Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density

Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 μg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a −0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (−4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 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).     

Oxygen-mediated enhancement of primary hepatocyte metabolism,functional polarization,gene expression,and drug clearance

The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R² of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures.     

Directional Stimulation in Parkinson's Disease and Essential Tremor: The Cleveland Clinic Experience

ObjectiveTo assess use of directional stimulation in Parkinson's disease and essential tremor patients programmed in routine clinical care.Materials and MethodsPatients with Parkinson's disease or essential tremor implanted at Cleveland Clinic with a directional deep brain stimulation (DBS) system from November 2017 to October 2019 were included in this retrospective case series. Omnidirectional was compared against directional stimulation using therapeutic current strength, therapeutic window percentage, and total electrical energy delivered as outcome variables.ResultsFifty-seven Parkinson's disease patients (36 males) were implanted in the subthalamic nucleus (105 leads) and 33 essential tremor patients (19 males) were implanted in the ventral intermediate nucleus of the thalamus (52 leads). Seventy-four percent of patients with subthalamic stimulation (65% of leads) and 79% of patients with thalamic stimulation (79% of leads) were programmed with directional stimulation for their stable settings. Forty-six percent of subthalamic leads and 69% of thalamic leads were programmed on single segment activation. There was no correlation between the length of microelectrode trajectory through the STN and use of directional stimulation.ConclusionsDirectional programming was more common than omnidirectional programming. Substantial gains in therapeutic current strength, therapeutic window, and total electrical energy were found in subthalamic and thalamic leads programmed on directional stimulation.     

Myocardial perfusion imaging with technetium-99m sestamibi SPECT in the evaluation of coronary artery disease

Technetium-99m hexakis-2-methoxy-isobutyl-isonitrile(^99mTc sestamibi) has been used for myocardial perfusion imaging in the evaluation of coronary artery disease (CAD) since 1990. The experience of its use in an Asian population with and without previous myocardial infarction (Ml), diabetes mellitus (DM), hypertension (HPT) and collateral circulation (COL) is reported. One hundred and thirty-nine patients who underwent treadmill exercise testing with ^99mTc sestamibi single photon emission computed tomography (SPECT) and coronary angiogram were studied. The overall sensitivity for the detection of CAD was 91.0% and specificity was 64.7%. For patients without previous myocardial infarction, the sensitivity was 83.8% and specificity was 83.3%. Patients with COL had a higher sensitivity while those with HPT had a lower specificity. Sensitivity was higher in patients with multi-vessel disease (MVD) than single vessel disease (SVD). The overall detection for individual artery stenosis was 74.1% with a specificity of 73.1 %. Amongst the three major coronary arteries, sensitivity was highest for the right coronary artery and specificity was highest for the left circumflex artery. Specificity was higher in patients without MI or COL. We found that the agreement between ^99mTc sestamibi SPECT and coronary angiogram for the extent of CAD was only 52.5%. The concordance rate was higher for patients with MVD than SVD. It is concluded that ^99mTc sestamibi SPECT is a sensitive and specific test for the detection of CAD and localization of disease to individual coronary arteries in our patients with some differences in the subgroups. Agreement between coronary angiogram and ^99mTc sestamibi for the extent of coronary artery disease was also satisfactory.     

One-year audit of admissions to the Intensive Care Unit of the Queen Elizabeth Central Hospital,Blantyre

The intensive care unit at Queen Elizabeth Central Hospital (QECH) has 4 beds and offers level 2 care. A retrospective audit of all admissions to the unit during 2002 was carried out. There were a total of 339 admissions giving a bed occupancy rate of 82 %. Surgical patients made up 81 % of admissions. 45% of all admissions were ventilated. Overall mortality was 38%. Ventilated patients had a mortality of 71% compared with 10% for non-ventilated. Data are also presented for mortality within the surgical and paediatric surgical admissions.     

Mediastinal and hilar fibrosis

A case is described of mediastinal and hilar fibrosis in a woman aged 22 years. The fibrotic mass compressed the lobar arteries as well as the veins of various lobes of both lungs. These large vessels as well as numerous smaller arteries and veins were to a large extent obstructed by organized thrombi. It seems likely that 3 years after the beginning of symptoms the fibrosing process was still active. The case provides some support for an immunopathological aetiology of this condition.     

