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Halogenation can be utilized for the purposes of labeling and molecular imaging, providing a means to, e.g., follow drug distribution in an organism through positron emission tomography (PET) or study the molecular recognition events unfolding by nuclear magnetic resonance (NMR) spectroscopy. For cancer therapeutics, where often highly toxic substances are employed, it is of importance to be able to track the distribution of the drugs and their metabolites in order to ensure minimal side effects. Labeling should ideally have a negligible disruptive effect on the efficacy of a given drug. Using a combination of NMR spectroscopy and cytotoxicity assays, we identify a site susceptible to halogenation in monomethyl auristatin F (MMAF), a widely used cytotoxic agent in the antibody-drug conjugate (ADC) family of cancer drugs, and study the effects of fluorination and chlorination on the physiological solution structure of the auristatins and their cytotoxicity. We find that the cytotoxicity of the parent drug is retained, while the conformational equilibrium is shifted significantly toward the biologically active trans isomer, simultaneously decreasing the concentration of the inactive and potentially disruptive cis isomer by up to 50%. Our results may serve as a base for the future assembly of a multifunctional toolkit for the assessment of linker technologies and exploring bystander effects from the warhead perspective in auristatin-derived ADCs.

Purpose of the study: Explore perceptions, expectations and challenges following a telerehabilitation programme using augmented reality glasses (ARG) in patients with idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or recently diagnosed myocardial infarction (MI). Materials and Methods: A qualitative approach was employed to track perspectives from a range of patients with chronic lung and/or heart diseases. COPD, IPF and MI outpatients from Denmark and Finland were invited to participate. Data were collected through focus group and semi-structured in-depth interviews. Qualitative analysis was performed using standard thematic analytical approaches. A topic guide was used to explore experiences and perceptions of the ARG telerehabilitation device among participants. Results: Thirteen patients (4 MI, 2 IPF and 7 COPD), 3 women and 10 men aged 56 to 75 years (mean age 63.3 years) were allocated into one focus group (9 patients) and 4 interviews (4 patients). Twelve patients reported the added value of ARG and suggested constructive changes such as the adjustable screen/brightness, robust head fixation for exercise performance, easy to navigate interface and supported feedback based on exercise performance. Conclusion: Patients with chronic heart or lung diseases described the added value in an ARG telerehabilitation programme. Improvements for a future version of the ARG were suggested.IMPLICATIONS FOR REHABILITATION Patients with chronic pulmonary and heart diseases have difficulties to change behaviour to a more active and healthy lifestyle, offers from the health sector to participate in rehabilitation programmes at the hospital are feasible and improves quality of life and exercise capacity. Not all the patients are capable of participating in such rehabilitation programmes due to frailty and long distance to the hospital. Telerehabilitation seems to be a potential treatment to cope with the needs expressed above. Patient involvement in the development of a telerehabilitation solution to empower chronic pulmonary and heart patients to train, ensures a positive contribution to the design of the expected augmented reality software and hardware envisioned solution for telerehabilitation. The development of a user-centered telerehabilitation platform responding to the preferences of patients with chronic disease will remove barriers that limit use and compliance and improve empowerment in future research projects.

Boron neutron capture therapy (BNCT) is a noninvasive binary therapeutic modality applicable to the treatment of cancers. While BNCT offers a tumor-targeting selectivity that is difficult to match by other means, the last obstacles preventing the full harness of this potential come in the form of the suboptimal boron delivery strategies presently used in the clinics. To address these challenges, we have developed delivery agents that target the glucose transporter GLUT1. Here, we present the chemical synthesis of a number of

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.

Dry eye syndrome (DES) is a prevalent disease in which the tear film homeostasis is compromised. One of the main causes of DES is thought to be an alteration in the composition of the outermost layer of the tear film, the tear film lipid layer (TFLL), resulting in an increased evaporation of water from the tear film and subsequent drying of the ocular surface. Recent studies have suggested that the specific TFLL lipids, namely, O-aryl-omega-hydroxy fatty acids (OAHFAs) and diesters (DiEs), may play a role in the development of DES. However, their specific connection to DES has remained largely unknown until now because of the lack of information on their biophysical properties and their role in the TFLL. Herein, we have addressed this issue by studying the biophysical properties and evaporation resistance of a library containing 10 synthetic analogues of TFLL OAHFAs and DiEs. Our results show how the variations of chain length and polar groups affect the phase behavior of these lipids at the tear film surface. In addition, the results revealed that the OAHFAs exhibiting a liquid-expanded to solid phase transition formed films with high evaporation resistance, whereas the DiEs were found to have no evaporation resistance. Altogether, our results shed new light on the role of the OAHFAs and DiEs in the TFLL and their connection to DES, suggesting that OAHFAs are likely a key lipid class in maintaining the TFLL evaporation resistance.

