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Unlabelled: A 41-year-old male sustained a massive crushing injury to his left posterior thigh and buttock and transection of the sciatic nerve; he underwent an above-knee amputation with fillet flap. He was interviewed 24 months postoperatively to determine his phantom limb experience. At 37 and 42 months, testing for touch-pressure sensitivity of the residual limb and buttock was done with a 1-gram monofilament.Results: (1) He described a typical phantom limb with some unusual features. (2) Stimulation of points on transposed and original skin were located accurately or roughly according to normal anatomy, were mislocated, or felt simultaneously at the point stimulated and another place, i.e., bilocations. It is hypothesized that such mislocations and bilocations represented clinical correlates of cortical somatosensory reorganization. It is not clear why a typical phantom limb could occur when there was only partial deafferentation of the limb. Further studies are recommended. [ABSTRACT FROM AUTHOR]

Background: Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes. Methods: Toxicities (≥ grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes. Results: Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136). Conclusions: This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib. [ABSTRACT FROM AUTHOR]

Background: The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. Methods: CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson x² test, Kaplan-Meier curves and Log-rank test. Results: Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. Conclusions: CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine if the C421A single nucleotide polymorphism (SNP) in the ATP-binding cassette transporter ABCG2 increases prostate cancer risk or affects survival. PATIENTS, SUBJECTS AND METHODS Numerous studies have suggested that dietary, hormonal and environmental factors all play a role in the initiation in prostate cancer; among these, the carcinogenic heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a known substrate of the ABCG2. A SNP of ABCG2, C421A, resulting in a glutamine to lysine change at amino acid 141, has been shown to result in decreased function of the protein. Due to the expression of ABCG2 in the prostate, together with the purported role of dietary carcinogens and steroids in the development and progression of prostate cancer, 311 individuals were genotyped for the ABCG2 C421A SNP, 170 patients with androgen-independent prostate cancer (AIPC) and 141 ‘healthy’ controls. We also evaluated the effect of this SNP on the intracellular accumulation of PhIP and testosterone in vitro. RESULTS There were no significant differences in the prevalence of prostate cancer based on ABCG2 genetic variation in this population. However, survival was significantly longer for individuals with wild-type ABCG2, as compared with those hetero- or homozygous for the C421A SNP (7.4 years vs 5.3 years, P = 0.044). Intracellular accumulation of PhIP was 80% higher in HEK293 cells transfected with Q141K ABCG2 than in wild-type cells, confirming that this SNP decreases transport of PhIP. In contrast, testosterone was not transported by either wild-type or variant transfected cells, nor did it act as in inhibitor of ABCG2 in subsequent transport assays. CONCLUSION Increased exposure to PhIP may decrease survival, but the ABCG2 C421A polymorphism does not appear to increase the risk of prostate cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine if patients with advanced prostate cancer carrying a polymorphism that codes for a more active testosterone transporter have less durable responses to androgen-deprivation therapy (ADT) than patients not carrying this polymorphism. PATIENTS AND METHODS We previously determined that a polymorphism in SLCO1B3 affects testosterone transport and that those men who have at least one wild-type T allele at the 334 T > G polymorphism in this gene have a shorter survival. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to prostate-specific antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure with no metastatic disease (D0). RESULTS When examined separately, patients in the individual stages tended to have a shorter time to androgen independence with the T allele in the D0 ( P = 0.11) and D2 ( P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically significant shorter time to androgen independence with the T allele ( P = 0.048). CONCLUSION A polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in patients with prostate cancer who are treated with ADT. [ABSTRACT FROM AUTHOR]

Objectives: Deoxyribonucleic acid (DNA) extraction from blood and genotyping for candidate single nucleotide polymorphisms (SNP) is now an important part of almost all molecular epidemiologic studies. However, in many studies the amount of blood sample is limited or only serum is available. We conducted several pilot studies to identify methods for DNA extraction and high-throughput SNP genotyping of both white blood cell (WBC) and serum DNA that can be done centrally and reliably for large numbers of samples. Methods: We used biospecimens from the Prostate Cancer Prevention Trial (PCPT), a phase III, double-blind, placebo-controlled trial that tested the efficacy of finasteride for the primary prevention of prostate cancer. DNA was extracted from WBCs, from serum, and also from serum after organic solvent extraction for analysis of hormones. We also conducted blinded high-throughput genotyping in three laboratories to assess feasibility and reliability of results with differing methodologies using DNA from WBCs and from serum. Results: Genotyping of DNA extracted from WBCs resulted in highly reliable, reproducible results across laboratories using different genotyping platforms. However, genotyping with DNA extracted from serum did not provide reliable data using high-throughput multiplex approaches such as Sequenom (hME and iPLEX) and Applied Biosystems SNPlex, but was successful using Taqman. Conclusions: Based on the results of these pilot studies, we conclude that DNA obtained from serum must be used judiciously, and that genotyping using multiplex methods is not suitable for serum DNA. [Copyright &y& Elsevier]

