Position of ST-deviation measurements relative to the J-point: Impact for ischemia detection

Background

There is no consensus about the time instant relative to the J point where ST deviation has to be measured for detection of acute ischemia in the ECG.

Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target

Monoclonal antibodies have therapeutic potential for treating diseases of the central nervous system, but their accumulation in the brain is limited by the blood-brain barrier (BBB). Here, we show that reducing the affinity of an antibody for the transferrin receptor (TfR) enhances receptor-mediated transcytosis of the anti-TfR antibody across the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Anti-TfR antibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower-affinity anti-TfR antibody variants are released from the BBB into the brain and show a broad distribution 24 hours after dosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to the enzyme β-secretase (BACE1), which processes amyloid precursor protein into amyloid-β (Aβ) peptides including those associated with Alzheimer's disease. Compared to monospecific anti-BACE1 antibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brain Aβ after a single systemic dose. TfR-facilitated transcytosis of this bispecific antibody across the BBB may enhance its potency as an anti-BACE1 therapy for treating Alzheimer's disease.     

The effect of three hemostatic agents on early bone healing in an animal model

Background  

Resorbable bone hemostasis materials, oxidized regenerated cellulose (ORC) and microfibrillar collagen (MFC), remain at the site of application for up to 8 weeks and may impair osteogenesis. Our experimental study compared the effect of a water-soluble alkylene oxide copolymer (AOC) to ORC and MFC versus no hemostatic material on early bone healing.     

Bacteriology of human gingivitis

The subgingival bacterial floras of naturally occurring gingivitis in adults and children were characterized and compared with the floras of other periodontal conditions previously studied. The composition of the gingivitis floras was found to be distinct from that of floras associated with health or with moderate, severe, or juvenile periodontitis. There were no major differences between the floras of naturally-occurring gingivitis and the floras of the human experimental gingivitis model. Data indicated that the flora of healthy sites within a mouth is influenced by the number of inflamed sites, which argues against independence of sites bacteriologically. Proportions of ten bacterial species increased in both gingivitis and periodontitis, as compared with health, in both adults and children. These species were found in both affected and unaffected sites of people with gingivitis. The numbers of five other cultivable species and the "large treponeme", which was not cultivated, increased in gingivitis and periodontitis of adults only. Significant differences in non-spirochetal floras between children and adults were not found, although they were in the experimental gingivitis model studied previously. Cultivable spirochetes did differ between children and adults. Children had fewer samples positive for spirochetes, and children's positive samples contained greater proportions of T. socranskii subsp. paredis. Some species that predominate in periodontitis, but which are absent from healthy gingivae, were found as a small percentage of the flora in gingivitis. This suggests that increased serum and blood in the gingival crevice encourage species that relate to periodontitis.     

Reduced skin capillary density during attacks of erythromelalgia implies arteriovenous shunting as pathogenetic mechanism

Erythromelalgia is characterized by burning pain, erythema, and increased temperature in acral skin. The pain is aggravated by warming and relieved by cooling. Increased microvascular arteriovenous shunting in deep dermal plexa has been hypothesized as the pathogenetic mechanism of pain in affected skin, inducing hypoxia during pain attacks. The aim of this study was to quantify skin capillary density in erythromelalgic patients before and after heat provocation, as increased skin temperature should increase the need for nutritive blood supply by the capillaries. Fourteen patients and 10 healthy control subjects were studied using an enhanced technique of computer-assisted analysis of capillary bed morphology and temperature measurements before and after central body heating. The increase in acral skin temperature was significantly higher (p < 0.05) in the eight patients where symptoms were induced after heat provocation, compared to asymptomatic patients and healthy control subjects. The number of visible capillaries in a field of view (1.7 mm2) decreased significantly (p = 0.01) in erythromelalgia patients from 105 (62-137) (median with total range) to 89 (49-118) after warming in areas with numerous arteriovenous anastomoses (nail bed region). In symptomatic patients an even more significant reduction was observed (p = 0.01). The capillary size was also significantly reduced (p < 0.05) from 41.0 (31.5-50.5) (arbitrary units) to 37.3 (33.0-46.0) in symptomatic patients. The change in capillary density in the nail bed area was significantly larger in erythromelalgia patients -17 (-49 to 39) compared to controls 0 (-47 to 13) (p < 0.05), and in symptomatic patients -19 (-49 to -12) compared to asymptomatic patients -8 (-48 to 39) (p < 0.05) and controls (p < 0.01). The reduced skin capillary density after heating is compatible with increased microvascular arteriovenous shunting of blood and a corresponding relative deficit in nutritive perfusion (steal phenomenon) with skin hypoxia, causing the symptoms in erythromelalgia.     

Symmetrical drug-related intertriginous and flexural exanthema secondary to topical 5-fluorouracil

We report the case of a 56-year-old man who developed a distinctive skin eruption after treating actinic keratoses on the dorsal aspects of his right and left hands with topical 5-fluorouracil (5-FU). The distribution of his rash was characteristic of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), also known as baboon syndrome.     

Novel Assay of Metformin Levels in Patients With Type 2 Diabetes and Varying Levels of Renal Function: Clinical recommendations

OBJECTIVE

To study trough levels of metformin in serum and its intra-individual variation in patients using a newly developed assay.

RESEARCH DESIGN AND METHODS

Trough serum levels of metformin were measured once using liquid chromatography–tandem mass spectrometry (LCMSMS) in 137 type 2 diabetic patients with varying renal function (99 men) and followed repeatedly during 2 months in 20 patients (16 men) with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² body surface.

RESULTS

Patients with eGFR >60, 30–60, and <30 ml/min/1.73 m² had median trough metformin concentrations of 4.5 μmol/l (range 0.1–20.7, n = 107), 7.71 μmol/l (0.12–15.15, n = 21), and 8.88 μmol/l (5.99–18.60, n = 9), respectively. The median intra-individual overall coefficient of variation was 29.4% (range 9.8–74.2).

CONCLUSIONS

Determination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values >20 μmol/l. Metformin measurement is less suitable for dose titration.Metformin is an insulin sensitizer used for treating type 2 diabetes, and the treatment is only rarely complicated by lactic acidosis. The substance is cleared from the blood through the kidneys (1), and impaired renal function may lead to accumulation.We have combined new technologies: liquid chromatography–tandem mass spectrometry (LCMSMS) and hydrophilic interaction liquid chromatography (2) in the development of a novel method for determination of metformin in serum. The aim was to study trough levels of metformin in type 2 diabetic patients and to assess intra-individual variations in patients with renal impairment.     

Microstructure Induced Rigidity of Polysiloxane Yielding Hierarchical Self‐Assembly of Alkyl Side Chains

The influence of a backbone microstructure on the side chain crystallization of a comb‐like polymer is analyzed systematically using a tailor‐made random versus block siloxane copolymer system. While the side alkyl chains of the random siloxane undergo a stepwise order–disorder (OD) transition to form well‐ordered orthorhombic structure at low temperature, the packing structure of the alkyl chains pertaining to the block siloxane maintains their original hexagonal lattice up to a temperature of as low as 173 K. The unit lattice ordering of side alkyl chains in the random siloxane polymer is also accompanied by a major restructuring of the backbone conformation ultimately losing out long range ordered structure in the solid state. The OD transitions of side alkyl chains and their dynamic relationship with the backbone conformation are established unambiguously by a combination of temperature dependent small‐angle X‐ray and wide‐angle X‐ray scattering techniques. The observed conformational variations in random versus block polymers are explicitly discussed in terms of molecular chain mobility and theory of macromolecular chain conformation.