The quest for novel natural-like biomolecular probes that can be used to gain information on biological recognition events is of topical interest to several scientific areas. In particular, the recognition of carbohydrates by proteins modulates a number of important biological processes. These molecular recognition events are, however, difficult to study by the use of naturally occurring oligosaccharides and polysaccharides owing to their intrinsic structural heterogeneity and to the many technical difficulties encountered during the isolation of sufficient quantities of pure material for detailed structural and biological studies. Therefore, the construction of homogenous biomolecular probes that can mimic both the biophysical properties of polysaccharide backbones and the properties of bioactive oligosaccharide fragments are highly sought after. Herein, synthetic methodology for the construction of well-defined bioconjugates consisting of biologically relevant disaccharide fragments grafted onto a dextran backbone is presented, and a preliminary NMR spectroscopy study of their interactions with galectin-3 as a model lectin is conducted. The authors thank the Magnus Ehrnrooth foundation, the Ruth and Nils‐Erik Stenbäck foundation, Åbo Akademi University, and Turku Centre for Lifespan Research for financial support. Jarl Hemming at the Laboratory of Wood and Paper Chemistry at Åbo Akademi is thanked for technical assistance with the SEC/MALLS analysis. Leena Kaven‐Honka is thanked for preparing the C. albicans mannans. The group at CIC bioGUNE thanks Agencia Estatal de Investigacion and MINECO of Spain (CTQ2015‐64597‐C2‐1P and SEV‐2016‐0644 Severo Ochoa Excellence Acreditation) and the European Commission for the TOLLerant and GlycoVAX ITN projects. The authors acknowledge Prof. Francisco Javier Cañada‐Vicinay and Pablo Valverde for the acquisition of some NMR spectra and Dr. Filipa Marcelo for the generous gift of the plasmid of the hGal3 CRD.

Antibody–drug conjugates (ADCs) are promising alternatives to naked antibodies for selective drug-delivery applications and treatment of diseases such as cancer. Construction of ADCs relies upon site-selective, efficient and mild conjugation technologies. The choice of a chemical linker is especially important, as it affects the overall properties of the ADC. We envisioned that hydrophilic bifunctional chemical linkers based on carbohydrates would be a useful class of derivatization agents for the construction of linker–drug conjugates and ADCs. Herein we describe the synthesis of carbohydrate-based derivatization agents, glycolinker–drug conjugates featuring the tubulin inhibitor monomethyl auristatin E and an ADC based on an anti-EGFR antibody. In addition, an initial in vitro cytotoxicity evaluation of the individual components and the ADC is provided against EGFR-positive cancer cells.

Many different glycoconjugates, including saponins (e.g., hellebrin) and anthracyclines (e.g., doxorubicin), are known to display cytotoxic activities. In recent work, we have developed synthetic protocols for the synthesis of various glycoconjugates, focusing on glycosylation methods for different classes of biomolecules. Simultaneously a number of saponins and anthracyclines have been generated. In this note, the cytotoxic activities of these synthesized compounds are briefly addressed.

9 p.-2 tab.-6 fig., Phosphorylated β-(1→2)-oligomannosides are found on the cell surface of several Candida species, including Candida albicans (an opportunistic pathogen). These molecules are believed to take part in the invasion process of fungal infections, which in the case of C. albicans can lead to severe bloodstream infections and death, and can therefore be considered important from a biological standpoint. Understanding the mechanism of their action requires access to the corresponding oligosaccharide model compounds in pure form. In the present work, synthesis of the model core structures involved in the invasion process of C. albicans, consisting of phosphorylated β-(1→2)-linked mannotriose and tetraose, is reported. In order to elucidate the nature of these molecules in more detail, an extensive NMR-spectroscopic study encompassing complete spectral characterization, conformational analysis and molecular modelling was performed. The obtained results were also compared to similar chemical entities devoid of the charged phosphate group., The authors thank the Academy of Finland (Research Grant #252371) and Stiftelsens för Åbo Akademi Forskningsinstitut for financial support. The CMST COST Action CM1102 Multivalent Glycosystems for Nanoscience—MultiGlycoNano is thanked for STSM funding to J.R., who also further acknowledges Suomalaisten Kemistien Seura for Young Scientist Award granted for his M.Sc. thesis work based on this study.

