Antibody mimics based on human fibronectin type three domain engineered for thermostability and high-affinity binding to vascular endothelial growth factor receptor two.

The tenth human fibronectin type three domain ((10)Fn3) is a small (10 kDa), extremely stable and soluble protein with an immunoglobulin-like fold, but without cysteine residues. Selections from (10)Fn3-based libraries of proteins with randomized loops have yielded high-affinity, target-specific antibody mimics. However, little is known about the biophysical properties of such antibody mimics, which will determine their suitability for in vitro and medical applications. We characterized target binding and biophysical properties of two related (10)Fn3-based antibody mimics that bind vascular endothelial growth factor receptor two (VEGF-R2). The first antibody mimic, which has a dissociation constant (K(d)) of 13 nM, is highly stable [melting temperature (T(m))=62 degrees C] and soluble, whereas the second, which binds VEGF-R2 with 40 x higher affinity, is less stable (T(m) < 40 degrees C) and relatively insoluble. We used our understanding of these two (10)Fn3 derivatives and of wild-type (10)Fn3 structure to engineer the next generation of antibody mimics, which have an improved combination of high affinity (K(d)=0.59 nM), stability (T(m)=53 degrees C) and solubility. Our findings illustrate that (10)Fn3-based antibody mimics can be engineered for favorable biophysical properties even when 20% of the wild-type (10)Fn3 sequence is mutated in order to satisfy target-binding requirements.

[Deep venous thrombosis as a complication of congenital absence of vena cava inferior]. / Diepe veneuze trombose als complicatie van congenitale afwezigheid van de V. cava inferior.

A 19-year-old man was admitted with fever, haematuria, general malaise, pain on the left side of the pelvis and a full feeling in the left lower abdominal quadrant of the abdomen. His history mentioned a varices operation. During admission he developed an acute abdomen and deep vein thrombosis in both legs. CT of the abdomen showed a pathologic mass and absence of the vena cava inferior. Laparotomy revealed extensive thrombosis in widened veins. Clinical improvement occurred following adequate thrombolysis. Congenital absence of the vena cava inferior results from aberrant development during organogenesis. Patients are typically asymptomatic, but may present with venous insufficiency at a young age and deep vein thrombosis. Absence of the vena cava inferior can be accompanied by other congenital abnormalities such as dextrocardia and congenital heart diseases. Diagnosis is made using CT or MRI. Treatment consists of lifelong anticoagulant therapy and, if necessary, surgery.

[Benign symmetrical lipomatosis]. / Benigne symmetrische lipomatose.

A man aged 51 for the last 3 months had displayed general malaise, epigastric pain, nausea, vomiting and constipation. Also, he had a pseudo-athletic appearance with symmetrical large accumulations of fat on the front of the trunk, the lower back, the shoulders and the proximal extremities, characteristic of 'benign symmetrical lipomatosis'. He died of embolism of the aortic bifurcation and autopsy revealed an extensive adenocarcinoma in the upper abdomen, probably originating from the pancreas or the stomach. Benign symmetrical lipomatosis mostly occurs in middle-aged men. The pathogenesis is unknown. Association with alcohol abuse, metabolic abnormalities, polyneuropathy and certain malignancies has been described. Treatment is symptomatic by surgery or liposuction.

[Blue toes and kidney insufficiency]. / Blauwe tenen en nierinsufficiëntie.

Three patients, two women aged 73 and 70 and one man aged 58 years, were known with hypertension and (or) coronary disease. They developed renal insufficiency and purple toes due to cholesterol crystal embolisation. In two of the three patients invasive procedures (femoropopliteal bypass surgery and replacement of the aortic valve, respectively) had provoked the embolisation process. Growing awareness of symptoms such as purple toes is important as the increasing use of intravascular procedures will lead to higher incidence of this syndrome with renal insufficiency as the most severe clinical complication.

Cystitis and interstitial nephritis related to the use of tiaprofenic acid (Surgam).

We describe a case of concurrent presentation of severe haemorrhagic cystitis and acute interstitial nephritis with eventually lethal outcome, associated with the use of tiaprofenic acid (Surgam), a propionic acid-derived non-steroidal anti-inflammatory drug (NSAID). Although interstitial nephritis and haemorrhagic cystitis are caused by all types of NSAIDs, a higher incidence of interstitial nephritis and especially haemorrhagic cystitis has been described related to propionic acid derivatives. Awareness of this serious adverse effect is important.

Clinical usefulness of abdominal CT-scanning in Henoch-Schönlein vasculitis.

The abdominal CT appearance is reported in a patient with Henoch-Schönlein vasculitis having symptoms of acute abdomen. Initial CT-scan showed segmented mural thickening of the small bowel loops, strongly suggesting the diagnosis of gastrointestinal involvement of vasculitis. Adequate treatment was started without the need for laparotomy. The CT appearance completely resolved after steroid therapy. Abdominal CT-scanning seems useful in the differential diagnosis of acute abdomen in patients with vasculitis.

Intramural diverticulosis of the esophagus.

A description is given of the etiology and pathology of intramural esophageal diverticulosis as so far discussed in the literature. In view of the course and the clinical findings in two young patients in whom this diagnosis was established, it is suggested that intramural diverticulosis develops as a result of a devolopmental disorder in the autonomic nervous system.