Closing the loop: Novel quantitative fMRI approach for manipulation of the sensorimotor loop in tremor.

Tremor is thought to be an effect of oscillatory activity within the sensorimotor network. To date, the underlying pathological brain networks are not fully understood. Disentangling tremor activity from voluntary motor output and sensorimotor feedback systems is challenging. To better understand the intrinsic sensorimotor fingerprint underlying tremor, we aimed to disentangle the sensorimotor system into driving (motor) and feedback/compensatory (sensory) neuronal involvement, and aimed to pinpoint tremor activity in essential tremor (ET) and tremor-dominant Parkinson's disease (PD) with a novel closed-loop approach. Eighteen ET patients, 14 tremor-dominant PD patients, and 18 healthy controls were included. An MR-compatible wrist manipulator was employed during functional MRI (fMRI) while muscle activity during (in)voluntary movements was concurrently recorded using electromyography (EMG). Tremor was quantified based on EMG and correlated to brain activity. Participants performed three tasks: an active wrist motor task, a passive wrist movement task, and rest (no wrist movement). The results in healthy controls proved that our experimental paradigm activated the expected motor and sensory networks separately using the active (motor) and passive (sensory) task. ET patients showed similar patterns of activation within the motor and sensory networks. PD patients had less activity during the active motor task in the cerebellum and basal ganglia compared to ET and healthy controls. EMG showed that in ET, tremor fluctuations correlated positively with activity in the inferior olive region, and that in PD tremor fluctuations correlated positively with cerebellar activity. Our novel approach with an MR-compatible wrist manipulator, allowed to investigate the involvement of the motor and sensory networks separately, and as such to better understand tremor pathophysiology. In ET sensorimotor network function did not differ from healthy controls. PD showed less motor-related activity. Focusing on tremor, our results indicate involvement of the inferior olive in ET tremor modulation, and cerebellar involvement in PD tremor modulation.

A chlorhexidine-releasing epoxy-based coating on titanium implants prevents Staphylococcus aureus experimental biomaterial-associated infection.

Prevention of biomaterial-associated infections (BAI) remains a challenging problem, in particular due to the increased risk of resistance development with the current antibiotic-based strategies. Metallic orthopaedic devices, such as non-cemented implants, are often inserted under high mechanical stress. These non-cemented implants cannot be protected by e.g. antibioticreleasing bone cement or other antimicrobial approaches, such as the use of bioactive glass. Therefore, in order to avoid abrasion during implantation procedures, we developed an antimicrobial coating with great mechanical stability for orthopaedic implants, to prevent Staphylococcus aureus BAI. We incorporated 5 and 10 wt % chlorhexidine in a novel mechanically stable epoxy-based coating, designated CHX5 and CHX10, respectively. The coatings displayed potent bactericidal activity in vitro against S. aureus, with over 80 % of the release (19 µg/cm2 for CHX5 and 41 µg/cm2 for CHX10) occurring within the first 24 h. In mice, the CHX10 coating significantly reduced the number of CFU (colony forming units), both on the implants and in the peri-implant tissues, 1 d after S. aureus challenge. The CHX10-coated implants were well-tolerated by the animals, with no signs of toxicity observed by histological analysis. Moreover, the coating significantly reduced the frequency of culture-positive tissues 1 d, and of culture-positive implants 1 and 4 d after challenge. In summary, the chlorhexidine-releasing mechanically stable epoxy-based CHX10 coating prevented implant colonisation and S. aureus BAI in mice and has good prospects for clinical development.

Fat/water ratios measured with diffuse reflectance spectroscopy to detect breast tumor boundaries.