Immunostimulatory properties of synthetic structures mimicking the β-(1→2)-linked mannans ofCandida albicanswere evaluatedin vitro. Contrary to earlier observations, tumor necrosis factor (TNF) production was not detected after stimulation with mannotetraose in mouse macrophages. Divalent disaccharide 1,4-bis(α-d-mannopyranosyloxy)butane induced TNF and some molecules induced low levels of gamma interferon (IFN-γ) in human peripheral blood mononuclear cells (PBMC).

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was first identified among a Swedish kindred with 17 cases. The average age of onset was 36 years. Autopsy in four cases revealed the presence of axonal spheroids. The causative gene is unknown.We performed genealogical and longitudinal observations of the original kindred. Forty members were examined, five telephone-interviewed, and one of the original HDLS cases from 1984 was neuropathologically examined. The clinical course was documented. The cerebrospinal fluid (CSF) findings of two recently affected cases were examined, and one of those autopsied.Of those examined, two developed HDLS during our survey and 38 were healthy. Those interviewed by telephone were healthy. One had symptoms suggestive of HDLS in 1984, but autopsy during our survey showed no spheroids. This patient, two relatives healthy at our examination and one without symptoms at telephone interview had HDLS diagnoses in the 1984 report. Thus, four HDLS diagnoses were unconfirmed. The number of identified patients amounts to 15 among 75 individuals in four generations, including two recent cases who demonstrated a subacute multisystem encephalopathy in Case 1 and an insidious course in Case 2. CSF showed signs of neurodegeneration without inflammation, and autopsy verified HDLS in Case 1.Some HDLS cases were misdiagnosed with unspecified psychiatric diagnoses in affected relatives from the original 1984 publication. However, HDLS is an encephalopathy dominated by a frontal lobe syndrome with an inexorably progressive and fatal course, where the different symptomatology in two recent cases confirmed the existence of acute and chronic variants.

The clinical value in neuropediatrics of [99mTc]HM-PAO brain single photon emission computed tomography was preliminary evaluated by the consecutive investigation of 79 children. Planned epilepsy surgery was the most common indication for the investigation. In 56 children investigated because of epilepsy, SPECT yielded relevant information in 79% of cases examined. The corresponding figures for magnetic resonance imaging and CT were 49% of 35 and 36% of 56 cases, respectively. All 22 children with an epileptic focus, ascertained by freedom from seizures after removal of the area or by consistent neurophysiological and neuroradiological findings, also had abnormal perfusion in the relevant area. Twenty-three children were examined because of neurological signs and symptoms other than epilepsy. SPECT findings were useful for elucidating neonatal brain impairments. Hypoperfused areas in the brain of asphyxiated infants and in posthemorrhagic hydrocephalus corresponded to neuroradiological and autopsy findings. SPECT was found to be an excellent tool when analysing cerebrovascular accidents. In cases with signs and symptoms of a diffuse severe encephalopathy, SPECT did not clarify the etiology but provided information on the distribution of the lesions and probable underlying pathophysiological mechanisms.

Changes in concentration of high energy phosphates and pH were studied during rest, exercise and subsequent recovery in the anterior tibial muscle of 10 patients with late effects of poliomyelitis and 10 age- and sex-matched healthy volunteers using 31P MRS. The exercise was dynamic and isometric, and the force levels were individually adapted to each subject and stepwise increased. In general, there were no differences in metabolite changes between the groups, except for lower Pi and Pi/PCr for the volunteers during the recovery phase, also reflected by shorter recovery half-time for Pi. The interindividual variation was much higher for the patient group. Some of the patients showed deviating results probably because of differences in muscle fibre type.

The LindqvistMalmgren's system was used to describe the outcome of organic psychiatric disorders (OPDs) after aneurysmal subarachnoid hemorrhage (aSAH) and their associations with age, bleeding severity, and pre-existing arterial hypertension (preAH).OPDs were diagnosed at 3, 6, and 12 months after aSAH in a prospective cohort study (n=63). Reaction level (RLS85), World Federation of Neurological Surgeons Committee SAH scale (WFNS), Fisher, and hydrocephalus grades were assessed at admission.At 3/6/12 months, 60/49/38% had an Astheno-emotional disorder (AED), 4/5/5% had emotional-motivational blunting disorder (EMD) and 19/19/16% had Korsakoffs amnestic disorder (KAD). AED was associated with preAH, whereas EMD/KAD, but not AED, was associated with a higher mean age, worse median RLS85 levels, WFNS grades, and Fisher grades.OPDs were diagnosed in 59% of the patients at 12 months after aSAH. AED, the most common OPD, had the highest recovery rate and was associated with preAH. Use of organic psychiatric diagnoses for evaluation of outcome after aSAH and other brain injuries is encouraged.

