Histomorphometry of bone marrow biopsies in primary osteomyelofibrosis/-sclerosis (agnogenic myeloid metaplasia) - correlations between clinical and morphological features

Summary Histomorphometry was performed on representative trephine biopsies of the bone marrow on admission of 50 patients (21 male, 29 female-age 67 years) with so-called primary osteomyelofibrosis/-sclerosis (OMF) not preceded by any other subtype of chronic myeloproliferative disorders. This study was firstly aimed at testing correlations between histological features (amount of haematopoiesis, cytological aspects of mega-karyocytes, density of reticulin and collagen fibres and degree of osteosclerosis) and laboratory data, as well as spleen size and duration of relevant prediagnostic symptoms. Secondly, we concentrated on a discrimination of OMF patients into two sub-groups according to bone marrow morphology and clinical variables. Statistical evaluation of histomorphometric variables and haematological findings disclosed that there was a progressive fibro-osteosclerotic process in the evolution of disease features. Increase in medullary fibrosis was significantly paralleled by an abnormal or pleomorphic megakaryopoiesis in the bone marrow: there was an increase in irregularity of perimeters for megakaryocytes and naked nuclei combined with smaller sizes of these elements including the nuclei. Additionally, there was a greater number of pycnotic bare nuclei. A number of morphometric features (density of fibres, degree of osteosclerosis, amount of haematopoiesis) were associated with corresponding clinical data (spleen size, length of preclinical history). By consideration of a set of basic histomorphometric variables our co-hort of 50 patients could be divided into an early hyperplastic subtype with no or minimal medullary reticulin and another group with conspicuous fibrotic and osteosclerotic alterations of the bone marrow. It was noticeable that we found no significant correlation between amount of haematopoiesis or marrow cellularity with splenomegaly. This result suggests that splenic haematopoiesis (myeloid metaplasia) may represent an autonomous or neoplastic process and not only compensation for a failing fibro-osteosclerotic bone marrow.Supported by a grant from the Deutsche Forschungsgemeinschaft (DFG-Th 390/1-1)     

Breast cancer risk associated with ovulation-stimulating drugs

BACKGROUND: Despite the recognized role of hormones in the aetiology of breast cancer, there has been little evaluation of hormonal preparations used to treat infertility. METHODS: A retrospective cohort study of 12,193 women evaluated for infertility between 1965 and 1988 at five clinical sites identified 292 in situ and invasive breast cancers in follow-up through 1999. Standardized incidence ratios (SIRs) compared breast cancer risks with those of the general population. Analyses within the cohort estimated rate ratios (RRs) associated with medications after adjustment for other breast cancer predictors. RESULTS: Infertile patients had a significantly higher breast cancer risk than the general population [SIR = 1.29, 95% confidence interval (CI) 1.1-1.4]. Analyses within the cohort showed adjusted RRs of 1.02 for clomiphene citrate and 1.07 for gonadotrophins, and no substantial relationships to dosage or cycles of use. Slight and non-significant elevations in risk were seen for both drugs after > or = 20 years of follow-up (RRs = 1.39 for clomiphene and 1.54 for gonadotrophins). However, the risk associated with clomiphene for invasive breast cancers was statistically significant (RR = 1.60, 95% CI 1.0-2.5). CONCLUSIONS: Although there was no overall increase in breast cancer risk associated with use of ovulation-stimulating drugs, long-term effects should continue to be monitored.     