Recognition of the tumor during breast-conserving surgery (BCS) can be very difficult and currently a robust method of margin assessment for the surgical setting is not available. As a result, tumor-positive margins, which require additional treatment, are not found until histopathologic evaluation. With diffuse reflectance spectroscopy (DRS), tissue can be characterized during surgery based on optical parameters that are related to the tissue morphology and composition. Here we investigate which optical parameters are able to detect tumor in an area with a mixture of benign and tumor tissue and hence which parameters are most suitable for intra-operative margin assessment. DRS spectra (400-1600 nm) were obtained from 16 ex vivo lumpectomy specimens from benign, tumor border, and tumor tissue. One mastectomy specimen was used with a custom-made grid for validation purposes. The optical parameter related to the absorption of fat and water (F/W-ratio) in the extended near-infrared wavelength region (~1000-1600 nm) provided the best discrimination between benign and tumor sites resulting in a sensitivity and specificity of 100 % (excluding the border sites). Per patient, the scaled F/W-ratio gradually decreased from grossly benign tissue towards the tumor in 87.5 % of the specimens. In one test case, based on a predefined F/W-ratio for boundary tissue of 0.58, DRS produced a surgical resection plane that nearly overlapped with a 2-mm rim of benign tissue, 2 mm being the most widely accepted definition of a negative margin. The F/W-ratio provided excellent discrimination between sites clearly inside or outside the tumor and was able to detect the border of the tumor in one test case. This work shows the potential for DRS to guide the surgeon during BCS.

Screening and surveillance of hepatocellular carcinoma by serum des-gamma-carboxy prothrombin in patients with glycogen storage disease type Ia.

No sensitive tumor marker for hepatocellular carcinoma (HCC) is available for patients with glycogen storage disease type Ia (GSDIa), in whom alpha-fetoprotein and carcino-embryonic antigen levels often remain normal. We describe increased levels of the HCC tumor marker des-gamma-carboxy prothrombin (DCP) in GSDIa patients with HCC. In one case DCP levels normalized after liver transplantation. We recommend including DCP as a screening HCC tumor marker in the surveillance of patients with GSDIa.

Bacterial reservoir in deeper skin is a potential source for surgical site and biomaterial-associated infections.

BACKGROUND: The origin of surgical site and biomaterial-associated infection is still elusive. Micro-organisms contaminating the wound may come from the air in the operating theatre, the surgical team or the skin of the patient. The skin of patients is disinfected prior to surgery, but bacteria deeper in the skin (e.g. in sweat glands or sebaceous glands) may not be reached. METHODS: A preliminary cohort study was performed to study the origin of surgical site and biomaterial-associated infection between May 2020 and February 2021. In order to investigate whether cutaneous microbiota colonize the wound when released from the skin upon cutting, aerobic and anaerobic bacteria were isolated, quantified and identified from the skin of 99 patients undergoing trauma surgery, before and after skin disinfection, from knife blades and from the wound directly after the first cut. RESULTS: Ninety-nine percent of the patients were culture-positive before disinfection with chlorhexidine. Of these, 40% were still culture-positive after disinfection. Of these, 54% had a positive culture of the wound after cutting the skin. Twenty percent of the patients with a negative culture after disinfection had a positive wound culture after cutting the skin. Staphylococcus epidermidis and Cutibacterium acnes were the most commonly cultured bacterial species. In 9% of cases, more than 100 bacterial colonies were cultured from the wound; this may cause biomaterial-associated infection. CONCLUSION: Bacteria residing in the skin and not eradicated by disinfection may enter the surgical wound upon cutting, resulting in contamination which may cause biomaterial-associated infection.

Lipoprotein(a) levels and carotid intima-media thickness in children: A 20-year follow-up study.

Elevated lipoprotein(a) [Lp(a)] is independently associated with cardiovascular disease (CVD). In a recent long-term follow-up study involving children with familial hypercholesterolemia, Lp(a) levels contributed significantly to early atherosclerosis, as measured by carotid intima-media thickness (cIMT). To determine if this holds true for children without FH, we conducted a 20-year follow-up study, examining 88 unaffected siblings (mean age: 12.9 years) of children with FH. No significant association was found between Lp(a) and cIMT during follow-up (ß-adjusted [95% CI] = 0.0001 [-0.008 to 0.008] mm per 50 nmol/L increase Lp(a), p = 0.97). In conclusion, our findings suggest that elevated levels of Lp(a) do not play a significant role in arterial wall thickening among children without FH during the 20-year follow-up period. This leads us to consider the possibility that cIMT may not be a suitable marker for detecting potential subtle changes in the arterial wall mediated by Lp(a) in the young, general population. However, it could also be that elevated Lp(a) is only a significant risk factor for atherosclerosis in the presence of other risk factors such as FH.

