A Pfs48/45-based vaccine to block Plasmodium falciparum transmission: phase 1, open-label, clinical trial.

BACKGROUND: The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibodies that block parasite development in the mosquito and mosquitoes becoming infectious. The Pfs48/45 protein is a leading Plasmodium falciparum transmission-blocking vaccine candidate. The R0.6C fusion protein, consisting of Pfs48/45 domain 3 (6C) and the N-terminal region of P. falciparum glutamate-rich protein (R0), has previously been produced in Lactococcus lactis and elicited functional antibodies in rodents. Here, we assess the safety and transmission-reducing efficacy of R0.6C adsorbed to aluminium hydroxide with and without Matrix-M™ adjuvant in humans. METHODS: In this first-in-human, open-label clinical trial, malaria-naïve adults, aged 18-55 years, were recruited at the Radboudumc in Nijmegen, the Netherlands. Participants received four intramuscular vaccinations on days 0, 28, 56 and 168 with either 30 µg or 100 µg of R0.6C and were randomised for the allocation of one of the two different adjuvant combinations: aluminium hydroxide alone, or aluminium hydroxide combined with Matrix-M1™ adjuvant. Adverse events were recorded from inclusion until 84 days after the fourth vaccination. Anti-R0.6C and anti-6C IgG titres were measured by enzyme-linked immunosorbent assay. Transmission-reducing activity of participants' serum and purified vaccine-specific immunoglobulin G was assessed by standard membrane feeding assays using laboratory-reared Anopheles stephensi mosquitoes and cultured P. falciparum gametocytes. RESULTS: Thirty-one participants completed four vaccinations and were included in the analysis. Administration of all doses was safe and well-tolerated, with one related grade 3 adverse event (transient fever) and no serious adverse events occurring. Anti-R0.6C and anti-6C IgG titres were similar between the 30 and 100 µg R0.6C arms, but higher in Matrix-M1™ arms. Neat participant sera did not induce significant transmission-reducing activity in mosquito feeding experiments, but concentrated vaccine-specific IgGs purified from sera collected two weeks after the fourth vaccination achieved up to 99% transmission-reducing activity. CONCLUSIONS: R0.6C/aluminium hydroxide with or without Matrix-M1™ is safe, immunogenic and induces functional Pfs48/45-specific transmission-blocking antibodies, albeit at insufficient serum concentrations to result in transmission reduction by neat serum. Future work should focus on identifying alternative vaccine formulations or regimens that enhance functional antibody responses. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov under identifier NCT04862416.

[Cerebral amyloid angiopathy: an easily missed diagnosis in patients with transient neurological deficits]. / Cerebrale amyloïdangiopathie.

Cerebral amyloid angiopathy (CAA) is a degenerative neurovascular disease in which the protein amyloid-beta accumulates in the vessel wall of cortical and leptomeningeal arteries. This may lead to acute lobar cerebral haemorrhage, which in case of CAA is fatal in 10-30% of cases. CAA may also present with transient focal neurological episodes (TFNE), the symptoms of which may mimic a transient ischaemic attack (TIA). Distinction between the two has important implications for therapy, as antithrombotics are relatively contra-indicated in CAA, but indicated after a TIA. We describe a patient with transient focal neurological deficits who was initially treated with antithrombotic therapy for a suspected TIA. Eventually, the diagnosis CAA was made and antithrombotic treatment was ceased. This case stresses the importance of considering the diagnosis CAA with TFNE in patients presenting with transient neurological deficits, in order to avoid an unnecessarily increased risk of symptomatic and possibly fatal cerebral haemorrhage.

Isolation of transcriptionally active umbilical cord blood-derived basophils expressing Fc epsilon RI, HLA-DR and CD203c.

