cutaneous vessels in the Pagetic extremities were already dilated. During heating, bloodflow in the normal extremities was similar to resting flow in the Pagetic extremities; this indicates that increases in cutaneous flow could account for most of the increase in total bloodflow in the Pagetic extremities. Adrenergic control of bloodflow to the Pagetic […]
Compared to sophisticated imaging techniques such as MRI, PET, CT, etc, the use of NIRS, TRS, PPG, IMS, DCS, and LDF may seem very simplified approaches to the study of bonebloodflow. Actually, this is a mis- leading point of view. Optical techniques have unique characteristics that might allow original investigations on bonebloodflowregulation in humans. In fact, we must not forget that these techniques are portable, have imag- ing capabilities, and can be used in special environments such as during water immersion , in flight simulators , in hyperbaric chambers [27, 28], during high altitude hiking , in microgravity, or during parabolic flights [29, 30]. Moreover, the non-invasiveness of the approach allows us to study the bone neurovascular system with- out the unwanted influence of, e.g., the mental stress that might modulate the activity of the autonomous nervous system and thus potentially bias the experimental results . The large spectrum of sampling rates (from fraction of second to seconds, depending on the specific imple- mentation of a given hardware), acquisition times (from a fraction of second to hours), and the repeatability of the measurements, without incurring in potential risks determined by ionizing radiation and/or contrast agents allow exploiting optical techniques for both functional studies and monitoring purposes, enabling the concep- tion of new investigations considered impossible until now for ethical reasons. The follow-up of acute or long term effects induced by pharmaceutical products modu- lating bonebloodflow might also represent an interesting application.
Secondly, in muscle tissue local hypoxia is known to be of great importance for peripheral bloodflow even though most details of this process are still unknown. The metaboreflex, i.e. activated chemically sensitive nerves located in muscle parenchyma evoke increases in sym- pathetic activity, has been shown to regulate cardiac output, blood pressure and regional bloodflow regula- tions . Hypoxia is a possible regulator of microcir- culation also in bone tissue. This has however not yet been studied in humans. Shim and Peterson  observed that the metabolic control mechanism was the most potent one regulating bonebloodflow in rabbits. The bloodflow appeared to be closely related to the oxygen and carbon dioxide tension, the pH, and the acid metabolites in blood. Following a period of ischemia, the outflow venous volume increased two to three times in their study. Brookes & Revell  suggested that local acidosis pro- vides a stimulus for bone accumulation, and Gross et al.  hypothesized that hypoxia was responsible for the bone vasoregulation found in their study. These state- ments are in accordance with our results showing that high intensity muscle work increased the post exercise patellar bloodflow 61%. Gross et al.  showed that, during low and moderate levels of exercise (treadmill running) in dogs, the vascular resistance in axial bone increased two to fourfold, while an increased vasodilata- tion in adjacent muscles was found. Our study indicates a reversed reaction in the patellar bone. In contrast to us, Gross et al.  studied bloodflowregulation during steady-state treadmill running and not post exercise hy-
from osteoblasts. The sclerotic bone is abnormally laid down with heavy collegan formation. Fibers are displayed in a haphazard way rather than linearly as occurs in normal bone. A high degree of bone turnover occurs due to the osteoclastic and osteoblastic activities. Paget called this process as “metabolic madness”. In the third phase, bone formation dominates in a disorganized pattern. This new bone is weaker than normal bone. There is infiltration of excessive fibrous connected tissue with blood vessels extending into the bone marrow. “The structure appears to have been almost entirely removed & laid down afresh in a different plane and in a different layer mould” stated Paget.
