In this study, we have demonstrated microscopic pathology ranging from minimal to moderate in multiple different tissues previously reported to be involved with LD, including the nervous system (central and peripheral), heart, skeletal muscle, joint-associated tissues, and urinary bladder 12 to 13 months following tick-inoculation of rhesus macaques by Bb strain B31
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Increased preconception omega-3 polyunsaturated fatty acid intake improves embryo morph... - 0 views
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Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Post-Tr... - 0 views
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Based on histomorphology, inflammation consisted predominantly of lymphocytes and plasma cells, with rare scattered histiocytes
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in rare instances, morphologically intact spirochetes were observed in inflamed brain and heart tissue sections from doxycycline-treated animals
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colocalization of the Bb 23S rRNA probe was not observed in any of the sections of experimental inoculated animals shown to harbor rare persistent spirochetes (Supplemental Figure S1). Previous in vitro work has shown large decreases in Bb rRNA levels when in a stationary phase of growth despite the majority of spirochetes remaining viable
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The possibility that the spirochetes were intact but dead also exists, though this may be unlikely given the precedence for viable but non-cultivable B. burgdorferi post-treatment
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The doxycycline dose utilized in this study (5mg/kg) was based on a previous pharmacokinetic analysis of oral doxycycline in rhesus macaques proven to be comparable to levels achieved in humans and was meant to mimic treatment of disseminated LD
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In addition to the brain of two treated animals, rare morphologically intact spirochetes immunoreactive to OspA were observed in the heart of one treated animal
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Although we did not measure the doxycycline levels in the cerebrospinal fluid, they have been found to be 12% to 15% of the amount measured in serum
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We and others have demonstrated the development of a drug-tolerant persister population when B. burgdorferi are treated with antibiotics in vitro
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The adoption of a dormant or slow-growing phenotype likely allows the spirochetes to survive and re-grow following removal of antibiotic
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The basic premise that antibiotic tolerance may be an adaptation of the sophisticated stringent response required for the enzootic cycle by the spirochetes is described in a recent review as well
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Although current IDSA guidelines recommend intravenous ceftriaxone (2g daily for 30 days) over oral doxycycline for treatment of neuroborreliosis, a randomized clinical trial failed to show any enhanced efficacy of I.V. penicillin G to oral doxycycline for treatment of Lyme neuroborreliosis (no treatment failures were reported in this study of 54 patients).
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we can speculate that the minimal to moderate inflammation that was observed, especially within the CNS and PNS can, in part, explain the breadth of symptoms experienced by late stage Lyme disease patients, such as cognitive impairment and neuralgia.
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Erythema migrans, the clinical hallmark of early localized Lyme disease, was observed in one of the rhesus macaques from this study.
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In 2014, a trailblazing study in mice demonstrated a dramatic decline in B. burgdorferi DNA in the tissues for up to eight months after antibiotic treatment followed by the resurgence of B. burgdorferi growth 12 months after treatment
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This study provides evidence that the slow-growing spirochetes which persist after treatment, but are not cultivable in standard growth media may remain viable.
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The first well-documented indication of Lyme disease (LD) in the United States occurred in the early 1970s
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Lyme disease is now known to be caused by multiple closely related genospecies classified within the Bb sensu lato complex, representing the most common tick-borne human disease in the Northern Hemisphere
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approximately 30,000 physician-reported cases occur annually in the United States, the annual incidence has been estimated to be 10-fold higher by the Centers for Disease Control and Prevention.6
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Current antibiotic therapy guidelines outlined by the Infectious Disease Society of America (IDSA) are successful in the treatment of LD for the majority of LD patients, especially when administered early in disease immediately following identification of erythema migrans (EM)
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host-adapted spirochetes that persist in the tissues, probably in small numbers, inaccessible or impervious to antibiotic
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Experimental studies on immunocompetent mice, dogs, and rhesus macaques have provided evidence for the persistence of Bb spirochetes subsequent to antibiotic treatment in the form of residual spirochetes detected within tissue by IFA and PCR, and recovered by xenodiagnoses
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half (five) of the NHP received antibiotic treatment, consisting of 5 mg/kg oral doxycycline twice per day.
