Objective
To retrospectively determine the frequency of N‐Methyl‐D‐Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia.
Methods
Clinical characterization of ...660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age‐matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients.
Results
Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with “unclassified dementia” followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease‐related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA‐associated cognitive decline.
Interpretation
Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy.
Abstract
Objective. To compare the efficacy and safety of olmesartan medoxomil (O) and ramipril (R) in elderly patients with essential arterial hypertension. Methods. After a 2-week placebo washout, ...351 elderly hypertensive patients aged 65-89 years (office sitting diastolic blood pressure, DBP, 90-109 mmHg and office sitting systolic blood pressure, SBP, 140-179 mmHg) were randomized double-blind to 12-week treatment with O 10 mg or R 2.5 mg once daily. After the first 2 and 6 weeks, doses could be doubled in non-normalized (blood pressure <140/90 mmHg for non-diabetic and <130/80 mmHg for diabetic) subjects, up to 40 mg for O and 10 mg for R. Office blood pressures were assessed at randomization, after 2, 6 and 12 weeks of treatment; 24-h ambulatory blood pressure (ABP) was recorded at randomization and after 12 weeks. Results. At week 12, in the intention-to-treat population (170 patients O and 175 R) the rate of normalized subjects was significantly larger in the O group (38.8% vs 26.3% R; p = 0.013). Baseline-adjusted mean sitting office blood pressure reduction at final visit was not significantly greater under O SBP: 16.6 (95% confidence interval 14.0/19.2) mmHg vs 13.0 (10.4/15.6) mmHg R, p = 0.206; DBP: 11.8 (10.3/13.3) mmHg vs 10.5 (9.0/12.0) mmHg, p = 0.351. In the subgroup of patients with valid ABP recordings (38 O and 47 R), the reduction in 24-h average blood pressure was significantly (p < 0.01) larger with O SBP: 8.9 (9.8/8.1) and DBP: 5.7 (6.3/5.1) mmHg than with R 6.7 (7.9/5.6) and 4.4 (5.1/3.7) mmHg. The superiority of O was particularly evident in the last 4 h from the dosing interval. The proportion of patients with drug-related adverse events was comparable in the two groups (4.0% O vs 4.5% R), as well as the number of patients discontinuing study drug because of a side-effect (8 O vs 7 R). Conclusions. In elderly patients with essential arterial hypertension, O provides an effective, prolonged and well tolerated blood pressure control, with significantly better blood pressure normalization than R and represents a useful option among first-line drug treatments of hypertension in this age group.
The force experienced while inserting an 18-gauge Tuohy needle into the epidural space or dura is one of only two feedback components perceived by an anaesthesiologist to deduce the needle tip ...position in a patient's spine. To the best of the authors knowledge, no x-ray validated measurements of these forces are currently available to the public. A needle insertion force recording during an automated insertion of an 18-gauge Tuohy needle into human vertebral segments of four female donors was conducted. During the measurements, x-ray images were recorded simultaneously. The force peaks due to the penetration of the ligamentum supraspinale and ligamentum flavum were measured and compared to the measurements of an artificial patient phantom for a hybrid patient simulator. Based on these force peaks and the slope of the ligamentum interspinale, a mathematical model was developed. The model parameters were used to compare human specimens and artificial patient phantom haptics. The force peaks for the ligamenta supraspinale and flavum were 7.55 ± 3.63 N and 15.18 ± 5.71 N, respectively. No significant differences were found between the patient phantom and the human specimens for the force peaks and four of six physical model parameters. The patient phantom mimics the same resistive force against the insertion of an 18-gauge Tuohy needle. However, there was a highly significant (p < 0.001, effsize = 0.949 and p < 0.001, effsize = 0.896) statistical difference observed in the insertion depth where the force peaks of the ligamenta supraspinale and flavum were detected between the measurements on the human specimens and the patient phantom. Within this work, biomechanical evidence was identified for the needle insertion force into human specimens. The comparison of the measured values of the human vertebral segments and the artificial patient phantom showed promising results.