Postnatal development of synaptic transmission in local networks of L5A pyramidal neurons in rat somatosensory cortex

The probability of synaptic transmitter release determines the spread of excitation and the possible range of computations at unitary connections. To investigate whether synaptic properties between neocortical pyramidal neurons change during the assembly period of cortical circuits, whole-cell voltage recordings were made simultaneously from two layer 5A (L5A) pyramidal neurons within the cortical columns of rat barrel cortex. We found that synaptic transmission between L5A pyramidal neurons is very reliable between 2 and 3 weeks of postnatal development with a mean unitary EPSP amplitude of ∼1.2 mV, but becomes less efficient and fails more frequently in the more mature cortex of ∼4 weeks of age with a mean unitary EPSP amplitude of 0.65 mV. Coefficient of variation and failure rate increase as the unitary EPSP amplitude decreases during development. The paired-pulse ratio (PPR) of synaptic efficacy at 10 Hz changes from 0.7 to 1.04. Despite the overall increase in PPR, short-term plasticity displays a large variability at 4 weeks, ranging from strong depression to strong facilitation (PPR, range 0.6–2.1), suggesting the potential for use-dependent modifications at this intracortical synapse. In conclusion, the transmitter release probability at the L5A–L5A connection is developmentally regulated in such a way that in juvenile animals excitation by single action potentials is efficiently transmitted, whereas in the more mature cortex synapses might be endowed with a diversity of filtering characteristics.     

Human Diversity of Killer Cell Immunoglobulin-Like Receptors and Human Leukocyte Antigen Class I Alleles and Ebola Virus Disease Outcomes

We investigated the genetic profiles of killer cell immunoglobulin-like receptors (KIRs) in Ebola virus–infected patients. We studied the relationship between KIR–human leukocyte antigen (HLA) combinations and the clinical outcomes of patients with Ebola virus disease (EVD). We genotyped KIRs and HLA class I alleles using DNA from uninfected controls, EVD survivors, and persons who died of EVD. The activating 2DS4–003 and inhibitory 2DL5 genes were significantly more common among persons who died of EVD; 2DL2 was more common among survivors. We used logistic regression analysis and Bayesian modeling to identify 2DL2, 2DL5, 2DS4–003, HLA-B-Bw4-Thr, and HLA-B-Bw4-Ile as probably having a significant relationship with disease outcome. Our findings highlight the importance of innate immune response against Ebola virus and show the association between KIRs and the clinical outcome of EVD.     

Can Met Expectations Moderate the Relationship Between Pain/Function and Satisfaction in Total Knee Arthroplasty?

BackgroundApproximately 20% of patients are dissatisfied with their total knee arthroplasty (TKA) at 1-year post-surgery. Met expectations have been found by some to significantly predict satisfaction. The role of met expectations in determining patient satisfaction has not been exhaustively explored. The primary aim of this study is to evaluate if met expectations moderate the relationship between pain and function variables and satisfaction.MethodsPatients who underwent primary TKA for osteoarthritis were included in the study (n = 304). Patient-reported outcomes at pre-surgery and 1-year post-surgery were collected. The Knee Society Score (KSS) satisfaction subscale was used as the dependent variable. Candidate independent variables included the following: demographics, KSS, Knee injury and Osteoarthritis Outcome Score (KOOS), 12-Item Short Form Health Survey (SF-12), Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, Self-Administered Comorbidity Questionnaire, and University of California Los Angeles activity score. Separate linear regression models were created to test interactions for KSS met expectations with pain and KSS met expectations with function.ResultsSignificant predictors of satisfaction were KSS symptoms (pain), KOOS activities of daily living (function), KSS met expectations, KOOS pre-surgery activities of daily living, body mass index, and SF-12 general health. A significant interaction between met expectations and pain was found (P = .043) and the met expectations and function interaction approached significance (P = .086). For both interactions, as met expectations increased, pain and function predicted satisfaction less strongly.ConclusionMet expectations were found to moderate the relationship between pain and satisfaction. There may be more value in improving pain for patients with low met expectations.Level of evidenceLevel IV.     

