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Kinesin motors mediate the intracellular transport of cargo molecules along microtubule tracks (1). The mechanism that regulates the activation of kinesin motors remains an issue of fundamental importance (2, 3). It has been reported that the full length conventional kinesin, kinesin-1, has very little microtubule-stimulated ATPase activity in solution as compared to its shorter motor domain constructs (4, 5). The intramolecular interactions mediated by the motor and tail domains keep the kinesin-1 in a compactly-folded inhibitory state (6–8). It is well established that the mechanical attachment of the inactive full length motor to a glass surface or latex beads is sufficient to transform the inactive motor to an active state, presumably by disrupting its inhibitory conformation (8, 9). Therefore, it is reasonable to speculate that this mode of self-inhibition of kinesin-1 is the general feature conserved in all kinesin-like proteins to keep their motor activity regulated in vivo. GAKIN/KIF13B (10) belongs to the kinesin-3 family. The family also includes KIF1A/Unc104, which is responsible for the transport of synaptic vesicles (11). Our previous studies have identified two cargo molecules for GAKIN; the membrane-associated guanylate kinase homologue (MAGUK) scaffolding protein hDlg/SAP97 (12) and a PIP3 binding protein termed PIP3BP (13). Both MAGUKs and PIP3 have been implicated in the regulation of cell polarity pathways, and their subcellular localization is considered to be important for their functions in vivo. Recently, we have shown that the transport of PIP3 containing vesicles to the distal ends of neurites by the GAKIN-PIP3BP complex regulates the axon-dendrite polarity determination in the hippocampal neurons (13). Human Dlg is an important component of cell-cell contact sites such as epithelial adherence junctions and neuronal synaptic membranes, where it forms a multi-protein complex containing transmembrane receptors and cytoskeletal proteins (14). The loss of Drosophila Dlg disrupts epithelial apical-basal polarity resulting in the tumor-like overgrowth in imaginal discs (15). MAGUK proteins are also implicated in the transport of multi-protein complexes to specialized sites. For example, SAP97, the rat orthologue of hDlg, regulates the transport of AMPA receptor complex to the synapse (16–18). A scaffolding complex containing Lin-2, another MAGUK, mediates the transport of the NMDA receptor (19). These findings prompted us to investigate the regulatory mechanism of the hDlg-GAKIN cargo-motor complex and its role in the transport phenomenon. Here, we report that a specific segment of hDlg encodes the activation signal for converting an inactive GAKIN to an active motor in vitro. To our knowledge, this is the first demonstration of the regulation of a kinesin motor by direct interaction of its natural cargo using in vitro measurements of purified components.

Aim To compare the long‐term efficacy of sodium‐glucose co‐transporter‐2 inhibitors and dipeptidyl peptidase‐4 inhibitors as second‐line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD). Materials and methods In a 52‐week randomized open‐label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks. Results Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m2, 61.3% men), 54 patients received ipragliflozin and 57 received sitagliptin. After 52 weeks, achievement of the primary endpoint was not significantly different (37.0% and 40.3%; P = 0.72). HbA1c reduction rate at 24 weeks was greater for sitagliptin (56.1%) than for ipragliflozin (31.5%; P = 0.01). From 24 to 52 weeks, the HbA1c reduction with sitagliptin was attenuated, with no significant difference in HbA1c reduction after 52 weeks between sitagliptin (54.4%) and ipragliflozin (38.9%; P = 0.10). Improvements in BMI, C‐peptide and high‐density lipoprotein cholesterol were greater with ipragliflozin than with sitagliptin. Adverse events occurred in 17 patients with ipragliflozin and in 10 patients with sitagliptin (P = 0.11). Conclusion The HbA1c‐lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.

