Characteristics of a large mumps outbreak: Clinical severity, complications and association with vaccination status of mumps outbreak cases.

In recent years, large mumps outbreaks, involving mainly adolescents and young adults, have re-emerged in several countries. We investigated a large mumps outbreak, evaluated the association between mumps clinical severity (complications, hospitalization) and vaccination status (number of previous measles, mumps and rubella - MMR vaccine doses), and assessed vaccine effectiveness. The first mumps cases emerged in an ultra-orthodox boys' school in Jerusalem and were epidemiologically linked to the mumps outbreak in New York. Overall, 3130 mumps cases were notified in the Jerusalem district during September 2009-August 2011 (median age 13y, 64% males). Most cases were reported from community clinics. Patients with systemic symptoms and/or complications (419, 13.4%) were either hospitalized (n = 79) or treated in an emergency medical center (n = 340). The main complications included orchitis (3.8% males> age 12y) and meningoencephalitis (0.5%). The mumps virus genotype was G5. The distribution of previous MMR vaccine doses (n = 0,1,2) was: 24.8%, 28.3% and 46.9%, respectively. The number of previous vaccine doses was inversely associated with clinical severity. Adjusted values for MMR vaccine effectiveness against complications were estimated as 52.1% (95% CI -4 -78%) for one vaccine dose and 62.7% (95% CI 25.7-81.3%) for 2 doses. The outbreak was characterized by predominance of male students; the majority of whom had been previously vaccinated. The reported complication rate was relatively low. Vaccination status was associated with age and disease severity. The combination of limited mumps vaccine effectiveness and the specific school setting (dense learning and living conditions) probably contributed to the disease spread.

Uracil DNA glycosylase (UNG) loss enhances DNA double strand break formation in human cancer cells exposed to pemetrexed.

Misincorporation of genomic uracil and formation of DNA double strand breaks (DSBs) are known consequences of exposure to TS inhibitors such as pemetrexed. Uracil DNA glycosylase (UNG) catalyzes the excision of uracil from DNA and initiates DNA base excision repair (BER). To better define the relationship between UNG activity and pemetrexed anticancer activity, we have investigated DNA damage, DSB formation, DSB repair capacity, and replication fork stability in UNG(+/+) and UNG(-/-) cells. We report that despite identical growth rates and DSB repair capacities, UNG(-/-) cells accumulated significantly greater uracil and DSBs compared with UNG(+/+) cells when exposed to pemetrexed. ChIP-seq analysis of γ-H2AX enrichment confirmed fewer DSBs in UNG(+/+) cells. Furthermore, DSBs in UNG(+/+) and UNG(-/-) cells occur at distinct genomic loci, supporting differential mechanisms of DSB formation in UNG-competent and UNG-deficient cells. UNG(-/-) cells also showed increased evidence of replication fork instability (PCNA dispersal) when exposed to pemetrexed. Thymidine co-treatment rescues S-phase arrest in both UNG(+/+) and UNG(-/-) cells treated with IC50-level pemetrexed. However, following pemetrexed exposure, UNG(-/-) but not UNG(+/+) cells are refractory to thymidine rescue, suggesting that deficient uracil excision rather than dTTP depletion is the barrier to cell cycle progression in UNG(-/-) cells. Based on these findings we propose that pemetrexed-induced uracil misincorporation is genotoxic, contributing to replication fork instability, DSB formation and ultimately cell death.

Who are the children at risk? Lessons learned from measles outbreaks.

We investigated a measles outbreak in the Jerusalem district in 2007-2008 (992 cases). Most cases (72·6%) were aged <15 years, 42·9% aged <5 years, and 12·8% were infants aged <1 year. The peak incidence rate was in infants aged 6-12 months (916·2/100 000). This represents a significant shift from former outbreaks in 2003-2004, where the peak incidence was in the 1-4 years age group. Of children aged <5 years the proportion aged 6-12 months tripled (7·7% vs. 25·6%). In a case-control study (74 cases, 148 controls) children who developed measles were less likely to be registered in a well-baby clinic and had lower overall immunization coverage. The differences in proportions for registration, DTaP3 and MMR1 coverage were 35·1%, 48·6% and 80·8%, respectively (all P<0·001). Rising birth order of cases and their siblings was associated with non-registration and non-compliance with MMR immunization. The vulnerability of young infants and the risk markers noted above should be taken into account in planning intervention programmes.