Medical-grade honey enriched with antimicrobial peptides has enhanced activity against antibiotic-resistant pathogens.

Honey has potent activity against both antibiotic-sensitive and -resistant bacteria, and is an interesting agent for topical antimicrobial application to wounds. As honey is diluted by wound exudate, rapid bactericidal activity up to high dilution is a prerequisite for its successful application. We investigated the kinetics of the killing of antibiotic-resistant bacteria by RS honey, the source for the production of Revamil® medical-grade honey, and we aimed to enhance the rapid bactericidal activity of RS honey by enrichment with its endogenous compounds or the addition of antimicrobial peptides (AMPs). RS honey killed antibiotic-resistant isolates of Pseudomonas aeruginosa, Staphylococcus epidermidis, Enterococcus faecium, and Burkholderia cepacia within 2 h, but lacked such rapid activity against methicillin-resistant S. aureus (MRSA) and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. It was not feasible to enhance the rapid activity of RS honey by enrichment with endogenous compounds, but RS honey enriched with 75 µM of the synthetic peptide Bactericidal Peptide 2 (BP2) showed rapid bactericidal activity against all species tested, including MRSA and ESBL E. coli, at up to 10-20-fold dilution. RS honey enriched with BP2 rapidly killed all bacteria tested and had a broader spectrum of bactericidal activity than either BP2 or honey alone.

Two years' experience with inspiration breath-hold in liver SBRT.

•The workflow of inspiration breath-hold SBRT for liver metastases is described.•Inspiration breath-hold in liver SBRT is feasible for 95% of the patients.•An individual margin recipe for inspiration breath-hold liver SBRT is explained.•Margin reduction of 10 mm using inspiration breath-hold compared to free breathing.

Fabrication of oxide layer on zirconium by micro-arc oxidation: Structural and antimicrobial characteristics.

The aim of this study was to cover the surfaces of zirconium (Zr) with an antimicrobial layer for biomedical applications. For this purpose, the micro-arc oxidation (MAO) process was employed in a sodium silicate and sodium hydroxide containing base electrolyte with and without addition of silver acetate (AgC2H3O2). In general, synthesized MAO layers were composed of zirconium oxide (ZrO2) and zircon (ZrSiO4). Addition of AgC2H3O2 into the base electrolyte caused homogenous precipitation of silver-containing particles in the MAO layer, which exhibited excellent antibacterial efficiency against methicillin-resistant Staphylococcus aureus (MRSA) as compared to the untreated and MAO-treated Zr.

Prevention of Staphylococcus aureus biomaterial-associated infections using a polymer-lipid coating containing the antimicrobial peptide OP-145.

The scarcity of current antibiotic-based strategies to prevent biomaterial-associated infections (BAI) and their risk of resistance development prompted us to develop a novel antimicrobial implant-coating to prevent Staphylococcus aureus-induced BAI. We incorporated the antimicrobial peptide OP-145 into a Polymer-Lipid Encapsulation MatriX (PLEX)-coating to obtain high peptide levels for prolonged periods at the implant-tissue interphase. We first confirmed that OP-145 was highly effective in killing S. aureus and inhibiting biofilm formation in vitro. OP-145 injected along S. aureus-inoculated implants in mice significantly reduced the number of culture-positive implants. OP-145 was released from the PLEX coating in a controlled zero-order kinetic rate after an initial 55%-burst release and displayed bactericidal activity in vitro. In a rabbit intramedullary nail-related infection model, 67% of rabbits with PLEX-OP-145-coated nails had culture-negative nails after 28days compared to 29% of rabbits with uncoated nails. In rabbits with PLEX-OP-145-coated nails, bone and soft tissue samples were culture-negative in 67% and 80%, respectively, whereas all bone samples and 71% of the soft tissue samples of rabbits with uncoated nails were infected. Together, PLEX-OP-145 coatings, of which both compounds have already been found safe in man, can prevent implant colonization and S. aureus-induced BAIs.