who have PDB do not know they have it, since the disease may be so mild that is not symptomatic. Moreover, the symptoms are often confused with arthritis or other skeletal disorders. Sometimes, the physician is alerted to the possibility of PDB when physical deformities appears (ie, enlargement of the skull or bowing of the tibia) or when a blood test reveals an elevated level of bone turnover markers. In most cases, the diagnosis of PDB is made only after complica- tions have developed. These complications mainly include osteoarthritis, fractures, severe bone deformity, neurological syndromes and, rarely, osteosarcoma, which significantly affect the morbidity and reduce the quality of life of patients. Osteoarthritis is common, affecting up to 50% of patients with PDB and can be quite painful. 6,13 A variety of
Recent reports demonstrated a crucial role for miRNAs in VSMC differentiation. MiR-143 and miR-145 are abundantly expressed in VSMCs of arteries (Cheng et al., 2009; Ji et al., 2007), and the heart (Boettger et al., 2009; Cordes et al., 2009). During postnatal development the expression in heart is down regulated. To highlight the importance of miR-143 and miR-145 in VSMCs, Boettger and colleagues generated a mouse mutant for the microRNA cluster miR-143/145. Analysis of homozygous miR-143/145 mutant mice revealed a decrease in contractile VSMCs, an increase in prolif- erative precursors and formation of neointimal lesions (Boettger et al., 2009). Contractile behavior in other organs including, the gastrointestinal motility was not affected. Closer characteriza- tion of the physiology of the mutant mice exhibits defects in the agonist-induced SMC contractility in arteries. Changes of the blood pressure were also observed in another study (Xin et al., 2009), and angiotensin I-converting enzyme (ACE), which is implied in promoting vasoconstriction and alteration of VSMC phenotype, by converting angiotensin-I into the vasoactive hormone angiotensin-II, was suggested to be a potential target. Comparison of healthy with injured murine carotid arteries showed a decreased expression of miR-143 and miR-145 in the diseased artery (Cordes et al., 2009). Moreover down-regulation of miR-145 in dedifferentiated cultured SMCs was found. Overexpression of miR-145 led to inhibition of PDGF-induced VSMC proliferation (Cheng et al., 2009). The vascular remodeling in response to injury was also tested in the miR-143/145-null mice from Xing. Ligation of the carotid artery of miR-145 -/- mice showed virtually no formation of neointima, whereas
A number of additional candidate genes have been evaluated to determine whether they might be linked to PD, including genes known to be involved in osteoclast biology or genes whose dele- tion results in mice that display an osteoclast phenotype. For example, the gene encoding OPG, a decoy receptor for RANKL, is on chromosome 18q24.2. OPG decreases osteoclast formation by binding to RANKL and interfering with its binding to the RANK receptor (3). Mutations in OPG have been reported in patients with idiopathic hyperphosphatasia, a rare congenital disorder that occurs in childhood and is characterized by deafness and bone lesions that affect the entire skeleton (82), but OPG muta- tions have not been reported in adults with PD. However, it is likely that additional genes linked to PD will be identified, and it is reasonable to hypothesize that they may be involved in the regulation of osteoclast formation, function, or lifespan, since increased osteoclast activity is central to PD. These genes may be components of the RANK or other signaling pathways that con- trol osteoclast formation or may result in increased expression of transcription factors such as c-fos or NFATc 1 that are critical
HCL therapy with PAs has improved treatment outcomes, with long-term remissions and a life expectancy, which is not significantly different from that of a healthy matched population. However, long-term follow-up studies have shown that relapse-free survival curves do not reach a plateau with PAs and late relapses can occur; therefore, the treatment for relapsed and refractory disease remains a challenge. In patients with HCL, due to its marked efficacy, brief treatment duration and favorable toxicity profile, our first-line treatment is cladribine, which is followed by a sec- ond cycle if CR is not achieved. MRD should be monitored and we recommend four to eight doses of rituximab to try to achieve complete MRD-negative remission. It is expected that the results of ongoing studies will provide information regarding the effectiveness of adding rituximab to first-line treatment. Upon relapse after a long remission, and espe- cially in patients treated with cladribine, we recommend an analysis of the mutational status of IGHV genes and a search for VH4-34 