The changing panorama of bacterial enteric infections.

We studied the age-specific population-based incidence of bacterial enteric infections caused by Shigella, Salmonella and Campylobacter, in Jerusalem. During 1990-2008, 32,408 cases were reported (incidence rate 232.1/100,000 per annum). The patterns of Shigella (47.4% of cases), Salmonella (34.4%) and Campylobacter (18.2%) infections evolved noticeably. Campylobacter rates increased from 15.0 to 110.8/100,000 per annum. Salmonella rates increased from 74.2 to 199.6/100,000 in 1995 then decreased to 39.4/100,000. Shigella showed an endemic/epidemic pattern ranging between 19.7 and 252.8/100,000. Most patients (75%) were aged <15 years; children aged <5 years comprised 56.4% of cases, despite accounting for only 12.9% of the population. Campylobacter was the predominant organism in infants aged <1 year and Shigella in the 1-4 years group. The hospitalization rates were: Shigella, 1.8%; Campylobacter, 2.3%; Salmonella, 6.9%. Infants were 2.2 times more likely to be hospitalized than children aged 1-14 years (P=0.001). Household transmission occurred in 21.2% of Shigella cases compared with 5% in the other bacteria.

Mumps outbreak in Jerusalem affecting mainly male adolescents.

From mid-September 2009 to 7 December 2009, 173 cases of mumps have been reported in the Jerusalem District. Most cases (82.1%) were male adolescents (median age 14.5 years) who are students in religious boarding schools. The majority of them (74%) are appropriately vaccinated for their age; 67% had received two doses of mumps-containing vaccine. An epidemiologic connection has been reported with visitors from New York, some of whom had recently had mumps.

An outbreak of measles in an ultra-orthodox Jewish community in Jerusalem, Israel, 2007--an in-depth report.

Measles elimination in Europe is hindered by recurrent outbreaks, typically in non-immunised specific sub-populations. In 2003 and 2004, two measles outbreaks occurred in Jewish ultra-orthodox communities in Jerusalem, Israel. In 2007, another measles outbreak emerged in Jerusalem. Epidemiological investigation and control activities were initiated. Three measles cases (15 years old, 22 years old and an infant; all unvaccinated) were diagnosed in Jerusalem in August 2007. All three belonged to Jewish ultra-orthodox communities in London, United Kingdom, and had had contact with patients in London. The epidemiological investigation did not reveal any connection between these cases other than their place of origin. The disease spread rapidly in extremely ultra-orthodox sub-groups in Jerusalem. Until 8 January 2008, 491 cases were reported. Most patients (70%) were young children (0-14 years old), 96% unimmunized. Frequently, all the children in a large family were infected; two thirds of the cases belonged to family clusters of more than two patients per family (in part due to non-compliance with post-exposure prophylaxis recommendations). The high age-specific incidence among infants 0-1-year- (408.5/100,000) and 1-4-year-olds (264.1/100,000) is a cause for concern. The hospitalisation rate was 15% (71/491), mainly due to fever, patients (26.7%) presented with pneumonitis or pneumonia and two patients presented with encephalitis. There have not been any deaths to date. The outbreak was apparently caused by measles importation into unprotected groups. Despite a high national immunisation coverage (94-95%), programmes to increase and maintain immunisation coverage are essential, with special focus on specific sub-populations.

Measles outbreaks affecting children in Jewish ultra-orthodox communities in Jerusalem.

In 2003 and 2004 two measles outbreaks occurred in Jewish ultra-orthodox communities in Jerusalem. The index case of the first outbreak (March 2003) was a 2-year-old unvaccinated child from Switzerland. Within 5 months, 107 cases (mean age 8.3+/-7.5 years) emerged in three crowded neighbourhoods. The first cases of the second outbreak (June 2004) were in three girls aged 4-5 years in one kindergarten in another community. By November 2004, 117 cases (mean age 7.3+/-6.5 years) occurred. The virus genotypes were D8 and D4 respectively. Altogether, 96 households accounted for the two outbreaks, with two or more patients per family in 79% of cases. Most cases (91.5%) were unvaccinated. Immunization coverage was lower in outbreak than in non-outbreak neighbourhoods (88.3% vs. 90.3%, P=0.001). Controlling the outbreaks necessitated a culture-sensitive approach, and targeted efforts increased MMR vaccine coverage (first dose) to 95.2%. Despite high national immunization coverage (94-95%), special attention to specific sub-populations is essential.

