were identified at Kaohsiung Chang Gung Memorial Hospital. To compare changes over time, the appearance of disease among our patients was divided into two equal time periods: an earlier time period (1986-1992) and a later time period (1993-1999). In this study, there was a decreasing proportion of community-acquired bacterial meningitis compared with nosocomial bacterial meningitis in adult patients in recent years. Its proportion declined dramatically from 81% in the earlier 7 years to 37% in the later 7 years. Of the pathogens, Klebsiella (K.) pneumoniae was the most frequently implicated pathogen, followed by Viridans (V.) streptococci, Streptococcus pneumoniae, and Staphylococcus aureus. Other rare organisms including Acinetobacter baumannii, Salmonella Group B and D, Proteus mirabilis, Group B, D, and non-A, non-B and non-D streptococci, and coagulase-negative staphylococci emerged during the second period. There was a decrease in the mortality rate from 44% in the first to 34% in the second time period, but the overall mortality rate remained high. Of the implicated pathogens, patients infected with V. streptococci had a consistently favorable prognosis, while a dramatic decrease in the mortality rate of those infected with K. pneumoniae was seen in recent years. In the multiple logistic regression analysis, only the presence of septic shock and seizures was independently associated with mortality. The timing of appropriate antimicrobial therapy, as defined by consciousness level, was a major determinant of survival and neurological outcomes for patients with community-acquired bacterial meningitis, and the first dose of an appropriate antibiotic should be administrated before a patient's consciousness deteriorates to a Glasgow coma scale score lower than 10.

Effect of t-butyl hydroperoxide on Ca2+ movement in PC12 pheochromocytoma cells.

The effect of the oxidant t-butyl hydroperoxide on intracellular free levels of Ca2+ ([Ca2+]i) in PC12 pheochromocytoma cells was examined by using fura-2 as a fluorescent dye. t-Butyl hydroperoxide induced an increase in [Ca2+]i in a concentration-dependent fashion between 50-250 microM with an EC50 of 100 microM. The [Ca2+]i signal consisted of a slow rise and a sustained phase. The response was decreased by 65% by removal of extracellular Ca2+. In Ca(2+)-free medium, pretreatment with 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) abolished 150 microM t-butyl hydroperoxide-induced [Ca2+]i increase, and conversely, pretreatment with t-butyl hydroperoxide abrogated thapsigargin-induced [Ca2+]i increase. The 150 microM t-butyl hydroperoxide-induced [Ca2+]i increase in Ca2+ medium was reduced by 42 +/- 5% by pretreatment with 0.1 microM nicardipine but not by 10 microM verapamil, nifedipine, nimodipine or diltiazem, or by 50 microM La3+ or Ni2+. Pretreatment with 10 microM t-butyl hydroperoxide for 40 min did not affect 10 microM ATP-induced [Ca2+]i increase. Together, the results show that t-butyl hydroperoxide induced significant [Ca2+]i increase in PC12 cells by causing store Ca2+ release from the thapsigargin-sensitive endoplasmic reticulum pool in an inositol 1,4,5-trisphosphate-independent manner and by inducing Ca2+ influx via a nicardipine-sensitive pathway.

Time dependent effects of sympathetic denervation on aqueous humor dynamics and choroidal blood flow in rabbits.

PURPOSE: This study investigates the time-dependent effects of superior cervical ganglionectomy (SCGx) on aqueous humor dynamics and ocular blood flow in rabbits. METHODS: Measurements were made at various times between 24 hours and 12 months after SCGx. Intraocular pressure (IOP) was measured by pneumatonometry, aqueous flow by fluorophotometry and outflow facility by tonography. Uveoscleral outflow was determined by an intracameral tracer infusion technique and blood flow to the choroid was evaluated with fluorescent microspheres. Values in denervated eyes were compared with the contralateral, normally-innervated eyes using a paired Student's two-tailed t-test. RESULTS: At 24 hours after SCGx, IOP in denervated eyes was less than in normally-innervated eyes (14.6 +/- 0.8 vs 20.1 +/- 1.5 mmHg, 27%, p < 0.002). At one month, IOPs were not different between eyes. Compared with normally-innervated eyes at 10-12 months, IOP in denervated eyes was greater (20.4 +/- 0.7 vs 17.2 +/- 0.9 mmHg, 19%, p < 0.001), outflow facility was less (0.15 +/- 0.02 vs 0.21 +/- 0.01 microl/min/mmHg, 29%, p < 0.01) and blood flow to the choroid was less (12.1 +/- 5.0 vs 16.2 +/- 6.0 ml/min/gm tissue, 25%, p < 0.05). Aqueous humor flow was not significantly altered by SCGx at any time. CONCLUSIONS: The reduction in IOP at 24 hours after SCGx was not due to any change in aqueous flow or uveoscleral outflow (current study) but rather to an increase in outflow facility (previous studies). At 10-12 months, IOP was elevated because outflow facility was significantly reduced. The reduction in choroidal blood flow at 10-12 months may have occurred because of the increased IOP.