A Novel HR-pQCT Image Registration Approach Reveals Sex-Specific Changes in Cortical Bone Retraction With Aging

During aging, changes in endosteal and periosteal boundaries of cortical bone occur that differ between men and women. We here develop a new procedure that uses high-resolution peripheral quantitative CT (HR-pQCT) imaging and 3D registration to identify such changes within the timescale of longitudinal studies. A first goal was to test the sensitivity of the approach. A second goal was to assess differences in periosteal/endosteal expansion over time between men and women. Rigid 3D registration was used to transform baseline and all follow-up (FU) images to a common reference configuration for which the region consisting of complete slices (largest common height) was determined. Periosteal and endosteal contours were transformed to the reference position to determine the net periosteal and endosteal expansion distances. To test the sensitivity, images from a short-term reproducibility study were used (15 female, aged 21 to 47 years, scanned three times). To test differences between men and women, images from a subset of the Geneva Retirees Cohort were used (248 female, 61 male, average age 65 years, 3.5 and 7 years FU). The sensitivity study indicated a least significant change for detecting periosteal/endosteal expansion of 41/31 microns for the radius and 17/26 microns for the tibia. Results of the cohort study showed significant net endosteal retraction only in females at the radius and tibia after 3.5 years (38.0 and 38.4 microns, respectively) that further increased at 7 years FU (70.4 and 70.8 microns, respectively). No significant net periosteal changes were found for males or females at 7 years. The results demonstrate that it is possible to measure changes in endosteal contours in longitudinal studies within several years. For the investigated cohort, significant endosteal retraction was found in females but not in males. Whether these changes in cortical geometry are related to fracture risk remains to be investigated in larger cohorts © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Misaligned spinal rods can induce high internal forces consistent with those observed to cause screw pullout and disc degeneration

BACKGROUND CONTEXTManual contouring of spinal rods is often required intraoperatively for proper alignment of the rods within the pedicle screw heads. Residual misalignments are frequently reduced by using dedicated reduction devices. The forces exerted by these devices, however, are uncontrolled and may lead to excessive reaction forces. As a consequence, screw pullout might be provoked and surrounding tissue may experience unfavorable biomechanical loads. The corresponding loads and induced tissue deformations are however not well identified. Additionally, whether the forced reduction alters the biomechanical behavior of the lumbar spine during physiological movements postoperatively, remains unexplored.PURPOSETo predict whether the reduction of misaligned posterior instrumentation might result in clinical complications directly after reduction and during a subsequent physiological flexion movement.STUDY DESIGNFinite element analysis.METHODSA patient-specific, total lumbar (L1–S1) spine finite element model was available from previous research. The model consists of poro-elastic intervertebral discs with Pfirrmann grade-dependent material parameters, with linear elastic bone tissue with stiffness values related to the local bone density, and with the seven major ligaments per spinal motion segment described as nonlinear materials. Titanium instrumentation was implemented in this model to simulate a L4, L5, and S1 posterolateral fusion. Next, coronal and sagittal misalignments of 6 mm each were introduced between the rod and the screw head at L4. These misalignments were computationally reduced and a physiological flexion movement of 15° was prescribed. Non-instrumented and well-aligned instrumented models were used as control groups.RESULTSPulling forces up to 1.0 kN were required to correct the induced misalignments of 6 mm. These forces affected the posture of the total lumbar spine, as motion segments were predicted to rotate up to 3 degrees and rotations propagated proximally to and even affect the L1–2 level. The facet contact pressures in the corrected misaligned models were asymmetrical suggesting non-physiological joint loading in the misaligned models. In addition, the discs and vertebrae experienced abnormally high forces as a result of the correction procedure. These effects were more pronounced after a 15° flexion movement following forced reduction.CONCLUSIONSThe results of this study indicate that the correction of misaligned posterior instrumentation can result in high forces at the screws consistent with those reported to cause screw pullout, and may cause high-tissue strains in adjacent and downstream spinal segments.CLINICAL SIGNIFICANCEProper alignment of spinal posterior instrumentation may reduce clinical complications secondary to unfavorable biomechanics.     