BACKGROUND: Basophils are inflammatory cells associated with allergy and parasite infections. Investigation of their true biological function has long been hampered by the difficulty in obtaining sufficient amounts of pure basophils and by the lack of phenotypic markers. Moreover, it has been very difficult to clone and identify basophil-specific granule proteins, partially because of an almost complete lack of mRNA in mature circulating basophils. METHODS: To obtain transcriptionally active immature basophils, umbilical cord blood cells were cultured in the presence of interleukin (IL)-3. The cells were analysed by flow cytometry and by histological staining. RESULTS: The continuous presence of IL-3 in cord blood cultures resulted in the expansion of basophil precursors co-expressing FcepsilonRI and the recently described mast cell/basophil marker, 97A6 (CD203c). Several nonbasophil markers (i.e. CD3, CD14, CD15, CD16, CD19 and CD21) were absent on the cultured basophils. However, we show that in early cultures, almost 60% of the CD203c+ cells co-express human leukocyte antigen (HLA)-DR, a marker that is absent on mature circulating basophils. The presence of HLA-DR on basophil precursors may explain the low recovery (24+/-5.2%) obtained after isolation of cultured basophils, when using a conventional basophil isolation kit that removes HLA-DR+ cells. A novel purification method was developed, including a two-step cocktail of antibodies against selected markers, which resulted in both high purity (95+/-0.5%) and recovery (59+/-1.5%) of cultured basophils. CONCLUSIONS: We here establish cord blood cultures as a source from which transcriptionally active basophil precursors can be isolated in reasonable quantities for thorough biochemical characterization.

Uroperitoneum in the hospitalised equine neonate: retrospective study of 31 cases, 1988-1997.

Historical, physical and diagnostic data were reviewed retrospectively in 31 equine neonates with uroperitoneum. Gender predilection was not observed, and classic electrolyte abnormalities were seen in less than 50% of the cases. Aetiologies for uroperitoneum have been well described, but this review found that septicaemia/severe illness played a crucial role the outcome of uroperitoneum. Approximately half the individuals with uroperitoneum had positive sepsis scores. Foals receiving fluid therapy were more likely to be septic and to have normal electrolyte concentrations. Ultrasonographic findings, serum creatinine and serum:peritoneal creatinine ratios were not affected by previous fluid therapy and were invaluable aids in the diagnosis of uroperitoneum, even with multisystemic disease such as sepsis.

Twin reduction in the mare: current options.

Twin pregnancy in the mare causes economic loss. Early transrectal ultrasonographic detection of twins and manual crush of one embryonic vesicle is the method of choice for managing equine twins (90% success rate). Transcutaneous and transvaginal ultrasound-guided twin reduction techniques are described for twin pregnancies that advance beyond 25 days of gestation. Reported success rates for the ultrasound-guided procedures are 50% and 20%, respectively.

Aorto-cardiac fistulas in seven horses.

This report describes the history, clinical, electrocardiographic and echocardiographic findings, treatment, outcome and post-mortem findings in seven horses with aorto-cardiac fistula. Affected horses included 5 stallions, one gelding and one mare; 2 each of the Thoroughbred, Arabian and Standardbred breeds and one Thoroughbred-cross with a mean +/- s.d. age of 12 +/- 4 years, range 6-18 years. The presenting signs were acute distress (four horses), exercise intolerance (two horses) and the lesion was detected during a routine examination in one horse. Five horses had monomorphic ventricular tachycardia on admission and one other had a history of this arrhythmia. Five horses had a characteristic continuous murmur loudest in the right fourth intercostal space. Echocardiography (six horses) and/or post-mortem examination (four horses) revealed the horses had aorto-cardiac fistulas arising from the right aortic sinus in all five horses in which the site was recorded. Two horses had ruptured aneurysmal dilatations of the aortic wall at this site. Fistulas extended into the right ventricle in four horses; the right atrium in two horses, the left ventricle in one horse, and five horses had dissecting tracts in the septal myocardium. Horses survived for periods ranging from 24 h to 4 years. Aorto-cardiac fistula should be considered in the differential diagnosis for horses presenting with acute distress, bounding arterial pulse, a right-sided continuous murmur and/or monomorphic ventricular tachycardia, particularly in middle-aged or older stallions. Echocardiography is the technique of choice for confirming the diagnosis and demonstrating accompanying cardiac changes.