To analyse the diagnostic and prognostic value of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) magnetic resonance imaging (MRI) changes and their relation to symptoms and cerebrospinal fluid (CSF) markers of demyelination (sulphatide) and axonal degeneration [neurofilament triplet protein (NFL)] in a large series of patients with normal pressure hydrocephalus (NPH) and Binswanger disease (BD).PVH and DWMH were determined by a semi-automatic segmentation method on T2-weighted images in 29 patients with NPH and 17 patients with BD. CSF analyses, psychometric testing and quantification of balance, gait and continence were performed in all patients and also postoperatively in NPH patients.No MRI variable could identify NPH or BD patients. Abundant PVH and DWMH preoperatively correlated with improvement in gait, balance and psychometric performance after shunt surgery (P0.05). CSF sulphatide correlated positively with the amount of DWMH (P0.05) while NFL was correlated to both PVH and DWMH (P0.05). Abundant PVH correlated with poor psychometric performance while DWMH correlated with gait disturbance (P0.05). Postoperative reduction in PVH correlated with improvement in gait, balance and psychometric performance.In spite of a refined quantification method, NPH and BD patients exhibited similar MRI changes. MRI had a predictive value in NPH patients. DWMH might relate to demyelination and PVH to neuronal axonal dysfunction. NPH and BD share the major part of symptoms and MRI changes, indicating a common pathophysiological pattern, and we raise the question of how to treat BD patients.

Image selected in vivo spectroscopy (ISIS) is a volume selection method often used for in vivo (31)P MRS, since it is suitable for measurements of substances with short T(2). However, ISIS can suffer from significant signal contributions caused by T(1) smearing from regions outside the VOI. A computer model was developed to simulate this contamination. The simulation results for the ISIS experiment order implemented in our MR system (ISIS-0) were in agreement with results obtained from phantom measurements. A new extended ISIS experiment order (E-ISIS) was developed, consisting of four "optimal" ISIS experiment orders (ISIS-1 to ISIS-4) performed consecutively with dummy ISIS experiments in between. The simulation results show that contamination due to T(1) smearing is, effectively, eliminated with E-ISIS and is significantly lower than for ISIS-0 and ISIS-1. E-ISIS offers increased accuracy for quantitative and qualitative determination of substances studied using in vivo MRS. Hence, E-ISIS can be valuable for both clinical and research applications.

Anatomical and neurological correlates of visuospatial neglect were studied in 53 patients with a CT-documented right hemisphere stroke. Evidence of neglect at the acute stage poststroke was strongly related to large lesions involving the middle temporal gyrus and/or the temporo-parietal paraventricular white matter. Thus, out of 18 patients with evidence of visuospatial neglect at the acute stage, 12 showed a lesion in the middle temporal gyrus and/or the deep temporo-parietal white matter. Among the 35 patients that failed to show visuospatial neglect, only one patient had a lesion within these areas. Comparing those patients who recovered from neglect with those that did not, a high correlation was found between persisting neglect and a lesion involving the paraventricular white matter in the temporal lobe. On the basis of above findings, it was suggested that a simultaneous damage to the cortico-thalamic system for regulation of arousal and to the neural systems mediating visual orienting, is likely to be followed by persisting neglect symptoms.

Image quality in preimplant computerized tomography (CT) examinations made with different radiation doses (40 to 280 mAs) and scanning modes (standard and helical axial, 15-degree angled, and frontal) and in conventional spiral tomography (Scanora) was compared. Mandibular canal and alveolar bone crest visibility was evaluated in images from mandibular jaw segments. Visibility was unaffected by radiation dose in CT examinations except in frontal scanning, where a small actual difference was statistically significant. Differences among CT scanning modes and between CT and conventional spiral tomography were highly significant. Low-dose mandibular preimplant tomography can be performed with CT using lower-than-normal radiation doses or with conventional spiral tomography.

The addition of sodium to nonionic contrast media has reduced the incidence of arrhythmias in animal models. The influence on cardiac function and safety of sodium addition to the nonionic contrast medium iohexol (Omnipaque) was studied in a randomized, double-blind trial in patients undergoing cardioangiography. Fifty-nine patients received iohexol 350 mg I/ml with NaCl 28 mmol/l and 58, iohexol only. ECG changes after contrast injections were evaluated with continuous computerized dynamic vectorcardiography (VCG). QRS-vector difference (QRS-vd), which reflects changes in the QRS-complex, was chosen as the main parameter. Both contrast media caused changes in the QRS-complex, but there was no significant difference between the two. No serious arrhythmias were observed. Both contrast media were well tolerated. No beneficial effects from enriching iohexol with sodium were found. VCG was found to be a valuable tool in the study of contrast medium-induced ECG changes.