Healthcare Workers’ (HCWs) attitudes towards mandatory influenza vaccination: A systematic review and meta-analysis

Influenza is a disease responsible for thousands of deaths every year. Although healthcare workers (HCWs) represent a way of contagion for patients, vaccination coverage among them is low. Mandatory vaccination has been proposed, but controversies remain. This systematic review and meta-analysis aimed to assess the acceptance of mandatory vaccination by HCWs, and to investigate associated characteristics. MEDLINE, Scopus, Embase, PsycInfo, CINAHL and Web of Science were used to search for studies assessing the topic. PRISMA statements were followed. Of the 13,457 univocal records found, 52 studies were included in the systematic review and 40 in the meta-analysis. The pooled proportion of HCWs accepting the policy was of 61% (95% CI: 53%- 68%) but with great heterogeneity between continents (from 54% in Europe to 69% in Asia) and in different professionals (from 40% in nurses to 80% in students). Vaccinated HCWs agreed more frequently with mandatory vaccination than non-vaccinated ones. More studies that consider mandatory vaccination acceptance as the main outcome are needed, but the results of this study confirm that in some settings the majority of HCWs favour mandatory vaccination. This, combined with effects that a flu epidemic could have if overlapped to pandemics with similar symptoms, requires renewed considerations on mandatory vaccination.     

Primary afferent origin of substance P-containing axons in the superficial dorsal horn of the rat spinal cord: depletion, regeneration and replenishment of presumed nociceptive central terminals

Substance P-like immunoreactivity (SPLI) was localized in the superficial spinal dorsal horn of the rat by means of light and electron microscopic immunocytochemical techniques. Serial immunocytochemical sections were subjected to densitometric measurements with an electronic Image Analyser, and with aid of a computer program, a two-dimensional reconstruction of the fine neuroanatomical structure of the SPLI-active regions of the lumbosacral upper superficial spinal dorsal horn was obtained. SPLI activity in the superficial dorsal horn outlines four well-marked and distinctly differing regions, called, in the mediolateral sequence, areas A, B, C, and D, plus Cajal's noyeau interstitiel ("lateral spinal nucleus" = "nucleus of the dorsolateral fascicle," L). Lumbosacral dorsal rhizotomy results in an almost complete depletion of SPLI from ipsilateral areas A, B, C, and D; it induces decreased SPLI in the area of the lateral spinal nucleus (L), ipsi- or contralaterally in an alternating fashion. Transection of the segmentally related, ipsilateral peripheral nerve induces a marked depletion of SPLI from areas A, B, and C but only a slight decrease in area D and virtually none in the area of L. Whereas a simple crush of the peripheral nerve (axocompression) induces only a slight depletion of SPLI, if any, semiautomatic densitometric analysis of serial immunocytochemical sections proves that a controlled crush injury (axocontusion) results in depletion of SPLI from the upper dorsal horn, similar to transection of the peripheral nerve. Following regeneration of the ipsilateral, segmentally related peripheral nerve, the original immunocytochemical structure of the superficial dorsal horn is re-established by SPLI-positive axonal sprouts originating from previously damaged dorsal root axons.     

Effects of high and low anxiety provoking instructions on the responses to the hyperventilation provocation test

This study examined the effect of high and low anxiety provoking instructions in subjects submitted to a Hyperventilation Provocation Test (HVPT). Subjects were 43 out-patients referred to our clinic for a diagnostic examination of Hyperventilation Syndrome (HVS). Results showed that anxiety levels were affected by the instruction manipulation, but the magnitude of this effect was less than expected and the instruction manipulation had no effect on intensity arid type of reproduced symptoms, nor on symptom recognition. Subjects who met Diagnostic and Statistical manual of Mental Disorders (3rd ed., rev,; American Psychiatric Association, 1987) criteria for Panic Disorder (PD) were not more responsive to the instruction manipulation than non-PD patients. It is argued that the small effect of the manipulation is probably not due to the solidity of the HVPT but to the pervasiveness of pretest cognitions and expectations. In line with this, the report of HVS symptoms appeared highly related to psychological trait measures like anxiety, fear of bodily sensations, and a general tendency to report somatic symptoms.