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Peripheral nerves contained minimal to moderate lymphoplasmacytic inflammation with a predilection for collagen-rich epineurium and perivascular spaces
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Minimal to mild lymphoplasmacytic inflammation of either the myocardial interstitium (Figure 2Figure 2A), pericardium (Figure 2Figure 2B), or combination therein was observed in 60% of NHPs
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A single morphologically intact spirochete, as indicated by positive red immunofluorescence (Figure 2Figure 2C), was observed in the myocardium of one treated animal
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three animals exhibited minimal to mild lymphoplasmacytic inflammation affecting joint-associated structures
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Multiple randomized placebo-controlled studies which evaluated sustained antimicrobial therapy concluded that there is no benefit in alleviating patients’ symptoms and indicated that long-term antibiotic therapy may even be detrimental to patients due to potential associated complications (ie, catheter infection and/or clostridial colitis)
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shared by Nathan Goodyear on 26 Oct 12
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Decline in semen quality among fertile men in P... [N Engl J Med. 1995] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...7816062
men decline declining sperm count number male low T testosterone infertility
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shared by Nathan Goodyear on 30 Nov 16
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Influence of increasing body mass index on semen and reproductive hormonal parameters i... - 0 views
www.fertstert.org/...fulltext
BMI male obesity male hormones hormones Testosterone Testosterone:Estradiol Estradiol sperm sperm concentration sperm count sperm motility fertility
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retrospective cohort finds mild but significant relationships b/t BMI and total Testosterone, Testosterone:Estradiol and Estradiol alone. BMI was inversely correlated with Testosterone and the T:E2 ratio; but directly correlated with E2 alone. There was also a negative correlation with sperm concentration, motility and morphology.
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shared by Nathan Goodyear on 28 Jul 14
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http://gut.bmj.com/content/23/7/608.full.pdf - 0 views
gut.bmj.com/...608.full.pdf
celiac disease celiac disease hypogonadism low T Testosterone sperm infertility men male hormone hormones
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shared by Nathan Goodyear on 04 Sep 14
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Evaluation of atorvastatin efficacy and toxicity on spermatozoa, accessory glands and g... - 0 views
www.ncbi.nlm.nih.gov/...PMC4114109
statin statin therapy statins sperm men male fertility atorvastatin hormones
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I really don't understand the purpose of this study. Why give "healthy" men with normal lipids atorvastatin??? The study found a reduction in TC and LDL, but also a reduction in sperm number, decreased sperm vitality, increased sperm morphology, decreased prostatic acid pho sphatases, epididymal neutral alpha-glucosidase and L-carnitine levels resulted.
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shared by Nathan Goodyear on 16 Jan 12
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PPARs, Obesity, and Inflammation - 0 views
www.ncbi.nlm.nih.gov/...PMC1783744
obesity inflammation PPARs perioxisome proliferator-activated receptor
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Many of the inflammatory markers found in plasma of obese individuals appear to originate from adipose tissue
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obesity is a state of chronic low-grade inflammation that is initiated by morphological changes in the adipose tissue.
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secretion of MCP-1, resistin, and other proinflammatory cytokines is increased by obesity, the adipose secretion of the anti-inflammatory protein adiponectin is decreased
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the peroxisome proliferators- activated receptor (PPAR) family are involved in the regulation of inflammation and energy homestasis
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upregulation of COX-2 is seen in alcoholic steatohepatitis and nonalcoholic steatohepatitis and has been directly linked to the progression of steatosis to steatohepatitis, the inhibitory effect of PPARα on COX-2 may reduce steatohepatitis
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PPARα agonists have a clear anorexic effect resulting in decreased food intake, evidence is accumulating that PPARα may also directly influence adipose tissue function, including its inflammatory status.