Invasive meningococcal disease in children in Jerusalem.

Neisseria meningitidis is an important cause of childhood meningitis and septicaemia. Between 1999 and 2005, 133 invasive meningococcal disease (IMD) cases occurred in Jerusalem, 112 (84.2%) of them in children aged 0-14 years. The annual incidence rate in Jerusalem was higher than the national average (2.45+/-0.6 vs. 1.13+/-0.16/100 000 population, P=0.002). Most of the children (82.1%) were from low socio-economic Arab and Jewish ultra-orthodox communities; mortality was higher among Arab than Jewish children (1.3 vs. 0.22/100 000 person-years, P=0.004). A cluster of 10 children with severe meningococcal sepsis (three fatalities) emerged in the winter of 2003-2004. Compared to the other 102 cases in 1999-2005 both meningococcaemia (100% vs. 51%, P=0.003) and mortality (30% vs. 6.9%, P=0.014) rates were higher. Serogroup B comprised 77.6% of the bacterial isolates. Pulsed-field gel electrophoresis showed considerable variability among cluster isolates, but significant resemblance in Arab cases throughout 1999-2005. The increased susceptibility of specific sub-populations to IMD necessitates further evaluation.

Biodegradable block copolymers for delivery of proteins and water-insoluble drugs.

Release of several drugs from new ABA-type biodegradable thermal gels, ReGel, including proteins and conventional molecules, are presented. These are biodegradable, biocompatible polymers that demonstrate reverse thermal gelation properties. Organic solvents are not used in the synthesis, purification, or formulation of these polymers. The unique characteristics of ReGel hinge on the following two key properties: (1) ReGel is a water soluble, biodegradable polymer at temperatures below the gel transition temperature; (2) ReGel forms a water-insoluble gel once injected. This is consistent with a hydrophobically bonded gel state where all interactions are physical, with no covalent crosslinking. An increase in viscosity of approximately 4 orders of magnitude accompanies the sol--gel transition. The gel forms a controlled release drug depot with delivery times ranging from 1 to 6 weeks. ReGel's inherent ability to solubilize (400 to >2000-fold) and stabilize poorly soluble and sensitive drugs, including proteins is a substantial benefit. The gel provided excellent control of the release of paclitaxel for approximately 50 days. Direct intratumoral injection of ReGel/paclitaxel (OncoGel) results in a slow clearance of paclitaxel from the injection site with minimal distribution into any organ. Efficacies equivalent to maximum tolerated systemic dosing were observed at OncoGel doses that were 10-fold lower. Data on protein release (pGH, G-CSF, insulin, rHbsAg) and polymer biocompatibility are discussed.

New biodegradable polymers for injectable drug delivery systems.

Many biodegradable polymers were used for drug delivery and some are successful for human application. There remains fabrication problems, such as difficult processability and limited organic solvent and irreproducible drug release kinetics. New star-shaped block copolymers, of which the typical molecular architecture is presented, results from their distinct solution properties, thermal properties and morphology. Their unique physical properties are due to the three-dimensional, hyperbranched molecular architecture and influence microsphere fabrication, drug release and degradation profiles. We recently synthesized thermosensitive biodegradable hydrogel consisting of polyethylene oxide and poly(L-lactic acid). Aqueous solution of these copolymers with proper combination of molecular weights exhibit temperature-dependent reversible sol-gel transition. Desired molecular arrangements provide unique behavior that sol (at low temperature) form gel (at body temperature). The use of these two biodegradable polymers have great advantages for sustained injectable drug delivery systems. The formulation is simple, which is totally free of organic solvent. In sol or aqueous solution state of this polymer solubilized hydrophobic drugs prior to form gel matrix.

Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes.