The ancient Egyptians considered the heart to be the most important organ. The belief that the heart remained in the body is widespread in the archeological and paleopathological literature. The ...purpose of this study was to perform an overview of the preserved intrathoracic structures and thoracic and abdominal cavity filling, and to determine the prevalence and computed tomography (CT) characteristics of the myocardium in the preserved hearts of ancient Egyptian mummies. Whole‐body CT examinations of 45 ancient Egyptian mummies (23 mummies from the Ägyptisches Museum und Papyrussammlung, Berlin, Germany, and 22 mummies from the Museo Egizio, Turin, Italy) were systematically assessed for preserved intrathoracic soft tissues including various anatomical components of the heart (pericardium, interventricular septum, four chambers, myocardium, valves). Additionally, evidence of evisceration and cavity filling was documented. In cases with identifiable myocardium, quantitative (measurements of thickness and density) and qualitative (description of the structure) assessment of the myocardial tissue was carried out. Heart structure was identified in 28 mummies (62%). In 33 mummies, CT findings demonstrated evisceration, with subsequent cavity filling in all but one case. Preserved myocardium was identified in nine mummies (five male, four female) as a mostly homogeneous, shrunken structure. The posterior wall of the myocardium had a mean maximum thickness of 3.6 mm (range 1.4–6.6 mm) and a mean minimum thickness of 1.0 mm (range 0.5–1.7 mm). The mean Hounsfield units (HU) of the myocardium at the posterior wall was 61 (range, 185–305). There was a strong correlation between the HU of the posterior wall of the myocardium and the mean HU of the muscles at the dorsal humerus (R = 0.77; p = 0.02). In two cases, there were postmortem changes in the myocardium, most probably due to insect infestation. To our knowledge, this is the first study to investigate the myocardium systematically on CT scans of ancient Egyptian mummies. Strong correlations between the densities of the myocardium and skeletal muscle indicated similar postmortem changes of the respective musculature during the mummification process within individual mummies. The distinct postmortem shrinking of the myocardium and the collapse of the left ventriclular cavity in several cases did not allow for paleopathological diagnoses such as myocardial scarring.
Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper‐transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B ...variant in a number of patients with WD. Synonymous single‐nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10−6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10−5; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.
Wilson disease is caused by recessive pathogenic variants in ATP7B. In a subgroup of patients no or only one genetic defect can be identified. The present study shows that one in 100 patients with WD have a synonymous (silent) genetic variant, which had not been previously recognized as disease‐causing. This variant causes alternative splicing resulting, predicted to result in an in‐frame deletion of 78 residues of the ATP7B protein.
Summary
Background
Primary warm autoimmune hemolytic anemia (WAIHA) is a rare autoimmune disorder frequently responding to corticosteroid first-line treatment and effective second-line treatment ...options such as splenectomy or anti-CD20 antibody therapy. Disease management is frequently hampered by a lack of evidence.
Methods
We have investigated the probability of sustained treatment-free remission after steroid induction to facilitate clinical decision making regarding timing and necessity of second-line treatments. Response data from 31 patients with primary WAIHA initially treated with steroids were retrospectively analyzed. All patients responded by achieving a hemoglobin of at least 10 mg/dl.
Results
After steroid tapering and final withdrawal, 9 of 30 patients remained in unsustained complete remission (CR). The probability of remaining in CR after steroid treatment only was 38.2 % (2 SD 20.6 %) at 15 months. The median remission duration was 100 + months with a range of 12 + to 163 + months. Of note, none of the remaining patients still on steroids achieved CR beyond 15 + months.
Conclusion
These data indicate that a considerable proportion of patients do not need further treatment and that relapses will not occur after 15 months in CR.
Biomechanical study on cadaveric bones using physiological loading conditions to quantify interfragmentary movements in a tibial shaft fracture model fixed by intramedullary nailing.
Six fresh frozen ...human cadaveric tibiae were sequentially tested in axial, torsional, 4-point bending, and shear loading configurations. Tests were performed in intact specimens and osteotomized specimens equipped with interlocked intramedullary nails. The amount of clearance of the nail within the intramedullary canal was measured on computed tomography scans. Linear and angular deformations of the fragments were continuously measured in all directions to obtain the exact interfragmentary movements.
The amount of movement at the site of the fracture was substantial. Especially shear and torsion resulted in gap movements of up to 10 mm. Movements in the transverse plane were significantly larger than axial movements for all loading conditions. For torsion and bending, a significant portion of the movement of the fracture gap resulted from the flexibility of the intramedullary nail; for compression and shear, the majority of the movement was related to the clearance of the nail within the bone.