Surgery was performed in the maxillary sinus with restoration of the surgical defect in the anterior wall with a resutured bone-lid, in 12 patients with an average age of 45 years, the technique is described and evaluated clinically and radiographically (computed tomography). During the followup time of 1-4 years, the condition of the maxillary sinus was normalized. It is our opinion that the bone-lid technique for maxillary sinus surgery is useful, especially when good overview and access is necessary.

The need for repositioning of surface coils and patients in MR examinations of the cervical and thoracic spine prolongs examination time. A new receiver design is proposed which overcomes this problem. The device is composed of two actively decoupled receiver coils mounted on the frame of a Philadelphia collar. These coils may be used separately to image either the thoracic or cervical spine or together to produce larger field-of-view images of the combined region. Signal-to-noise ratios of the separate cervical and thoracic spine images are not degraded as a result of mounting the receivers together. The full cervical and thoracic region is shown to be imaged at a signal-to-noise ratio significantly higher than that afforded by the body coil. A retrospective review of our case load suggests that a time saving could be achieved in approximately 1/3 of spine examinations by using this coil.

A double blind investigation comparing meglumine-Na diatrizoate (290 mg I/ml) and iohexol (300 mg I/ml) showed that patients receiving iohexol experienced significantly less discomfort. Patients who received diatrizoate commonly showed transient episodes of hypertension while those who received iohexol either showed no changes or transient episodes of hypotension. No significant changes in heart rate were observed in either group.

CT was used to document temporal lobe atrophy in 39 patients who were diagnosed clinically as having Alzheimer disease; the results were compared with those from 29 healthy elderly control subjects who were matched for age and education. The diagnosis of Alzheimer disease was made according to clinical criteria consistent with those specified by an NINCDS workshop. These included detailed medical and neuropsychological assessments. Temporal lobe atrophy was assessed by evaluating the temporal horns and sylvian cisterns. Temporal horn measurements greater than 3 mm occurred only in patients with Alzheimer disease while measurements less than or equal to this occurred in both Alzheimer patients and control subjects. Subjective evaluation of the sylvian cistern indicated that 24/29 controls had normal-appearing cisterns while only 5/39 Alzheimer patients had similar findings. In contrast to temporal horns, sylvian cisterns were more sensitive but less specific as discriminators between Alzheimer patients and normal controls.

It is now recognized that patients infected by the virus linked to the acquired immunodeficiency syndrome (AIDS) can develop dementia symptoms as the initial and sometimes only symptomatology for AIDS. This appears to be a syndrome whose origin is independent of secondary non-viral infection or malignancy. Magnetic resonance imaging (MRI) in three patients with well documented AIDS dementia revealed high signal periventricular white matter lesions. In one case, large lesions were not apparent on computed tomography and gross inspection of the fixed brain prior to autopsy. In two cases in which serial in vivo MR studies were obtained, there was a progressive increase in lesion volume over a short (several months) period of observation. Periventricular white matter lesions may be an early sign accompanying AIDS dementia, and the degree of changes correlated well with the clinical picture in our patients.

Technical aspects on surface coil magnetic resonance imaging of the spine using a superconducting system with a field strength of 1.5 tesla are described. By using a flat surface coil instead of the body coil the image quality was markedly improved and the signal-to-noise ratio (S/N) was increased approximately 2.6 times. Small voxels resulted in low S/N. The best image quality was achieved with a slice thickness of 5 mm, a field of view of 20 to 24 cm and a matrix of 256 X 256. Interleaved slices provided superior image quality compared with contiguous slices at the expense of acquisition time. For sagittal images the phase encoding gradient should be in the cranio-caudal direction to minimize motion artifacts. To obtain T1 and T2 images of high quality, spin echo pulse sequences with TR 600/TE 20 ms and TR 2000/TE 40 to 80 ms are useful.

Patients with a previous history of anaphylactic reactions to ionic iodinated contrast media were desensitised before a second radiologic examination was performed. The tolerance to the contrast medium was raised by repeated intravenous injections in increasing doses and concentrations. No serious side effects were noted when the examinations with contrast medium was repeated within a few days after the desensitisation. The positive effect of the desensitisation may depend on a successive consumption of complement proteins, probably responsible for the allergic reactions. Therefore, the available amount of complement for some days may be too low for the occurrence of a complement reaction.