Idiopathic hypocalcemia in foals.

Five thoroughbred foals (4 fillies and 1 colt), all in good to excellent body condition, ranging in age from 4 days to 5 weeks at the time of onset of signs, were presented to 2 Kentucky equine hospitals from 1992 through 1996. All 5 foals presented with tachycardia, hyperhidrosis, diarrhea or a recent history of diarrhea, and muscle rigidity or stiff gait. Four of the 5 foals presented for recumbency, seizure-like activity with opisthotonos, or pronounced extensor muscle rigidity. All 5 foals were hypocalcemic. All foals either died or had euthanasia performed. None responded to oral calcium supplementation. The cause of the hypocalcemia was unknown. Different idiopathic hypocalcemia syndromes may exist in foals.

An echocardiographic study of atrial fibrillation in horses: before and after conversion to sinus rhythm.

Two-dimensional and M-mode echocardiograms were recorded from 41 horses before they were successfully treated for atrial fibrillation. In addition, these examinations were performed in a subgroup of 20 horses after treatment, and the results were compared with pretreatment values. Atrial fibrillation in this group of horses was associated with a reduction of mean left ventricular fractional shortening (mean 31% +/- 5.24%), and 22 of the 41 horses were below the reference range. The remaining mean M-mode variables were within the normal reference range, although 12 horses had increased left ventricular lumen dimensions in systole, and 8 horses had decreased left ventricular ejection times. Abnormal motion of the mitral valve was present in all horses and was characterized by the absence of A peaks, which were replaced by small diastolic undulations in 55% of the horses. In horses 1 to 20, after conversion to sinus rhythm, the mean fractional shortening increased (35.34% +/- 5.4%, P = .004), but there were no significant differences in heart rate or left ventricular lumen diameters in systole or diastole. These results suggest that ventricular function may be compromised by the presence of atrial fibrillation. However, this improved after correction of the arrhythmia.

Treatment of atrial fibrillation in horses: new perspectives.

Forty-one horses were treated for atrial fibrillation (AF) with 22 mg/kg quinidine sulfate via nasogastric tube every 2 hours until conversion to sinus rhythm, a cumulative dose of 88 to 132 mg/kg had been administered in 2-hour increments, or the horse had adverse or toxic effects from the drug. Treatment intervals were prolonged to every 6 hours if conversion had not occurred. Digoxin was administered before treatment if the horse had a fractional shortening < or = 27% (3 horses), was prone to tachycardia (resting heart rate > or = 60 beats/min) (1 horse), or had a previous history of sustained tachycardia of over 100 beats/min during prior conversion (3 horses). Digoxin was administered during day 1 of quinidine sulfate treatment if the horse developed a sustained tachycardia of over 100 beats/min during treatment (11 horses) or on day 2 if conversion had not occurred (7 horses). Plasma quinidine concentrations within 1 hour of conversion of AF to sinus rhythm ranged from 1.7 to 7.5 micrograms/mL (mean, 4.05 +/- 1.6) and ranged from 1.7 to 4.7 micrograms/mL in 97% of horses. Most horses (92%) with plasma quinidine concentrations > 5 micrograms/mL exhibited an adverse or toxic effect of quinidine sulfate (clinical or electrocardiographic). There was no statistical association between plasma quinidine concentrations and sustained tachycardia (> 100 beats/min), diarrhea, or colic. Ataxia and upper respiratory tract stridor were significantly associated with plasma quinidine concentrations. In most instances (98%) conversion did not occur while toxic or adverse effects of quinidine sulfate were present or when plasma quinidine concentrations were > 5 micrograms/mL.

Sonographic findings in horses with mediastinal lymphosarcoma: 13 cases (1985-1992).