gene usage, together with an analysis of TP53 mutations. If negative, patients may be retreated with a second course of cladribine or pentostatin with rituximab. However, a change of the PA is recommended in patients who have only had a short remission. In patients in second relapse, refractoy disease, positivity for TP53 or BRAF V600E mutations or VH4-34 gene usage, treatment with targeted immunotoxins, BRAF inhibitors, either alone or in combination with MEK inhibitors, and BCR signaling inhibitors, such as ibrutinib, have provided new approaches. Positive Phase II data of moxetumomab pasudotox, an anti- CD22 immunotoxin, indicate that immunotoxin therapy can achieve durable MRD-negative CRs in patients with refractory disease. Vemurafenib and ibrutinib are currently
adenocarcinoma of the esophagus. Ishihara et al.  also reported a case of an early invasive carcinoma, which consisted of pagetoid squamous cell carcinoma in situ combined with early invasive components and choriocarcinoma at the metastatic site. Abraham et al.  reported a close relationship between Paget cells in the esophagus and an underlying poorly differentiated adenocarcinoma in the esophagus or esophagogastric junction. From these reports, all previously reported cases of Paget’s disease of the esophagus were thought to be secondary to an underlying carcinoma, although the malignant component varied in each case. In our case, we identified an SCC component, with squamous metaplasia and reserve cell hyperplasia, in the gastric mucosa of the esophagogastric junction, which was followed by Paget cells. However, unlike typical Paget’s disease, only few Paget cells were positive for PAS/ Alcian blue staining and immunohistochemically posi- tive for gastric gland mucin, whereas a strong p53 over- expression was observed in both SCC component and Paget cells.
Extensive local excision of the skin and subcutaneous tissue with immediate reconstruction is the main method for the treatment of EMPD. 8 Multidisciplinary comprehensive treatment may be a reasonable choice for invasive Paget ’ sdisease. Adjuvant therapy such as radiotherapy or systemic chemotherapy may be necessary. Chemotherapy using 5- ﬂ uorouracil, mitomycin-C and paclitaxel has been proven effective in inadequately excised and advanced EMPD. 5 Except for traditional chemotherapy, previous studies have reported HER2-targeted monoclonal antibody (trastuzumab) could yield signi ﬁ cant clinical bene ﬁ t in lymph node- metastatic penoscrotal EMPD patients with HER2 ampli ﬁ cation. 9 Pyrotinib is an oral irreversible tyrosine kinase inhibitor capable of inhibiting the HER1, HER2, and HER4. Until now, there has been no any report about the effective- ness of pyrotinib in those patients with HER2 gene alteration. Here, we present a case of an advanced penoscrotal EMPD patient harboring triple uncommon HER2 muta- tions, namely, ERBB2 R678Q in exon 17, S310Y in exon 8 and S310F in exon 8, who responds well pyrotinib.
Background: Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer ’ sdisease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS +/- mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels. Results: Combining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS +/- mice as early as 3 – 6 months of age but not in eNOS +/+ mice at any age. Remarkably, vascular occlusions in eNOS +/- mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS +/- mice.
When thyroid states were altered in the rat models, changes in e S ’Nase activity were not so apparent. H y p o t h y roidism was induced as described in Chapter 2, by the introduction of 6-n-propylthiouracil into the d rinking water combined with an iodine-deficient diet. W hen e S ’Nase activity was m e a su r e d in the white epididymal adipose tissue it was found to be 279. S ± 31. S nmol/min/mg protein, as compared to the euthyroid control animals in w h ic h the activity was m e a su r ed at 234.5 ± IS. 6 n mol/min/mg protein. Similarly, the e S ’Nase activity in the t ri iodothyronine- induced h y pe r th y ro i d animals was measured at 322.8 ± IS. 9 nmol/min/mg protein, whilst in the euthyroid animals it was 311.7 ± 19.4 nmol/min/ mg protein. Statistical a nalysis by the s t u d e n t ’s t-test showed that neither the h yp ot h yr o i d e S ’Nase activities, nor the hyperthyroid activities differed si gnificantly from their euthyroid controls (P>0.2 and P>0.3 r e s p e c t i v e l y ) . These hypothyroid results do not agree w ith the previous findings from this laboratory (Jamal & Saggerson, 1987) in which a 50% decrease of e S ’Nase a ct i vi ty was measured. However, it is important to note that the measurements in that report were made in membranes derived from isolated adipocytes, whilst the values given above from this study were made in whole white adipose tissue membranes.