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PPARα may govern adipose tissue inflammation in three different ways: (1) by decreasing adipocyte hypertrophy, which is known to be connected with a higher inflammatory status of the tissue [3, 11, 59], (2) by direct regulation of inflammatory gene expression via locally expressed PPARα, or (3) by systemic events likely originating from liver
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two different molecular mechanisms have been proposed by which anti-inflammatory actions of PPARγ are effectuated: (1) via interference with proinflammatory transcription factors including STAT, NF-κB, and AP-1
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and (2) by preventing removal of corepressor complexes from gene promoter regions resulting in suppression of inflammatory gene transcription
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diet-induced obesity is associated with increased inflammatory gene expression in adipose tissue via adipocyte hypertrophy and macrophage infiltration
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PPARγ is able to reverse macrophage infiltration, and subsequently reduces inflammatory gene expression
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Inflammatory adipokines mainly originate from macrophages which are part of the stromal vascular fraction of adipose tissue [18, 19], and accordingly, the downregulation of inflammatory adipokines in WAT by PPARγ probably occurs via effects on macrophages
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By interfering with NF-κB signaling pathways, PPARγ is known to decrease inflammation in activated macrophages
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PPARs may influence the inflammatory response either by direct transcriptional downregulation of proinflammatory genes
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shared by Nathan Goodyear on 21 Jan 14
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Comparative Studies of the Estrogen Receptors β and α and the Androgen Recept... - 0 views
ajp.amjpathol.org/...fulltext
ER beta ER-beta AR androgen receptors ER alpha ER-alpha prostate disease cancer estrogen receptor hormone hormones men male
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ER-β is predominately immunolocalized in basal cells and to a lesser extent in stromal cells of the morphologically normal human prostate
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AR was predominately localized in the nuclei of differentiated secretory cells and variably in basal cells of the normal acinar/duct unit as well as in stromal cells
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Hall and colleagues44 have reported that ER-β functions as a transdominant inhibitor of ER-α transcription and that it acts to decrease overall cellular sensitivity to estradiol
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proliferative signals mediated by AR in basal cells or by ER-α and AR in stromal cells may be opposed by the purported growth-inhibitory action of ER-β25, 26, 27, 28 localized in basal cells.
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The transition from normal to low/moderate dysplastic glands in the peripheral zone was marked by the appearance of ER-β homogeneously immunostained nuclei in secretory as well as basal cells with no changes in the localization of the other receptors.
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The expression of ER-β was diminished in high-grade dysplasias when compared to normal glands and lower grade lesions.
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The diminution of ER-β expression in high-grade dysplasias and grade 4/5 cancers may be therefore related to the alteration of DNA methylation pattern in CpG islands of the promoter, resulting in down-regulation of the receptor at the transcriptional level
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based on the proposed anti-proliferative function of the receptor,25, 26, 27, 28 the presence of ER-β in secretory cells of low/moderate-grade lesions may represent a transient abortive attempt to counter growth of these cells
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the attrition of receptor-positive basal cells in the high-grade dysplasias may signify a continuing loss of growth inhibitory function mediated by ER-β in these precursor lesions
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Our findings in prostate therefore differ from those reported for human colon cancer in which Folley and colleagues48 demonstrated that a selective loss of ER-β protein but not receptor message expression occurs in these neoplasms
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Our findings therefore differed from those of Bonkhoff and colleagues33 who found immunostaining for the receptor in high-grade dysplasias and grade 4/5 carcinomas. Using in situ hybridization these authors also reported that a high percentage of dysplasias and carcinomas in their study contained cells that expressed ER-α message
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Very nice study. The authors looked at normal prostate, early disease and late stage prostate cancer. The authors found that ER beta expression, as a general rule, was lost as progression occurred to the high-grade dysplasias and grad 4/5 carcinomas of the prostate. Early low/moderate dysplasia was associated with an increase in ER beta--the authors propose that this was due to an attempt of the basal epithelium to counter the paracrine effect of ER alpha. In contrast, androgen receptors appeared to be equally expressed across all.