Phosphatidylinositol 3,4,5-triphosphate (PIP3) plays a key role in neuronal polarization and axon formation. PIP3-containing vesicles are transported to axon tips by the kinesin KIF13B via an adaptor protein, centaurin α1 (CENTA1). KIF13B interacts with CENTA1 through its forkhead-associated (FHA) domain. We solved the crystal structures of CENTA1 in ligand-free, KIF13B-FHA domain-bound, and PIP3 head group (IP4)-bound conformations, and the CENTA1/KIF13B-FHA/IP4 ternary complex. The first pleckstrin homology (PH) domain of CENTA1 specifically binds to PIP3, while the second binds to both PIP3 and phosphatidylinositol 3,4-biphosphate (PI(3,4)P 2 ). The FHA domain of KIF13B interacts with the PH1 domain of one CENTA1 molecule and the ArfGAP domain of a second CENTA1 molecule in a threonine phosphorylation-independent fashion. We propose that full-length KIF13B and CENTA1 form heterotetramers that can bind four phosphoinositide molecules in the vesicle and transport it along the microtubule.

Resolvins, are specialized pro-resolving mediators (SPMs) derived from n-3 polyunsaturated fatty acids. They contribute actively to the resolution of inflammation, but little is known concerning their role in chronic inflammation, such as in rheumatoid arthritis (RA). Here, we performed lipid mediator (LM) profiling in tissues from the paws of SKG arthritic mice using lipid chromatography (LC)/mass spectrometry (MS)/MS-based LM metabololipidomics. We found elevated levels of SPMs including resolvin D5 (RvD5) in these tissues. Moreover, RvD5 levels were significantly correlated with arthritis disease activity. From experiments to assess the role of RvD5 in the pathology of RA, we concluded that RvD5 suppressed Th17 cell differentiation and facilitated regulatory T cell differentiation, as well as inhibiting CD4+ T cell proliferation. Furthermore, RvD5 attenuated osteoclast differentiation and interfered with osteoclastogenesis. Targeting the resolution of inflammation could be promising as a novel treatment for RA.

Efficacious antitumor immune responses must overcome multiple suppressive mechanisms in the tumor microenvironment to control cancer progression. In this study, we demonstrate that dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signaling and activation of antigen-presenting cells with agonist anti-CD40 treatment confers superior antitumor efficacy and increased survival compared with monotherapy treatment in preclinical tumor models. Concurrent CSF-1R blockade and CD40 agonism lead to profound changes in the composition of immune infiltrates, causing an overall decrease in immunosuppressive cells and a shift toward a more inflammatory milieu. Anti-CD40/anti–CSF-1R–treated tumors contain decreased tumor-associated macrophages and Foxp3+ regulatory T cells. This combination approach increases maturation and differentiation of proinflammatory macrophages and dendritic cells and also drives potent priming of effector T cells in draining lymph nodes. As a result, tumor-infiltrating effector T cells exhibit improved responses to tumor antigen rechallenge. These studies show that combining therapeutic approaches may simultaneously remove inhibitory immune populations and sustain endogenous antitumor immune responses to successfully impair cancer progression. Cancer Immunol Res; 5(12); 1109–21. ©2017 AACR.