When analyzing the results of the male and female groups, it has been observed that the differences in mean of all the variables in the left and right LL groups were not statistically significant. Theoretical implications of the lack of differences in the distribution of temperature and quality of bloodflow in lower extremities in elderly males and females are confirmed Table 3 Spearman’s rank correlation coefficient (ρ) for males and females for the thermal imaging study
Micropuncture studies have shown that glomerular filtration rate (GFR) falls in response to a rise in Na + or Cl - concentrations in the loop of Henle, whereas studies in isolated kidneys have shown that GFR falls in response to osmotic diuresis. To define the separate effects of an acute increase in plasma sodium (P Na ), chloride (P Cl ) or osmolality (P osmol ), changes in renal bloodflow (RBF) and GFR were measured during intrarenal infusions of hypertonic NaCl, NaHCO 3 , Na acetate, dextrose, NH 4 Cl or NH 4 acetate to denervated kidneys. The infusions raised P osmol at the experimental kidney by 30-45 mosmol. RBF increased
Figure 1.1: The long infinite cylinder model for MR-susceptometry measurements. The cylinder lies in x-z plane at an angle to the external B0 field. ..................................... 11 Figure 2.1: Interleaved 2D-GRE sequence alternating between two anatomic locations (Gx = frequency-encoding gradient, Gy = phase-encoding gradient, Gz = slice-selection gradient). All but the fourth interleave are flow compensated along the slice-select direction. The fourth interleave is flow encoded with VENC = 60cm/s. The echo time difference ( TE) between the first and third interleaves is 2.5ms (TE = 7.025ms). The dashed boxes represent sequence parameters that changed between the interleaves...... 28 Figure 2.2: Phase difference images of the cross-sectional area of the circular and triangular phantoms containing (a) 1mM, (b) 1.25mM, (c) 1.5mM and (d) 1.75mM Gd- DTPA in distilled water. ................................................................................................... 33 Figure 2.3: (a) Axial magnitude image of mouth orifice highlighting the major inflow vessels (internal carotid and vertebral arteries; red arrows); (b) corresponding velocity map used for the calculation of total cerebral bloodflow rate. ....................................... 34 Figure 2.4: (a) Sagittal (b) Coronal and (c) Axial magnitude images of the brain
While the waste products of aerobic glycolysis are nor- mally not too much of a problem, accumulation of lactic acid under anaerobic conditions leads to metabolic acid- osis, accentuating negative side effects as encountered in hypoxic tissue. These include loss of cardiac contractil- ity, loss of circulatory resistance regulation, a delayed and disturbed tissue healing process in the traumatized and critically ill patient, and, ultimately, death [2, 3]. Poorer cardiac contractility and loss of peripheral arter- ial resistance generally develop in acidotic settings, be these of respiratory or metabolic genesis. The decisive issue is the perturbation of the H + ion concentration. In particular, increase of H + attenuates glycolytic enzymes and causes hyperkalemia. These effects alone lead to a fall in cardiac force development. However, there may be some difference between metabolic and respiratory acid- osis. The difference is not one of a general nature, but is quantitative. For instance, nonrespiratory acidosis causes an increase in external K + of 0.6 mmol/l per change of pH by 0.1 unit; the corresponding value for respiratory acidosis is only 0.1 mmol/l per 0.1 pH unit. Also, quanti- tative effects will probably differ between acute and chronic acidosis. Lactate is chiefly a marker of the condi- tion, but, as an osmotically active particle, interstitial lac- tate adds to vascular dilatation via transient receptor potential-operated channels of the smooth muscle cells that respond to osmotic concentration (see below).