The feasibility of using modified Eudragit acrylic latexes as microporous coatings for osmotic devices was investigated. Potassium chloride tablets were coated with mixtures of Eudragit RS30D and RL30D acrylic latexes that also contained a plasticizer (triethyl citrate or acetyl tributyl citrate) and a pore-forming agent (urea). A 2(5-1) fractional factorial experimental design was employed to determine the effect of five formulation variables (RS30D:RL30D polymer ratio plasticizer type, plasticizer level, urea level, and cure) on the in vitro release rate of KCl in deionized water (di water), lag time, and coat burst strength. The RS30D:RL30D polymer ratio had the greatest effect on the release rate, and both lag time and burst strength were most affected by the urea level. Statistical optimization was performed, and a coat formulation with predicted desirable in vitro performance was prepared and tested. The in vitro release rate (di water), lag time, and coat burst strength agreed well with the prediction. Dissolutions were also performed in phosphate buffered saline (PBS; pH 7.4); several formulations released markedly slower in PBS than in di water. This discrepancy was dependent on the type of plasticizer and the amount of pore former. Only those coat formulations containing acetyl tributyl citrate as the plasticizer and a 100% urea [(g urea/g polymer solids) x 100] level exhibited similar release rates in di water and PBS. The mechanism of release from these devices was primarily osmotic, whereas the release from devices coated with a formulation containing triethyl citrate and 50% urea was not dependent on the osmotic pressure difference. Devices with an osmotic release mechanism behaved similarly in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of sustained/controlled-release dosage forms of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors in dogs and humans.

Seven sustained/controlled-release dosage forms were designed for gastrointestinal delivery of lovastatin or simvastatin, two potent HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. The in vivo performance of these formulations was evaluated in dogs and healthy volunteers in terms of the cholesterol lowering efficacy and/or systemic concentrations of HMG-CoA reductase inhibitors. Results from the present and previous studies suggest that, through the controlled release of HMG-CoA reductase inhibitors, sustained lower plasma concentrations of HMG-CoA reductase inhibitors may result in an equal or better therapeutic efficacy.

Formulation and optimization of a modified microporous cellulose acetate latex coating for osmotic pumps.

A cellulose acetate (CA) latex was modified for use as a microporous coating for osmotic devices. Potassium chloride core tablets were coated with a CA latex formulation containing a plasticizer (triacetin) and a pore-forming agent (urea). To promote the coalescence of the cellulose acetate latex beads into a film on the surface of the tablet, it was necessary to cure the coated tablets, hereafter referred to as devices, at elevated temperatures. The objectives were to determine the effect of four formulation variables (plasticizer level, pore former level, cure time, and cure temperature) on the in vitro KCl release rate and coat burst strength using a full 2(4) factorial experimental design. Burst strength was measured as the number of grams force a depleted device could support before bursting. The results indicated that urea content was the most important variable, followed by triacetin content and cure time. Cure temperature did not influence the results. Response surfaces generated with the experimental values were used to predict a formulation which would have both a high release rate and a high burst strength. This formulation was prepared and tested both in vitro and in vivo in dogs. The in vitro release rate and burst strength results agreed with those predicted by the model. The in vitro and in vivo release rates were not statistically significantly different as determined by ALQ analysis.

Scrotal carcinoid. Presenting manifestation of multiple lesions in the small intestine.

A middle-aged man presented with a paratesticular carcinoid tumor, his first manifestation of multiple carcinoid tumors of the small bowel. Of the nine carcinoids reported in the English-language literature as metastatic to the scrotum, five simulated a primary lesion. Although the bulk of scrotal carcinoids arise in the testis, the differential diagnosis always should include metastasis from an extrascrotal source.

Enhancement of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor efficacy through administration of a controlled-porosity osmotic pump dosage form.

An extended-release osmotic dosage form was designed for gastrointestinal delivery of the water-soluble tromethamine salt of the beta-hydroxyacid form of simvastatin, a potent HMG-CoA reductase inhibitor and cholesterol lowering agent. The cholesterol lowering efficacy and systemic plasma drug levels resulting from peroral administration of this dosage form, relative to a powder-filled capsule oral bolus, were evaluated in dogs. A twofold improvement in cholesterol lowering efficacy was realized with the controlled-release dosage form that was accompanied by a drug AUC and Cmax that were 67 and 16%, respectively, of those achieved with the bolus dosage form. These results suggest that extended-release dosage forms have the potential for a dose-sparing advantage in the administration of HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia.

Use of modified ethylcellulose lattices for microporous coating of osmotic tablets.