OBJECTIVE To investigate how thalidomide confers its survival benefit in prostate cancer, by assessing its effect on circulating endothelial cells (CECs) and progenitors (CEPs) in a combined therapy of thalidomide and chemotherapy drugs in a human prostate cancer xenograft model, as in clinical trials patients treated with both thalidomide and docetaxel had a >50% decrease in prostate-specific antigen (PSA) levels and longer median overall survival than those treated with docetaxel monotherapy. MATERIALS AND METHODS A human prostate cancer xenograft model was used to evaluate the effect of either thalidomide, docetaxel or a combination of the two drugs on circulating ECs. Drug treatment was continued for 17 days, and tumours were measured two or three times a week. Blood samples were taken at three different time points: before the treatments, 4 days and 17 days into the treatments, and CECs and CEPs were measured by flow cytometry analysis. RESULTS There was an increased level of apoptotic/dead CECs shortly after the intravenous injection of docetaxel, and the addition of thalidomide further increased the apoptotic/dead CEC level, showing that thalidomide enhances the cytotoxicity of docetaxel against tumour vascular ECs. CONCLUSION Thalidomide increased the apoptotic/dead CEC level and enhanced the cytotoxicity of docetaxel against tumour vascular ECs, confirming its antiangiogenic property in vivo in combined anticancer treatments. In addition, there was a correlation between the increased apoptotic/dead CEC levels early in the treatment and antitumour efficacy later, suggesting that the apoptotic/dead CEC level could be used as a marker, at an early stage, to predict tumour response to antiangiogenic therapies. [ABSTRACT FROM AUTHOR]

Following the discovery of its anti-angiogenic properties and despite its tragic history, thalidomide has re-surfaced in the field of oncology. Concurrent with its evaluation in various clinical trials for cancer, thalidomide''s mechanism of action is sought and new analogues with improved efficacy and pharmacological profile are emerging. This review is a critical evaluation of thalidomide metabolism, molecular targets, anti-angiogenic activity and clinical efficacy with an emphasis on metastatic prostate cancer. [Copyright &y& Elsevier]

Presents several letters concerning medicine. Incidence of bacteremia in children with febrile convulsions; Case report of polyradiculitis associated with mycoplasma pneumoniae reversed by plasma exchange; Evidence of reduced sinus arrhythmia in diabetic autonomic neuropathy.

Mouse models of hyper- and hypothyroidism were used to examine the effects of thyroid hormone (TH) dyshomeostasis on the aging mammalian brain. 13-14 month-old mice were treated for 4months with either levothyroxine (hyperthyroid) or a propylthiouracil and methimazole combination (PTU/Met; hypothyroid). Hyperthyroid mice performed better on Morris Water Maze than control mice, while hypothyroid mice performed worse. Brain weight was increased in thyroxine-treated, and decreased in PTU/Met-treated animals. The brain weight change was strongly correlated with circulating and tissue T4. Quantitative measurements of microvessels were compared using digital neuropathologic methods. There was an increase in microvessel area in hyperthyroid mice. Hypothyroid mice showed a trend for elevated glial fibrillary acidic protein-immunoreactive astrocytes, indicating an increase in neuroinflammation. Gene expression alterations were associated with TH perturbation and astrocyte-expressed transcripts were particularly affected. For example, expression of Gli2 and Gli3, mediators in the Sonic Hedgehog signaling pathway, were strongly impacted by both treatments. We conclude that TH perturbations produce robust neurobehavioral, pathological, and brain gene expression changes in aging mouse models., Competing Interests: Disclosure statement The authors have no actual or potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD., (© 2019 American Association of Neuropathologists, Inc.)