Increased levels and pulsatility of follicle-stimulating hormone in mothers of hereditary dizygotic twins.

According to the endocrine model of hereditary dizygotic twinning, high FSH is responsible for multiple ovulation and pregnancy. Our study explored the underlying neuroendocrine causes. In a prospective clinical study, we compared the third day of menses parameters of episodic secretion of LH and FSH, the pituitary response to LHRH, plasma estradiol, and dimeric inhibin A and B in 16 regularly menstruating and 9 postmenopausal mothers of dizygotic twins with a family history of twinning and 14 premenopausal and 9 postmenopausal controls. Seven of 16 premenopausal mothers of twins had abnormally high FSH levels of more than 10 IU/L compared with 1/14 in controls (P = 0.024). In the premenopausal mothers of twins, mean FSH concentrations (P = 0.025) and FSH pulse frequency (P = 0.003) were significantly elevated, whereas FSH pulse amplitude and FSH response to LHRH were unaltered. For LH, neither the secretory parameters nor the response to LHRH was different. There were no differences between estradiol and inhibin A and B levels. Postmenopausal mothers of twin and controls did not differ with respect to the secretory pattern of LH and FSH. We conclude that under equal ovarian feedback conditions, premenopausal mothers of a dizygotic twin have hyper stimulation by endogenous FSH caused by neuroendocrine, hypothalamic, or pituitary mechanisms. This is the result of altered responsiveness to ovarian feedback and/or pituitary or suprapituitary, non-LHRH-like mechanisms that stimulate pulsatile FSH.

The diagnostic value of sural nerve T cells in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: T-cell infiltrates in sural nerve biopsy specimens of patients with inflammatory neuropathies have been reported, suggesting a role for T cells in the pathogenesis, but the specificity of the presence and localization of sural nerve T cells in chronic inflammatory demyelinating polyneuropathy (CIDP) is unknown. OBJECTIVE: To study the diagnostic value of the number and distribution of sural nerve T cells in CIDP. METHODS: We performed a quantitative immunohistochemical examination of T cells in sural nerve biopsy specimens taken from 23 patients with a CIDP and compared them with sural nerves of 15 patients with a chronic idiopathic axonal polyneuropathy (CIAP), 5 patients with a vasculitic neuropathy, and 10 normal controls. RESULTS: T cells were found in sural nerves of all CIDP patients as well as in all disease and normal controls. Only six CIDP patients had increased numbers and densities of T cells compared with CIAP patients and controls. Based on the distribution of endoneurial or epineurial T cells, it was not possible to differentiate CIDP patients from CIAP patients or normal controls. In patients and controls perivascular epineurial T cells predominated. Increased numbers and densities of sural nerve T cells in patients with CIDP were associated with female sex, a more severe disease course, worse outcome, highly elevated CSF protein level, and a larger sural nerve area, but not with loss of myelinated nerve fibers in the sural nerve biopsy sample or demyelinating features on electrophysiologic examination. CONCLUSIONS: In the majority of CIDP patients, the number and distribution of T cells in sural nerve biopsy samples were similar to patients with noninflammatory neuropathies and normal controls. Only large numbers of sural nerve T cells are specific for inflammatory neuropathies and therefore of diagnostic value for CIDP.

Effect of chronic phenelzine treatment on REM sleep: report of three patients.

Antidepressants belonging to the class of monoamine oxidase inhibitors (MAOI) such as phenelzine have long been known to drastically suppress REM sleep. Sleep and the electroencephalogram (EEG) in sleep and waking were studied in three depressed patients at regular time intervals before, during and after 6 to 18 months of phenelzine treatment. While REM sleep was initially eliminated in all patients, short REM sleep episodes reappeared after three to six months of medication. Total sleep time and EEG slow-wave activity (SWA, spectral power within 0.75-4.5 Hz) in nonREM sleep (stages 1-4) were not changed. In contrast, EEG theta frequency activity (TFA, power within 4.75-8.0 Hz) during a 5-min wake interval recorded prior to the sleep episodes was initially enhanced, and tended to correlate negatively with the percentage of REM sleep (p =.06). This observation indicates that compensatory REM sleep mechanisms may occur in wakefulness during chronic MAOI treatment.