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Effects of Tocopherol (Vitamin E) Acid Succinate on Morphological Alterations and Growt... - 0 views
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How We Read Oncologic FDG PET/CT | Cancer Imaging | Full Text - 0 views
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In early PET literature focusing on analysis of solitary pulmonary nodules, some researchers defined malignancy based on a SUVmax threshold of greater than 2.5
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Far more important than the SUVmax is the pattern rather than intensity of metabolic abnormality and the correlative CT findings
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Descriptively, we define SUV < 5 as “low intensity”, 5–10 as “moderate”, 10–15 as “intense” and >15 as “very intense”
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Evolving literature suggests that intensity of uptake is an independent prognostic factor and in some tumour subtypes superior to histopathologic characterisation.
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Our practice of thresholding the grey and colour scale to liver as detailed above results in similar image intensity to a fixed upper SUV threshold of 8 to 10
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The advantage of using the liver as a reference tissue is also aided by this organ having rather low variability in metabolic activity
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When the liver is abnormal and cannot be used as a reference organ, we use the default SUV setting of an upper SUV threshold of 8
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One of the most challenging aspects of oncologic FDG PET/CT review, however, is to recognise all the patterns of metabolic activity that are not malignant and which consequently confound interpretation
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Future articles in the “How I Read” series will address the specific details of reading PET/CT in various cancers
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For example, discordant low-grade activity in an enlarged lymph node in the setting of intense uptake in the primary tumour suggests it is unlikely malignant and more likely inflammatory or reactive
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By CT criteria the enlarged node is ‘pathologic’ but the discordantly low metabolic signature further characterises this is as non-malignant since such a node is not subject to partial volume effects and therefore the intensity of uptake should be similar to the primary site
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The exception is when the lymph node is centrally necrotic as a small rim of viable tumour is subject to partial volume effects with expectant lower intensity of uptake; integrating the CT morphology is therefore critical to reaching an accurate interpretation
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Small nodes that are visualised on PET are conversely much more likely to be metastatic as such nodes are subject to partial volume effects.
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The combination of FDG and a more specific tracer, which visualises the well-differentiated disease can be very useful to characterise this phenomenon
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For the majority of malignant processes, the intensity of metabolic abnormality correlates with degree of aggressiveness or proliferative rate.
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a negative PET/CT study in a patient with biopsy proven malignancy would be considered false-negative
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There, however, are a significant minority of tumours that utilise substrates other glucose such as glutamine or fatty acids as a source of the carbon atoms required for growth and proliferation
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This includes a subset of diffuse gastric adenocarcinomas, signet cell colonic adenocarcinomas and some sarcomas, particularly liposarcoma
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There may be a role for other radiotracers such as fluorothymidine (FLT) or amino acid substrates in this setting.
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Some tumours harbour mutations that result in defective aerobic mitochondrial energy metabolism, effectively simulating the Warburg effect
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Uterine fibroids, hepatic adenomas, fibroadenomas of the breast and desmoid tumours are benign or relatively benign lesions that can have quite high FDG-avidity.
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Common examples where patients have commenced active therapy but the referrer is requesting “staging” includes hormonal therapy (eg. tamoxifen) in breast cancer, oral capecitabine in colorectal cancer or high dose steroids in Hodgkin’s lymphoma
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Without intravenous contrast, additional identification of typical oncologic complications such as pulmonary embolism or venous thrombosis cannot be identified
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If the study is performed as an “interim” restaging study after commencement of therapy but before completion, in order to reach a valid or clinically useful conclusion findings must be interpreted in the context of known changes that occur at a specific timing and type of therapy
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The most well studied use of interim PET is in Hodgkin’s lymphoma where repeat PET after two cycles of ABVD-chemotherapy provides powerful prognostic information and may improve outcomes by enabling early change of management
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