Sonographic findings correlated with necropsy findings in 8 of 9 horses in which the cranial portion of the mediastinum was evaluated by use of both methods. Cranial mediastinal masses were imaged as multilobular and homogeneously hypoechoic; a complex echogenic pattern was observed with necrosis within the mass. Pleural effusion was a common finding in horses with mediastinal lymphosarcoma. Cytologic evaluation of pleural fluid samples was useful in diagnosis of lymphosarcoma in 10 of 12 horses that had thoracentesis. Sonographic examination of the thorax and cranial portion of the mediastinum can aid in the diagnosis of mediastinal lymphosarcoma in horses. Such examination should be performed in horses with clinical signs of cranial vena cava obstruction in which pleural effusion is detected, or when thoracic lymphosarcoma is suspected.

Power orientation: a study of female nurse and non-nurse managers.

Researchers studied the power orientations of female managers as related to career choice, education level, age, and years as a manager. The questionnaire includes six orientations to power: 1) power as good; 2) power as resource dependency; 3) power as instinctive drive; 4) power as political; 5) power as charisma; and 6) power as control and autonomy. Discerning power may explain how one perceives the managerial position.

Examination of the foal.

Recent advances in veterinary diagnostics have improved our ability to diagnose and treat foal diseases. However, these advances do not replace the physical examination as the most valuable diagnostic aid available to the equine practitioner. The basic physical examination provides the majority of information needed to make a presumptive diagnosis, provide a direction for ancillary tests, and formulate a plan for emergency therapy if needed.

Pharmacokinetics of digoxin administered to horses with congestive heart failure.

Nine horses with (naturally acquired) congestive heart failure were treated with 2.2 micrograms of digoxin/kg of body weight by the IV route, followed by 11 micrograms/kg administered orally every 12 hours thereafter. Furosemide was administered IV concurrently with IV administered digoxin every 12 hours. Serum concentration of digoxin was measured after the first (IV) and seventh (orally administered) dose. After IV administration, digoxin disposition was described by a 2-compartment model, with a rapid distribution phase (t1/2 alpha = 0.17 hour), followed by a slower elimination phase (beta = 0.096 +/- 0.055 h-1, t1/2 beta = 7.2 hours, where beta is the exponential term from the elimination phase of the concentration vs time curve). Bioavailability after oral administration was 21.2 +/- 10.8%. After the seventh orally administered dose, serum concentration of digoxin peaked 1 to 2 hours later, and was 1.9 +/- 0.7 ng/ml (mean +/- SD). In 4 horses, a second increase in serum digoxin concentration was observed 4 to 8 hours after the initial peak, which possibly was evidence of enterohepatic recycling of the drug. Response to treatment included reduction in heart rate, peripheral edema, and pulmonary edema, but these could not be attributed to the digoxin alone because the horses were treated concurrently with furosemide.

Postsurgical ventricular tachycardia in a horse.

A 2-year-old Thoroughbred racehorse developed ventricular tachycardia after elective laryngoplasty and ventriculectomy were performed while anesthesia was maintained with halothane. During surgery, the horse became febrile and developed transient mild hypercarbia. The horse was treated with an IV infusion of quinidine gluconate. Continuous electrocardiographic monitoring was used to evaluate cardiac rhythm during treatment, and conversion was achieved after 12 hours of IV infusion. The inciting cause for the arrhythmia was not determined.

Ventricular arrhythmias in horses: 21 cases (1984-1989).