Mutations in the NSD1 gene in patients with Sotos syndrome associate with endocrine and paracrine alterations in the IGF system.

OBJECTIVE: To investigate the effect of nuclear receptor Su-var, 3-9, enhancer of zeste, trithorax (SET) domain-containing protein 1 (NSD1) gene alteration in patients with Sotos syndrome on plasma IGFs and IGF-binding proteins (IGFBPs), as well as on the IGF/IGFBP system activity at the tissue level. DESIGN: Twenty-nine patients suspected of Sotos syndrome were divided into two groups: patients with heterozygous deletions or mutations in the NSD1 gene (NSD1(+/-)) (n=11) and subjects without (NSD1(+/+)) (n=18). Plasma samples (n=29) and skin fibroblasts (n=23) were obtained. The results of both groups were compared and related to reference values. METHODS: IGF-I, IGF-II, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6 levels were determined by RIAs. The mitogenic response of fibroblasts to IGFs was investigated by [methyl-(3)H]thymidine incorporation. IGFBP-3 levels in the culture media were measured by RIA. IGFBP-3 mRNA expression was determined by real time RT-PCR. RESULTS: NSD1(+/-) patients showed significantly altered levels of IGF-I (mean-1.2 SDS), IGF-II (-1.2), IGFBP-3 (-1.7), IGFBP-4 (-0.4), IGFBP-2 (+0.8) and IGFBP-6 (+1.5). The NSD1(+/+) patients did not differ from the reference, with the exception of the mean IGFBP-3 level (-1.3). Basal proliferation and mitogenic response to IGFs was diminished in NSD1(+/-) fibroblasts compared with NSD1(+/+) (basal, P=0.02; IGF-I, P<0.001; IGF-II, P=0.02). Compared with control fibroblasts, only the mitogenic response was diminished (basal, P=0.07; IGF-I, P=0.04; IGF-II, P=0.04). A trend of higher IGFBP-3 secretion after IGF-I stimulation (P=0.09) and 3.5-5 times higher mRNA expression of IGFBP-3 in basal conditions was found in NSD1(+/-) fibroblasts in comparison to controls. CONCLUSIONS: NSD1(+/-) patients show endocrine and paracrine changes in the IGF system. These changes may contribute to the abnormal growth pattern.

Banding patterns of the chromosomes of Presbytis cristatus pyrrhus and P. obscurus.

The G- and Q-bands and the location of the nucleolar organizer regions (NOR) in the chromosomes of Presbytis obscurus and the Q- and C-bands of P. cristatus pyrrhus are described. Their chromosomes are compared to those of Macaca mulatta and to other Cercopithecidae and Hylobatidae. The origin of the two different banding patterns of pair no. 1 in our specimen of P. cristatus pyrrhus is discussed.

Plasma insulin-like growth factors (IGFs), IGF-Binding proteins (IGFBPs), acid-labile subunit (ALS) and IGFBP-3 proteolysis in individuals with clinical characteristics of Sotos syndrome.