Mild cognitive impairment (MCI) is considered to be an early stage in the progression of Alzheimer's disease (AD) providing an opportunity to investigate brain pathogenesis prior to the onset of dementia. Neuroimaging studies have identified the posterior cingulate gyrus (PostC) as a cortical region affected early in the onset of AD. This association cortex is involved in a variety of different cognitive tasks and is intimately connected with the hippocampal/entorhinal cortex region, a component of the medial temporal memory circuit that displays early AD pathology. We quantified the total number of synapses in lamina 3 of the PostC using unbiased stereology coupled with electron microscopy from short postmortem autopsy tissue harvested from cases at different stage of AD progression. Individuals in the early stages of AD showed a significant decline in synaptic numbers compared to individuals with no cognitive impairment (NCI). Subjects with MCI exhibited synaptic numbers that were between the AD and NCI cohorts. Adjacent tissue was evaluated for changes in both pre and postsynaptic proteins levels. Individuals with MCI demonstrated a significant loss in presynaptic markers synapsin-1 and synaptophysin and postsynaptic markers PSD-95 and SAP-97. Levels of [3H]PiB binding was significantly increased in MCI and AD and correlated strongly with levels of synaptic proteins. All synaptic markers showed a significant association with Mini-Mental Status Examination scores. These results support the idea that the PostC synaptic function is affected during the prodromal stage of the disease and may underlie some of the early clinical sequelae associated with AD.

Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer's disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total synapses compared to the NCI cohort while the AD group did show a modest but significant decline. Synaptic numbers failed to correlate with several different cognitive tasks including the Mini-Mental State Examination scores and episodic memory scores. Although levels of [3H]PiB binding were elevated in both the aMCI and AD groups, it did not strongly correlate with synaptic counts. These results support the idea that despite increased amyloid load, the precuneus region does not show early changes in synaptic decline during the progression of AD.

One of the major neuropathological findings in the brains of individuals with Alzheimer's disease (AD) is a loss of synaptic contacts in both the neocortex and hippocampus. Here we report, for the first time, an estimate of the total number of synapses in the outer molecular layer (OML) of the human dentate gyrus, in individuals with early Alzheimer's disease (eAD), mild cognitive impairment (MCI), or no cognitive impairment (NCI). An unbiased stereologic sampling scheme coupled with transmission electron microscopy to directly visualize synaptic contacts, was used to estimate the total number of synapses in short postmortem autopsy tissue. Individuals with eAD had significantly fewer synapses than the other two diagnostic groups. Seventy-five percent of the individuals with MCI had synaptic values that were lower than the NCI group mean. The number of synapses showed a significant correlation with the subject's Mini-Mental State score and with cognitive tests involving delayed recall. Synaptic loss showed no relationship to Braak stage or to apoE genotype. The volume of the OML was significantly reduced in eAD compared to the other two diagnositic groups that were not different from each other. These data suggest that a loss of afferents from the entorhinal cortex underlie the synapse loss seen in eAD. This study supports the concept that synapse loss is an early event in the disease process and suggests that MCI may be a transition stage between eAD and NCI with synaptic loss a structural correlate involved in cognitive decline.

Alzheimer's disease (AD) is a progressive disorder that is characterized by the accumulation of neuropathologic lesions and neurochemical alterations. Ultrastructural investigations in many association regions of the neocortex and the hippocampal dentate gyrus have demonstrated a disease-related decline in numerical synaptic density. This decline in brain connectivity occurs early in the disease process and strongly correlates with the cognitive decline observed in AD. The synapse loss does not appear to be an inevitable consequence of the aging process. This article reviews the ultrastructural studies assessing AD-related synaptic loss and the possible compensatory changes in the synaptic complex that occur as a result of the loss in brain connectivity.

Morphologic studies of the neuropathology in Alzheimer's disease (AD) have demonstrated significant loss of synaptic connectivity in many regions of the neocortex and hippocampus. The strongest correlation with cognitive decline in AD is with the synaptic density. This article discusses the ultrastructural studies that have documented changes in synaptic numbers in many areas of association cortex and in the hippocampal dentate gyrus molecular layer. Changes in the synaptic complex are discussed as a possible compensatory mechanism in response to synapse loss and a model is proposed to help relate the significance of these synaptic changes. Comparisons are made between results observed with ultrastructural technique and those utilizing immunohistochemistry to assess changes in synaptic pathology. Possible reasons underlying the synaptic neuropathology are discussed.

Synapse loss is considered a profound neuropathology associated with Alzheimer's disease (AD). This AD-related change in connectivity can be demonstrated in many regions of the neocortex. The posterior cingulate cortex has been identified as an area involved early in the disease process but has not been well studied. The anterior cingulate cortex, which is morphologically distinct from the posterior cingulate, is also involved in AD. The present study employed ultrastructural techniques to assess synaptic numbers in these two regions of association cortex. Both cingulate areas demonstrated a significant loss in lamina III in AD, while only the posterior cingulate manifested a loss in lamina V. The failure to find a significant change in lamina V of the anterior cingulate may be related to its connectivity with the motor system. The heterogeneity of synaptic change in this cortical region may reflect important information concerning corticocortico connectivity changes in AD.