Cyclin D1 amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors

OBJECTIVES/HYPOTHESIS: Cyclin D1, a cell cycle regulator localized to chromosome 11q13, is amplified in several human tumors including head and neck squamous cell carcinoma (HNSCC). Amplification and/or overexpression of cyclin D1 have been correlated to a poor prognosis. Deletion of the p16 gene, localized to 9p21, has also been observed in a significant proportion of HNSCC. The p16 gene regulates cyclin D1-CDK4 activity and prevents retinoblastoma tumor suppressor gene phosphorylation, thereby downregulating cellular proliferation. Detection of cyclin D1 amplification and p16 deletion using a simple and sensitive method will be valuable for the development of effective treatment modalities for head and neck cancer. STUDY DESIGN: We have used fluorescence in situ hybridization (FISH) to study cyclin D1 amplification and p16 gene deletion in head and neck tumors. Both single- and dual-color FISH were performed. METHODS: Paraffin-embedded tissues from 103 patients with HNSCC were analyzed using genomic DNA probes for cyclin D1 and p16. Dual-color FISH was performed with chromosome 11 or 9 centromeric probes as a control. Twenty-eight of these samples were analyzed for p16 expression by immunohistochemistry. RESULTS: Cyclin D1 amplification was observed in 30% (31/103) of patients, and p16 deletion in 52% (54/103). Lack of p16 expression was observed in 64% (18/28) of patients. There was a good correlation between the deletion of p16 sequences and the loss of p16 expression (P = .008). Amplification of cyclin D1 had a statistically significant association with recurrence, distant metastasis, and survival at 36 months. There was a significant association between p16 deletion and the development of distant metastases. Cyclin D1 amplification and p16 deletion together correlated with recurrence, distant metastasis, and survival. CONCLUSIONS: We demonstrate that FISH is a simple and sensitive method for detecting cyclin D1 amplification and p16 deletion in head and neck cancer. Our results suggest that these two genetic aberrations together portend a poorer outcome than either of the abnormalities alone in head and neck cancer.     

Unexplained diarrhoea and failure to thrive in 2 siblings with unusual facies and abnormal scalp hair shafts: a new syndrome

A family is described in which 2 siblings born to healthy parents presented with abnormal facies, persistent diarrhoea, and early death. Exhaustive pathological and biochemical investigations failed to find a cause. The scalp hair of both babies had an abnormal amino-acid composition, and presented an appearance that was unique on scanning electron microscopical examination; this fact and the clinical picture probably represents a new syndrome.     

Predicting Hip Fracture Type With Cortical Bone Mapping (CBM) in the Osteoporotic Fractures in Men (MrOS) Study

Hip fracture risk is known to be related to material properties of the proximal femur, but fracture prediction studies adding richer quantitative computed tomography (QCT) measures to dual‐energy X‐ray (DXA)‐based methods have shown limited improvement. Fracture types have distinct relationships to predictors, but few studies have subdivided fracture into types, because this necessitates regional measurements and more fracture cases. This work makes use of cortical bone mapping (CBM) to accurately assess, with no prior anatomical presumptions, the distribution of properties related to fracture type. CBM uses QCT data to measure the cortical and trabecular properties, accurate even for thin cortices below the imaging resolution. The Osteoporotic Fractures in Men (MrOS) study is a predictive case‐cohort study of men over 65 years old: we analyze 99 fracture cases (44 trochanteric and 55 femoral neck) compared to a cohort of 308, randomly selected from 5994. To our knowledge, this is the largest QCT‐based predictive hip fracture study to date, and the first to incorporate CBM analysis into fracture prediction. We show that both cortical mass surface density and endocortical trabecular BMD are significantly different in fracture cases versus cohort, in regions appropriate to fracture type. We incorporate these regions into predictive models using Cox proportional hazards regression to estimate hazard ratios, and logistic regression to estimate area under the receiver operating characteristic curve (AUC). Adding CBM to DXA‐based BMD leads to a small but significant (p < 0.005) improvement in model prediction for any fracture, with AUC increasing from 0.78 to 0.79, assessed using leave‐one‐out cross‐validation. For specific fracture types, the improvement is more significant (p < 0.0001), with AUC increasing from 0.71 to 0.77 for trochanteric fractures and 0.76 to 0.82 for femoral neck fractures. In contrast, adding DXA‐based BMD to a CBM‐based predictive model does not result in any significant improvement. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.