OBJECTIVE: Sotos syndrome is an overgrowth syndrome of poorly understood aetiology. We investigated whether this syndrome is related to alterations in plasma insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), acid-labile subunit (ALS) and serum IGFBP-3 proteolysis. DESIGN: Based on clinical criteria, 32 patients with clinical characteristics of Sotos syndrome (median age 8.4 years, range 1.8-48.4) were categorised into three groups: typical (n = 10, group 1), dubious (n = 12, group 2) and atypical (n = 10, group 3). Blood samples were obtained from 29 patients. MEASUREMENTS: Plasma IGF-I, IGF-II, E-II (pro-IGF-II and E-domain fragments), IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6 and ALS were measured by specific radioimmunoassays (RIAs). Except for E-II immunoreactivity, the concentrations were compared with those of age references, and expressed as standard deviation scores (SDS). IGFBP-3 proteolysis was assessed by incubation of serum with [125I]-IGFBP-3, followed by gel electrophoresis and was then compared with that in normal serum and third trimester pregnancy serum. RESULTS: Patients in group 1 showed significantly reduced plasma levels of IGF-II (median -0.9 SDS; p = 0.01), IGFBP-4 (-0.5 SDS; p = 0.02) and IGFBP-3 (-1.0 SDS; p = 0.01). Mean IGFBP-3 proteolysis was higher than in normal standard serum (61% vs 37%; p < 0.01) but lower than in third trimester pregnancy serum (94%; p < 0.01). Plasma IGF-I showed a tendency towards low values (median -0.9 SDS; p = 0.09), IGFBP-6 and ALS a tendency towards elevated levels (median values +0.8 SDS; p = 0.07 and +2.3 SDS; p = 0.09), and IGFBP-2 was normal. The mean value of E-II immunoreactivity was 8.7 nmol/l, similar to that in pooled normal plasma (8.6 nmol/l). Plasma and serum parameters in groups 2 and 3 were similar to reference values with the exception of plasma IGFBP-3 (in groups 2 and 3 median < or = -1.1 SDS; p < or = 0.02) and ALS (in group 3 median +1.3 SDS; p < 0.01). CONCLUSIONS: Patients with typical Sotos syndrome show low plasma IGF-II, IGFBP-3, IGFBP-4, and increased proteolysis of IGFBP-3 in serum. The extent to which these findings are associated with the pathophysiology of Sotos syndrome remains uncertain.

Development and test of an extendable endoprosthesis for bone reconstruction in the leg.

A malignant bone tumour may develop in the femur of a child. In the majority of cases it will be necessary to resect the bone involved, growth plate and adjacent tissues. A modular endoprosthetic system has been developed which can be extended non-invasively to bridge the defect resulting from such a resection. Elongation is achieved by using an external magnetic field. In vitro tests with a prototype showed that the lengthening element met all requirements. Six animal experiments showed that the lengthening element also functioned in vivo.

Elastomeric valves, a new design.

The convex bileaflet valve replaces the flat biflap inflow valve designed by Long Sheng Yu and the tricusp semilunair outflow valve. One reason is easier manufacturing. Convex bileaflet valves are developed for the 11, 20, 40, 70 and 140cc ventricles. Testing included curves (Cardiac Output versus Venous Pressure, Cardiac Output versus Heart rate), flow visualization studies, paint and bloodbag studies. The curves and flow visualization were done by connecting ventricles to one of our standard mock circulations. Paint and bloodbag studies were done by connecting the hearts to a bloodbag, but the bag was filled with water for the paint studies. The curves show high cardiac output, even with pumping at high heart rates (150 BPM+). The flow visualization shows a good stream through the sinus Valsalvae. No stagnating flow is visible. The bloodbag studies which provoke thrombosis show it on the edges of the heart valves, and little in the groove between the valve and the sinus Valsalvae. Heparninzation prevents the thrombosis. Results of our tests were good. The convex bileaflet valve seems to have good future.

A case of combined hermaphroditism and autofertilisation in a domestic rabbit.

A true hermaphrodite rabbit served several females and sired more than 250 young of both sexes. In the next breeding season the rabbit, which was housed in isolation, became pregnant and delivered seven healthy young of both sexes. It was kept in isolation and when autopsied was again pregnant and demonstrated two functional ovaries and two infertile testes. A chromosome preparation revealed a diploid number of autosomes and two sex chromosomes of uncertain configuration.

Design of a load cell for the Wagner distractor.

A leg length inequality can be treated by using a Wagner distractor. With this apparatus, it is possible to extend the upper or lower leg slowly. By analysing the measurements of the axial force acting on the femur or tibia the treatment can be optimized and soft tissue damage prevented. To measure the axial force, a load cell has been designed and constructed. This load cell is built into a Wagner distractor and connected with a specially designed measuring amplifier. The load cell and amplifier do not interfere with the lengthening procedure. They are safe for the patient and have an acceptable error of 7 per cent. So far, some test measurements were performed on two patients in the Rummelsberg Hospital in West Germany. The load cell proved to function in a clinical situation.