Aims The EURO-ENDO registry aimed to study the management and outcomes of patients with infective endocarditis (IE). Methods and results Prospective cohort of 3116 adult patients (2470 from Europe, 646 from non-ESC countries), admitted to 156 hospitals in 40 countries between January 2016 and March 2018 with a diagnosis of IE based on ESC 2015 diagnostic criteria. Clinical, biological, microbiological, and imaging [echocardiography, computed tomography (CT) scan, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)] data were collected. Infective endocarditis was native (NVE) in 1764 (56.6%) patients, prosthetic (PVIE) in 939 (30.1%), and device-related (CDRIE) in 308 (9.9%). Infective endocarditis was community-acquired in 2046 (65.66%) patients. Microorganisms involved were staphylococci in 1085 (44.1%) patients, oral streptococci in 304 (12.3%), enterococci in 390 (15.8%), and Streptococcus gallolyticus in 162 (6.6%). 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 518 (16.6%) patients and presented with cardiac uptake (major criterion) in 222 (42.9%) patients, with a better sensitivity in PVIE (66.8%) than in NVE (28.0%) and CDRIE (16.3%). Embolic events occurred in 20.6% of patients, and were significantly associated with tricuspid or pulmonary IE, presence of a vegetation and Staphylococcus aureus IE. According to ESC guidelines, cardiac surgery was indicated in 2160 (69.3%) patients, but finally performed in only 1596 (73.9%) of them. In-hospital death occurred in 532 (17.1%) patients and was more frequent in PVIE. Independent predictors of mortality were Charlson index, creatinine > 2 mg/dL, congestive heart failure, vegetation length > 10 mm, cerebral complications, abscess, and failure to undertake surgery when indicated. Conclusion Infective endocarditis is still a life-threatening disease with frequent lethal outcome despite profound changes in its clinical, microbiological, imaging, and therapeutic profiles.

Background Systemic sclerosis (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undetermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90 % of patients. Soluble guanylate cyclase (sGC) stimulator is used to treat pulmonary artery hypertension (PAH) and has been shown to inhibit experimental skin fibrosis. Methods Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract was analyzed by real-time PCR, and the levels of collagen in the tissue were measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [dyeing distance × (duodenum − appendix)] − 1 × 100 (%). We treated BLM-treated mice with sGC stimulator or DMSO orally and analyzed them on day 42. Results Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal hyperproliferative and prefibrotic response in C57BL/6J mice. In addition, the gene expression levels of Col3a1, CCN2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in the esophagus were significantly increased in BLM-treated mice. More severe hyperproliferative and prefibrotic response was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC stimulator treatment significantly reduced hyperproliferative and prefibrotic response of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay. Conclusions These findings suggest that BLM induces gastrointestinal hyperproliferative and prefibrotic response in C57BL/6J mice, and treatment with sGC stimulator improves the BLM-induced gastrointestinal lesion.

An important emerging form of immunotherapy targeting B cell malignancies is chimeric antigen receptor (CAR) T cell therapy. Despite encouraging response rates of anti-CD19 CAR T cell therapy in B cell lymphomas, limited durability of response necessitates further study to potentiate CAR T cell efficacy. Antibody-targeted interferon (IFN) therapy is a novel approach in immunotherapy. Given the ability of IFNs to promote T cell activation and survival, target cell recognition, and cytotoxicity, we asked whether antibody-targeted IFN could enhance the antitumor effects of anti-CD19 CAR T cells. We produced an anti-CD20-IFN fusion protein containing the potent type 1 IFN isoform alpha14 (α14), and demonstrated its ability to suppress proliferation and induce apoptosis of human B cell lymphomas. Indeed, with the combination of anti-CD20-hIFNα14 and CAR T cells, we found enhanced cell killing among B cell lymphoma lines. Importantly, for all cell lines pretreated with anti-CD20-hIFNα14, the subsequent cytokine production by CAR T cells was markedly increased regardless of the degree of cell killing. Thus, several activities of CD19 CAR T cells were enhanced in the presence of anti-CD20-hIFNα14. These data suggest that antibody-targeted IFN may be an important novel approach to improving the efficacy of CAR T cell therapy.

Early diagnosis and access to treatment for infants with human immunodeficiency virus-1 (HIV-1) is critical to reduce infant mortality. The lack of simple point-of-care tests impedes the timely initiation of antiretroviral therapy. The development of FINA, filtration isolation of nucleic acids, a novel DNA extraction method that can be performed by clinic personnel in less than 2min has been reported previously. In this report, significant improvements in the DNA extraction and amplification methods are detailed that allow sensitive quantitation of as little as 10 copies of HIV-1 proviral DNA and detection of 3 copies extracted from 100μl of whole blood. An internal control to detect PCR inhibition was also incorporated. In a preliminary field evaluation of 61 South African infants, the FINA test demonstrated 100% sensitivity and specificity. The proviral copy number of the infant specimens was quantified, and it was established that 100 microliters of whole blood is required for sensitive diagnosis of infants.