Clearance of the implant within the medullary canal, the flexibility of the implant itself, and the compliance of the implant (nail and locking screws) within the bone determine the extent of movement. The implant flexibility and the clearance are strongly dependent on the thickness of the intramedullary nail.
Objective
To define the number and distribution of osteophytes (OPs) in bilateral knee MRI (magnetic resonance imaging) of patients with unilateral anterior cruciate ligament (ACL) rupture.
Materials ...and methods
Bilateral knee MRIs of 20 patients with unilateral ACL rupture and reconstruction were retrospectively analyzed for OPs. OPs were graded following the KOSS (knee OA scoring system) classification and their compartmental distribution was assessed following the WORMS (Whole-Organ Magnetic Resonance Imaging Score) classification.
Results
All examined knees revealed OPs. Knees with ACL rupture showed significant (
p
< 0.001) higher total numbers of OPs (mean 11.6; SD ± 4.4) than knees with intact ACL (mean 5.1; SD ± 2.3). Knees with ACL rupture showed increased OP formation in all knee compartments with predominance of marginal OPs in the lateral femorotibial compartment especially on the tibia.
Conclusions
Our results show that after knee injury with ACL rupture and reconstruction, all knee compartments were involved in post-traumatic increase of OP formation. The most affected compartment was the lateral femorotibial compartment on the tibial side.
Summary
A total of 20 patients with cold antibody hemolytic anemia were evaluated in a retrospective study of them, 15 had a monoclonal gammopathy of unknown significance (MGUS): 14 with MGUS of ...immunoglobulin M (IgM) subtype and 1 with immunoglobulin G subtype. One patient had smoldering Waldenström’s macroglobulinemia, but four patients had no monoclonal protein and no evidence of lymphoma. However, in three of these patients, we were able to demonstrate a (mono-)clonal rearrangement of their immunoglobulin heavy and/or light chains. Of the 20 patients, 5 had IgHV34 nucleotide sequence indicating that the antibody was directed against the “I” antigen. Two patients exhibited a progressive increase of IgM over time, however without increasing hemolytic activity. Moreover, in two patients with long-term follow-up, we were able to correlate recurrent hemolytic activity with low environmental temperatures. Among four patients treated with rituximab, all four responded to treatment. However, treatment effect was only transient in all of them.
The underlying mechanism of the prothrombotic state associated with the lupus anticoagulant (LAC) has not been fully elucidated. Evidence suggests involvement of inflammation in arterial and venous ...thrombosis, and it may be hypothesized that subclinical inflammation aggravates the tendency to thrombosis in patients with LAC.
Levels of high sensitivity C-reactive protein (hs-CRP), fibrinogen, and factor VIII (VIII) were measured in 38 patients with LAC and a history of thrombosis, 27 with LAC and no history of thrombosis, and 33 healthy controls.
Hs-CRP, fibrinogen, and factor VIII levels were significantly higher in patients with LAC with thrombosis (hs-CRP median = 0.3 mg/dl, interquartile range, IQR, 0.11-0.62, p < 0.001 vs controls; fibrinogen mean = 395 +/- 90 SD mg/dl, p < 0.001; factor VIII mean = 181 +/- 50%, p = 0.005) as well as in those without thrombosis (median = 0.21, IQR 0.10-0.12, p < 0.001; mean = 378 +/- 91, p = 0.003; mean = 179 +/- 39, p = 0.015) compared to controls (median = 0.07, IQR 0.03-0.12; mean = 308 +/- 48; mean = 137 +/- 39). After adjustment for age, body mass index, smoking status, and blood group (only for factor VIII) the differences between LAC groups and controls remained significant, except for the comparison of fibrinogen between patients without thrombosis and controls. The association between LAC and markers of inflammation was confirmed using linear regression analysis. Markers of systemic inflammation did not differentiate between LAC patients with and without thrombosis (p = 0.829 for hs-CRP, p = 0.649 for fibrinogen, p = 0.996 for factor VIII).
Our results show that LAC is associated with an inflammatory state. However, there was no evidence for an association between inflammatory markers and thromboembolism in patients with LAC.
PDF