cerebral perfusion and theta rhythm. Neverthless, the con- nection rises just when considering the distinctive groups exclusively utilizing the a3/a2 EEG power ratio. This is affirmed by the finding that when the groups are combined, no relationship could be found. This is the principle part of the study and the particular curiosity of the outcomes. Low levels of hippocampal theta EEG power is maintained in patients at lower risk of AD, who have a steady pat- tern toward a higher brain local blood perfusion, while in patients at higher risk, with a fundamentally lower cerebral blood perfusion, theta frequency power tends to be greater in the hippocampus. Theta rhythms are for the most part not detected in the remaining EEG recordings.
database, PCR primer sequence (Table 2) was designed with Primer 5.0 software (Shanghai GenePharm Co., Ltd., Shanghai, People’s Republic of China). The PCR system was 12.5 µ L of SYBR Premix Ex Taq II (Takara Bio Inc., Dalian, People’s Republic of China); 1 µ L of forward and 1 µ L of reverse primers; 2 µ L of DNA template; 8.5 µ L of sterile water; internal reference gene, β -actin. The PCR con- dition was initial denaturation at 95 ° C for 30 s; denaturation at 95 ° C for 5 s, annealing at 51 ° C for 25 s, and elongation at 65 ° C for 10 s, 40 cycles of these three procedures in total. The PCR results were evaluated by dissolution curve. The threshold cycle (CT) was obtained at the inflection point of amplification curve. ∆ Ct = CT (target gene) - CT ( β -actin), ∆∆ Ct = ∆ Ct (HCC tissue) - ∆ Ct (adjacent tissue). The relative expression of target gene was calculated as 2 -∆∆Ct . 17
Patients were identified as having metastatic bonedisease by (1) at least one inpatient claim or two outpatient claims on dif- ferent days within any 12-month interval, carrying the Inter- national Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code for secondary malignant neoplasm of bone or bone marrow (198.5); or (2) at least one claim carrying Healthcare Common Procedure Coding System codes for intravenous (IV) bisphosphonates zoledronic acid (Zometa, J3487) or pamidronate (J2430) with at least one qualifying code on the same claim. Quali- fying codes included the ICD-9-CM diagnosis codes for primary cancer (see Table 1); metastatic cancer in lymph nodes (196.xx), respiratory and digestive systems (197.xx), and other sites including bone and bone marrow (198.xx); and V codes for encounters for antineoplastic chemotherapy (V58.11) and immunotherapy (V58.12). The earliest date of
Although a large body of evidence has been acquired over the past decade suggesting that astrocytes are potential mediators of func- tional hyperemia, the idea remains controversial. The presence, prevalence, and timing of astrocyte Ca 2+ signaling in response to neural activity and its role in the regulation of CBF is cur- rently hotly debated. In a recent review, Cauli and Hamel (2010) discuss the relative timings of astrocytic and neuronal calcium responses to neuronal activity. Rapid calcium events are thought to reflect activation of ionotropic receptors (which are expressed frequently in neurons), while slower calcium responses are pro- posed to reflect activation of metabotropic receptors (expressed by astrocytes and neurons) and the release of calcium from intra- cellular stores. These calcium signal dynamics agree with the observation that calcium events in neurons often precede those in astrocytes (Wang et al., 2006; Schummers et al., 2008; Nizar et al., 2013). These data would suggest that astrocytes may only con- tribute to functional hyperemia in the late phase of the response. Recent studies have suggested that arteriole dilations resulting from neural activity may not only precede astrocytic [Ca 2 + ] i sig-