Sequential Treatment of Guillain-Barré Syndrome with Extracorporeal Elimination and Intravenous Immunoglobulin

Abstract: Plasma exchange and administration of intravenous immunoglobulin (IgG) are established treatments for Guillain-Barré syndrome (GBS). Elimination of postulated pathogenetic factors by plasma exchange or selective adsorption treatment using affinity-type adsorption columns and subsequent immunomodulation by intravenous IgG may provide a more effective treatment. Forty-five patients with acute GBS were prospectively examined using a clinical score. We treated 11 patients by plasma exchange, 13 patients by selective adsorption using a tryptophan-linked polyvinyl alcohol gel adsorbent, and 21 patients by selective adsorption followed by intravenous IgG. The patients treated sequentially by selective adsorption and intravenous IgG improved significantly better than the patients who received plasma treatment only. The results suggest that sequential treatment of GBS may be superior to plasma treatment alone. The higher cost of combined treatment may be offset by lower overall expenditure.     

Churg‐Strauss syndrome with poor‐prognosis factors: A prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty‐eight patients

Objective

To compare long and short durations of adjunctive cyclophosphamide for the treatment of severe Churg‐Strauss syndrome (CSS).

Methods

In this prospective multicenter therapeutic trial, 48 patients with CSS with at least 1 poor‐prognosis factor at baseline were treated with glucocorticoids and either 12 or 6 intravenous cyclophosphamide pulses.

Results

At 8 years, complete remission rates and severe side effects of therapy were comparable for both groups. The overall difference in relapses was not significant between the 12‐pulse and the 6‐pulse regimens (P = 0.07), but when considering only the number of mild relapses this difference became statistically significant (P < 0.02). Although the total number of inclusions was not reached, the study was stopped prematurely in response to the superiority of the 12‐pulse regimen.

Conclusion

We concluded that 12 cyclophosphamide pulses were better able to control severe CSS than a 6‐pulse regimen. The optimal duration of therapy remains to be determined.     

Discontinuation of nonsteroidal anti-inflammatory drug therapy and risk of acute myocardial infarction

BACKGROUND: Systemic inflammation has been shown to be associated with an increased risk of acute myocardial infarction (AMI). However, the effect of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of AMI has not yet been well defined. We therefore studied the risk of AMI during NSAID exposure and after the cessation of NSAID therapy. METHODS: We conducted a large case-control analysis on the British General Practice Research Database. The study included 8688 cases with a first-time AMI between 1995 and 2001 and 33 923 controls, matched to cases on age, sex, calendar time, and general practice attended. RESULTS: After adjusting for hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, rheumatoid arthritis, systemic lupus erythematosus, acute chest infection, body mass index, smoking, and aspirin use, the risk of AMI was 1.52 (95% confidence interval [CI], 1.33-1.74) for subjects who stopped taking NSAIDs 1 to 29 days prior to the index date, compared with nonusers. The risk was highest in subjects with rheumatoid arthritis or systemic lupus erythematosus (adjusted OR, 3.68 [95% CI, 2.36-5.74]) and for subjects who discontinued therapy with NSAIDs after previous long-term use (adjusted OR, 2.60 [95% CI, 1.84-3.68]). Current and past NSAID use (discontinued therapy >/=60 days prior to the index date) were not associated with an increased risk of AMI (adjusted OR, 1.07 [95% CI, 0.96-1.19] and 1.05 [95% CI, 0.99-1.12], respectively). CONCLUSION: Our findings suggest that the risk of AMI is increased during several weeks after the cessation of NSAID therapy.     

Cytomegalovirus (CMV) glycoprotein B genotypes and response to antiviral therapy,in solid-organ-transplant recipients with CMV disease

Cytomegalovirus (CMV) can be classified into 4 glycoprotein B (gB) genotypes, on the basis of sequence variation in the UL55 gene. We assessed the effect that CMV gB genotype has on virologic and clinical response to therapy, in 50 solid-organ-transplant recipients with CMV disease. CMV loads were determined at regular intervals after the start of therapy. Genotype results were correlated with CMV-load kinetics in response to therapy with ganciclovir. At the onset of treatment, the distribution of CMV gB genotypes was as follows: gB1, 19/50 (38%); gB2, 9/50 (18%); gB3, 12/50 (24%); gB4, 2/50 (4%); and mixed-genotype infection, 8/50 (16%). Between viral genotype groups, time to clearance of CMV, failure to clear CMV, and calculated CMV-load half-life after the start of therapy were not significantly different. The CMV gB genotype did not affect the rate of disease recurrence or occurrence of tissue-invasive disease. It appears that the gB genotype, which causes CMV disease, does not significantly influence CMV-load kinetics or clinical response to therapy.     

beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids

Most mu-opioid receptor agonists recruit beta-arrestin2, with some exceptions such as morphine. Surprisingly, however, the acute analgesic effect of morphine is enhanced in the absence of beta-arrestin2. To resolve this paradox, we examined the effects of morphine and fentanyl in acute brain slices of the locus coeruleus and the periaqueductal gray from beta-arrestin2 knockout mice. We report that, in these mice, presynaptic inhibition of evoked inhibitory postsynaptic currents was enhanced, whereas postsynaptic G protein-coupled K(+) (Kir3/GIRK) currents were unaffected. The frequency, but not amplitude, of miniature inhibitory postsynaptic currents was increased in beta-arrestin2 knockout mice, indicating a higher release probability compared to WT mice. The increased release probability resulted from increased cAMP levels because of impaired phosphodiesterase 4 function and conferred an enhanced efficacy of morphine to inhibit GABA release. Thus, beta-arrestin2 attenuates presynaptic inhibition by opioids independent of mu-opioid receptor-driven recruitment, which may make beta-arrestin2 a promising target for regulating analgesia.     