Ventricular premature depolarizations (VPD) were identified in 21 horses in which unexplained tachycardia or an arrhythmia was detected on auscultation. Horses were categorized into 3 groups on the basis of ECG findings. Seven horses had uniform isolated VPD (group 1); 7 horses had repetitive uniform VPD at a rate < 100 VPD/min (group 2); and 7 horses had either multiform VPD, R-on-T, or > or = 100 VPD/min (group 3). Concurrent systemic disease was identified in 12 horses, 7 of which had gastrointestinal tract disorders. Serum cardiac isoenzyme activities were high in 6 (2 from each group) of 13 horses in which they were measured. Serum electrolyte concentrations were normal in all but 1 of 11 horses in which they were measured. Antiarrhythmic drugs were given to 9 horses (all of which were in group 2 or group 3), 6 of which converted to sinus rhythm. Two horses that had R-on-T in the ECG died shortly after initiation of antiarrhythmic treatment. An accelerated idioventricular rhythm persisted in 1 horse for at least 8 months and failed to respond to antiarrhythmic drugs. Ventricular premature depolarizations resolved or decreased considerably in frequency in 11 horses without the administration of antiarrhythmic agents. Treatment in these horses included therapy for any underlying systemic disease, corticosteroids, nonsteroidal antiinflammatory drugs, or stall rest. The remaining horse was euthanatized several hours after hospitalization. Five horses died or were euthanatized either during hospitalization or several months after being discharged. Myocardial lesions were identified at necropsy in 2 horses.

Echocardiographic diagnosis of an anomaly of the tricuspid valve in a male pygmy goat.

A 3-year-old male pygmy goat was evaluated because of a grade III/V plateau pansystolic murmur that was auscultated over the tricuspid valve area and a grade II/V plateau pansystolic murmur that was auscultated over the left heart base. Echocardiography revealed a large right atrium and ventricle, an atrial septal defect, and a dysplastic tricuspid valve displaced apically into the right ventricle. Contrast echocardiography and color-flow Doppler echocardiography revealed flow from right to left through the atrial septal defect and severe tricuspid regurgitation. A diagnosis of tricuspid valve dysplasia and severe tricuspid regurgitation was made. This anomaly (Ebstein's anomaly) of the tricuspid valve should be considered in goats that have systolic, with or without diastolic, murmurs over the tricuspic valve. Two-dimensional echocardiography can confirm the diagnosis of the anomaly. The associated tricuspid regurgitation and interatrial right-to-left shunt flow can be detected and semiquantitated by use of contrast, continuous wave, and color-flow Doppler echocardiography.

Echocardiographic detection of pulmonic valve rupture in a horse with right-sided heart failure.

Pulmonic valve rupture was determined to be the cause of severe right-sided heart failure in a 20-year-old Thoroughbred gelding. A flail in the intermediate pulmonic valve cusp was detected by 2-dimensional echocardiography. Significant pulmonic and tricuspid valvular regurgitation were confirmed by Doppler echocardiography. Despite treatment, the horse's condition deteriorated, and euthanasia was performed. At necropsy, a tear in the pulmonary artery extending into the right valve cusp and a tear at the base of the intermediate valve cusp were identified at the junction of the right and intermediate pulmonic valve cusps. Careful echocardiographic evaluation of the pulmonic valve is warranted for horses with right-sided heart failure, for which more common causes cannot be found.

Ultrasonographic diagnosis of small-intestinal intussusception in three foals.

Small-intestinal intussusceptions were diagnosed in 3 foals. Cross-sectional ultrasonography through the apex of the intussusceptum revealed a target-like pattern with a thick hypoechoic rim. The thick hypoechoic rim was caused by severe edema of the entering and returning walls of the intussusceptum. At the more proximal portion of the intestines, where parietal edema was less severe, the image appeared as 2 concentric rings and an inner circular area. The outer ring and inner circular area were hypoechoic and represented the returning and the entering wall of the intussusceptum. An additional cross-sectional pattern can be described as double concentric rings, with the inner lumen represented by a central echogenic core. Longitudinal scannings of the involved intestinal section revealed a different view of the same anatomic situation, with 2 hyperechoic areas delineated by 3 stripes of hypoechoic intestine. Ultrasonography of a foal's abdomen provides a clinician with a rapid noninvasive technique that may aid in the differential that may aid in the differential diagnosis of colic. The ultrasonographic diagnosis of intussusception may improve the recognition of a surgical lesion and improve the potential for successful treatment.