Demonstration of In Vitro Host-Guest Complex Formation and Safety of para-Sulfonatocalix[8]arene as a Delivery Vehicle for Two Antibiotic Drugs

The macrocycle para-sulfonatocalix[8]arene, sCX[8], was examined with 2 antibiotic drugs, ciprofloxacin (CIP) and isoniazid. The drugs were shown to form complexes with sCX[8] using proton nuclear magnetic resonance, thermogravimetric analysis, fluorescence spectroscopy, and molecular modeling. Both drugs form 1:1 hydrated (H₂O: 13%-14% w/w) host-guest complexes, with sCX[8] binding around the pyridine ring of isoniazid, and around the piperazine and cyclopropane rings of CIP. From proton nuclear magnetic resonance, the binding constant of isoniazid to sCX[8] was 6.8 (±0.3) × 10³ M^?1. Addition of 2 equivalents of sCX[8] to CIP resulted in a 58% decrease in fluorescence, and time-resolved fluorescence anisotropy of CIP doubles with sCX[8]. Each drug binds into the cavity of the macrocycle, with binding stabilized via combinations of hydrogen bonding, electrostatic interactions, π-π stacking, and hydrophobic effects. The safety of sCX[8] was examined in vitro with human embryonic kidney 293 cells. The IC₅₀ of sCX[8] was 559 μM, which is a minimum of 5-fold higher than the concentration that would be used in the clinic. The in vitro effect of sCX[8] on the action of CIP was examined on a panel of bacterial lines. The results showed that sCX[8] has no inherent antibiotic activity and had no negative effect on the action of CIP.     

A noninterventional study evaluating the effectiveness of rotigotine and levodopa combination therapy in younger versus older patients with Parkinson’s disease

Background: PD0013 was a 6-month noninterventional study in clinical practice comparing effectiveness/tolerability of rotigotine+levodopa in younger (<70 years) vs. older (≥70 years) Parkinson’s disease (PD) patients.

Methods: Patients previously received levodopa for ≥6 months as monotherapy/in combination with another dopamine-agonist (DA). Primary variable: Unified PD Rating Scale (UPDRS) Part-II change from baseline to end-of-observation-period (EOP).

Results: 91 younger/99 older patients started rotigotine; 68 younger/62 older patients completed the study. Most switched from levodopa+another DA. Addition of rotigotine as first DA was more common in older patients (20.2% vs.15.4%). Mean ± SD rotigotine-exposure: 6.1 ± 3.4 mg/24h younger vs. 4.9 ± 2.4 mg/24h older. Eleven patients changed levodopa dose.

At EOP, improvement in mean UPDRS-II was greater in younger patients (p = 0.0289). UPDRS-II responder-rate (≥20% decrease in UPDRS-II score) was higher in younger patients (42.3% vs. 25.9%). Improvement across age groups was similar on PD Sleep Scale-2 and Clinical Global Impressions-Improvement Scale. Adverse drug reactions (ADRs), and discontinuations because of ADRs, were more common among older patients. There were no new safety signals.

Conclusions: Despite low rotigotine doses, when added to levodopa/switched from levodopa+another DA, rotigotine led to greater improvement in UPDRS-II in younger patients (<70 years). Individual patient data revealed clinically meaningful improvements in UPDRS-II in both groups.     

Liver involvement in multiple myeloma

One hundred twenty-eight records of patients with multiple myeloma were reviewed to assess the incidence and manifestations of liver involvement. Histologic study of the liver was available in 21 patients. Diffuse infiltration of the liver by plasma cells was observed in 10 patients, myeloid metaplasia in four, amyloidosis in two, toxic hepatitis in two, and extrahepatic cholestasis secondary to infiltration of the peripancreatic tissue by plasma cells in one. The clinical signs of plasma cell infiltration of the liver consisted of hepatomegaly in seven patients, mild elevation of liver enzymes in five, and portal hypertension in two. Jaundice was only observed in patients with hepatitis or extrahepatic cholestasis. Liver infiltration by plasma cells did not appear to have a major prognostic significance.     

Estudio de coste-beneficio comparando la reparación de la hernia ventral abierta y laparoscópica

Objective

Laparoscopic surgery is a successful treatment option offering significant advantages to patients compared with open ventral hernia repair. A cost-benefit analysis was performed to compare the clinical results and economic costs of the open and laparoscopic techniques for anterior abdominal wall hernia repair, in order to determine the more efficient procedure.

Material and methods

We performed a prospective study of 140 patients with primary and incisional hernia, and analyzed clinical data, morbidity, costs of surgery and hospital stay costs.

Results

The cost of disposable surgical supplies was higher with laparoscopic repair but reduced the average length of stay (P < .001) and patient morbidity (P < .001). The total cost of the laparoscopic procedure was, therefore, less than initially estimated, yielding a savings of 1,260 € per patient (2,865 € vs. 4,125 €).

Conclusions

Laparoscopic ventral hernia repair is associated with a reduced complication rate, a lower average length of stay and with lower total costs. Laparoscopic repair can save 1.260 € for each patient, and so this procedure should be considered a cost-effective approach.     

Listeria monocytogenes meningoencephalitis in adults: analysis of factors related to unfavourable outcome

Purpose

To analyse the short-term outcome in patients with Listeria monocytogenes meningoencephalitis (LMME) to improve management and outcome.

Methods

Observational study with adult patients with LMME between 1977 and 2009 at a tertiary hospital in Barcelona, Spain. Parameters that predicted outcome were assessed with univariate and logistic regression analysis.

Results

Of 59 cases of LMME, 28 occurred in the last decade. Since 1987, a new protocol has been used and 29/45 patients (64 %) treated since then received adjuvant dexamethasone. In patients who received this treatment there was a trend towards fewer neurological sequelae (5 vs 33 %; p = 0.052). Antiseizure prophylaxis with phenytoin was administered in 13/45 (28 %) patients. Seizures occurred in 7/45 (16 %) patients, all in the group who did not receive phenytoin. Hydrocephalus presented in 8/59 (14 %). It was never present at admission and five patients needed neurosurgical procedures. Sequelae after 3 months were present in 8/45 (18 %), mostly cranial nerve palsy. Rhombencephalitis (RE) was related to the presence of neurologic sequelae (OR: 20.4, 95 % CI: 1.76–236). Overall mortality was 14/59 (24 %), 9/59 (15 %) due to neurological causes related to hydrocephalus or seizures. Mortality was defined as early in 36 % and late in 64 %. In the multivariate analysis, independent risk factors for mortality were presence of hydrocephalus (OR: 17.8, 95 % CI: 2.753–114) and inappropriate empirical antibiotic therapy (OR: 6.5, 95 % CI: 1.201–35).

Conclusions

Outcome of LMME may be improved by appropriate empirical antibiotic therapy, suspicion and careful management of hydrocephalus. Use of adjuvant dexamethasone or phenytoin in a subgroup of these patients might have a benefit.     

Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10⁻⁸; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10⁻¹⁴). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.