Commercially available lattices are often used to coat nonpareils or beads. Drug release occurs via diffusion through the polymer coating. Adequate release rates may be achieved with small particles because the surface area is large. However, tablets coated with unmodified lattices have exceedingly slow release rates. Therefore, a pore-forming agent, urea, was added to a commercially available ethyl cellulose latex, Aquacoat, to increase the release rate of drugs from coated osmotic tablets. Modified lattices were used to coat KCl and diltiazem.HCl tablets. Release of KCl and diltiazem into water or buffer solutions was determined in a standard U.S.P. dissolution apparatus. Rates varying from 1 to 100% release in 12 hr were obtained by varying the coating thickness, pore-former level, and plasticizer type and concentration. Scanning electron microscopy (SEM) showed that the urea was eluted from the coat in aqueous solution leaving a porous coating. Coat burst strengths were dependent on the coat thickness and the concentrations of pore former and plasticizer. Hence, modified lattices hold potential for use as coatings for controlled release osmotic formulations.

The solubility-modulated osmotic pump: in vitro/in vivo release of diltiazem hydrochloride.

A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem.HCl as a model drug. Diltiazem.HCl has an aqueous solubility greater than 590 mg/ml (37 degrees C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ml; 37 degrees C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of greater than 80% of an initial diltiazem.HCl load. Devices were prepared with cores that contained diltiazem.HCl and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of approximately 75% of the initial diltiazem.HCl load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.

Ultrasonically mediated solute permeation through polymer barriers.

The effects of ultrasound on the permeation of benzoic acid through polydimethylsiloxane, and hydrocortisone through cellulose was investigated. Ultrasonic irradiation resulted in a 23% increase in the permeability coefficient of hydrocortisone in a cellulose film. A 14% increase in permeability coefficient was observed for benzoic acid in a polydimethylsiloxane film. The effects of ultrasound on stagnant aqueous diffusion layers, membrane-solution interfacial temperature, membrane integrity, and diffusant stability were investigated. These factors were not responsible for the observed increases in permeability.

Free fatty acid-induced platelet aggregation: studies with solubilized and nonsolubilized fatty acids.

The aggregation response of washed porcine platelets to the sodium salts of stearic, oleic, palmitic, and myristic acids was analyzed turbidometrically. The fatty acids were prepared as aqueous suspensions and as taurocholate- or albumin-solubilized systems. The final concentration of fatty acid in the platelet preparation varied between 70 and 600 microM. This range was within or below the normal physiological limits of 300-1200 microM. Platelet aggregation was observed with both the suspended and taurocholate-solubilized fatty acids. The extent of platelet aggregate formation increased with the fatty acid concentration and chain length. With the exception of stearate, the taurocholate-solubilized fatty acids were more active than the suspensions. Albumin-solubilized fatty acids were devoid of platelet aggregating activity. Particle-size analysis of the solubilized fatty acids indicated that fatty acid precipitation had occurred subsequent to the addition of taurocholate-solubilized fatty acids to the platelets. This precipitation did not occur with the albumin-solubilized systems, suggesting that the fatty acids must assume a particulate physical state to induce aggregation. Platelet aggregation induced by fatty acids was not inhibited by 80 nM epoprostenol, 75 microM alprostadil, or 150 microM indomethacin. This finding indicated that the fatty acid-induced platelet aggregation was independent of cyclic AMP-related calcium shift, cyclooxygenase-arachidonate, or granular nucleotide release mechanisms.

Progestin permeation through polymer membranes IV: Mechanism of steroid permeation and functional group contributions to diffusion through hydrogel films.

Hydrogel films were prepared from hydroxyethyl methacrylate, both with (Film II) and withouth (Film I) 5.25 mole% of ethylene glycol dimethacrylate. Permeation, diffusion, and partition coefficients for progesterone, testosterone, nandrolone, norethindrone, 17 alpha-hydroxyprogesterone, estradiol, and hydrocortisone were determined. A solute permeation model was proposed based on the separation of a domain (B) composed of "bulk-like" water and a doman (A) composed of polymer, interfacial water, and bound water present in the films. The separate contributions from the "pore" and "solution-diffusion" mechanisms to the total permeability were calculated from the model. Steroid permeabilities through Films I and II were analyzed in accordance with this model. Permeation of Film II occurred via the solution-diffusion mechanism. Permeation of Film I occurred predominately by the pore mechanism with a small contribution (approximate 20%) from the solution-diffusion mechanism. The latter contribution was dependent on the solubility of the solute within the A domains of the hydrogel film. Functional group contributions to permeation of Film II were ascribed to either steric or hydrogen bonding effects.