Prevalence of C282Y and E168X HFE mutations in an Italian population of Northern European ancestry

BACKGROUND AND OBJECTIVES: In Italy, the prevalence of C282Y is lower than in Northern European countries. We hypothesized a higher prevalence of C282Y in Northern than in Southern Italian populations. We previously identified a nonsense mutation (E168X) in hemochromatosis probands originating from a region in the north-west of Italy. We aimed to define the prevalence of C282Y and E168X in that region and the origin of the E168X mutation by haplotype analysis. DESIGN AND METHODS: Six-hundred and six blood donors were investigated for C282Y, H63D, S65C and E168X mutations by polymerase chain reaction (PCR)-restriction assays. Three hundred were also tested for rare HFE and TFR2 mutations by reverse-hybridization test strips. D6S265, D6S105 and D6S1281 microsatellites were analyzed to define E168X 6p-associated haplotypes. RESULTS: One C282Y homozygote, thirteen C282Y/ H63D compound heterozygotes, four E168X heterozygotes and three E168X/H63D compound heterozygotes were found. The allele frequencies of C282Y, H63D, S65C, and E168X were 4.7%, 14.9%, 0.74% and 0.58%, respectively. INTERPRETATION AND CONCLUSIONS: The prevalence of C282Y in the region investigated was much higher than that previously reported in Italy. This finding is probably due to the heavy Celtic component of this north-western population and suggests that in populations of Northern Italian descent screening studies for hemochromatosis could be cost-effective. The prevalence of E168X in this region, although low, suggests that the mutation probably originated here many years ago and its frequency increased as a result of a local founder effect. Given its severity, we suggest that the E168X mutation should be searched for in all hemochromatosis patients of Northern ancestry with an incomplete HFE genotype.     

Non-episodic angioedema associated with eosinophilia following <Emphasis Type="Italic">Mycoplasma pneumoniae</Emphasis> infection

Episodic angioedema with eosinophilia is characterized by recurrent angioedema, peripheral eosinophilia, fever, weight gain, elevated serum immunoglobulin M (IgM), and a benign course lacking any internal organ involvement. A non-episodic variant has also been reported which is limited to a single attack and normally is less severe than the episodic type. We report a case of Mycoplasma pneumoniae infection with dermatological manifestation that was followed by non-episodic angioedema with eosinophilia including fever, weight gain, and elevated serum IgM. Even though the patient’s clinical characteristics resemble episodic angioedema with eosinophilia as reported by Gleich, angioedema was non-episodic. This may be due to systemic corticosteroid treatment which was prescribed because of persistent skin manifestation following M. pneumoniae infection. The current report is the first observation suggesting that angioedema associated with eosinophilia may be triggered by atypical bacterial infection.     

Trypsinogen Activation Peptides (TAP) in Peritoneal Fluid as Predictors of Late Histopathologic Injury in Necrotizing Pancreatitis of the Rat

The levels of trypsinogen activation peptides(TAP) were quantified by ELISA immunoassay in acutepancreatitis of the rat and compared to the degree oflate histopathological sequelae and exocrine functional impairment 4 and 12 weeks after the acute phaseof the disease. For this purpose acute pancreatitis ofdifferent severity was induced using a suitable ratmodel recently described. Forty five surviving animals were studied. The level of TAP inperitoneal exudate measured 3 and 6 hr afterpancreatitis induction correlated well with the amountof the late histopathological injury at the end of thecorresponding observation period (at 4 weeks after 3 hr: r =0.75, P = 0.003, after 6 hr: r = 0.72, P = 0.005,Pearson; and at 12 weeks after 3 hr: r = 0.86, P =0.0001, after 6 hr: r = 0.84, P = 0.0001, Pearson). A negative correlation of TAP with the impairmentof exocrine function was found only at 4 weeks for thesecretion of total protein (r = –0.76 after 3 hr;r = –0.62 after 6 hr) and for exocrine function (r = –0.67 after 3 hr, r = –0.57 after6 hr), but not at 12 weeks after acute pancreatitis. Nocorrelation with plasma amylase and lipase was found. Weconclude that quantitation of TAP in ascites provides an accurate prediction of late histopathologicsequelae. Pancreatic exocrine function could bepredicted by TAP assay only in the early stage afterpancreatitis induction (eg, four weeks). In later stages of the disease (eg, 12 weeks) remainingpancreatic tissue seems to compensate for any exocrinedeficits that have occurred.     

Passive smoking increases platelet thromboxane

Although active smoking is known to enhance platelet thromboxane production, no data on passive smoking are available yet. In an 18 m³ room, the influence of single and repeated exposure to passive smoke for 60 minutes was assessed in nonsmokers and smokers. Smokers and nonsmokers were matched for sex and age. All the evaluated parameters (plasma TXB₂, serum TXB₂, malondialdehyde, 11-dehydro-TXB₂, conversion of exogenous arachidonic acid to hydroxy-5,8,10-heptadecatrienoic acid, and TXB₂) were higher in smokers than nonsmokers at baseline conditions, immediately and 6 hours after passive exposure to cigarette smoke. Repeated exposure of nonsmokers rendered their platelets more activated, so they became closer to the behavior of smokers. Contributing to the development of hemostatic imbalance, these results indicate that passive smoking may enhance thromboxane A₂ release from the platelets.Presented at the 36^th Annual World Congress, International College of Angiology, New York, New York, July 1994