Cytomegalovirus (CMV) is a DNA virus belonging to the Herpesviridae family, which causes various diseases with diverse symptoms, such as pneumonia, hepatitis, meningitis, retinitis, gastrointestinal ulcers, and cutaneous ulcers, especially in immunocompromised patients. CMV-related cutaneous ulcers often develop in the anogenital region and occasionally cause life-threatening complications. We report two patients with CMV-related cutaneous ulcers indicating an ominous clinical prognosis and severe [...]

Summary The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration. Introduction Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration. Methods This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study. Results Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern. Conclusion Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing. Trial registration ClinicalTrials.gov: NCT01384188, registered on June 27, 2011 EudraCT: 2008-006284-37 Electronic supplementary material The online version of this article (doi:10.1007/s00198-015-3342-4) contains supplementary material, which is available to authorized users.

The authors examined the long-term cognitive implications of cancer treatment among breast cancer survivors over 65 years old who received treatment during midlife. Thirty women survivors were matched with 30 noncancer, healthy older adults in terms of age, education, and IQ. The cancer survivors scored significantly lower in the cognitive domains of executive functioning, working memory, and divided attention, reflecting potential dysfunction in frontal-subcortical brain regions. Our findings suggest that among breast cancer survivors who remain disease-free for more than a decade, the previous cancer treatment may further augment cognitive dysfunction associated with age-related brain changes.

PCR detection of human immunodeficiency virus type 1 (HIV-1) proviral DNA is the method recommended for use for the diagnosis of HIV-1 infection in infants in limited-resource settings. Currently, testing must be performed in central laboratories, which are usually located some distance from health care facilities. While the collection and transportation of samples, such as dried blood spots, has improved test accessibility, the results are often not returned for several weeks. To enable PCR to be performed at the point of care while the mothers wait, we have developed a vertical filtration method that uses a separation membrane and an absorbent pad to extract cellular DNA from whole blood in less than 2 min. Cells are trapped in the separation membrane as the specimen is collected, and then a lysis buffer is added. The membrane retains the DNA, while the buffer washes away PCR inhibitors, which get wicked into the absorbent blotter pad. The membrane containing the entrapped DNA is then added to the PCR mixture without further purification. The method demonstrates a high degree of reproducibility and analytical sensitivity and allows the quantification of as few as 20 copies of HIV-1 proviral DNA from 100 μl of blood. In a blinded study with 182 longitudinal samples from infants (ages, 0 to 72 weeks) obtained from the Women and Infants Transmission Study, our assay demonstrated a sensitivity of 99% and a specificity of 100%.

Endothelial apoptosis is a pivotal process for angiogenesis during embryogenesis as well as postnatal life. By using a retrovirus-mediated signal sequence trap method, we identified a previously undescribed gene, termed ARIA (apoptosis regulator through modulating IAP expression), which regulates endothelial apoptosis and angiogenesis. ARIA was expressed in blood vessels during mouse embryogenesis, as well as in endothelial cells both in vitro and in vivo. ARIA is a unique protein with no homology to previously reported conserved domain structures. Knockdown of ARIA in HUVECs by using small interfering RNA significantly reduced endothelial apoptosis without affecting either cell migration or proliferation. ARIA knockdown significantly increased inhibitor of apoptosis (cIAP)-1 and cIAP-2 protein expression, although their mRNA expression was not changed. Simultaneous knockdown of cIAP-1 and cIAP-2 abolished the antiapoptotic effect of ARIA knockdown. Using yeast 2-hybrid screening, we identified the interaction of ARIA with 20S proteasome subunit α-7. Thereafter, we found that cIAP-1 and cIAP-2 were degraded by proteasomes in endothelial cells under normal condition. Overexpression of ARIA significantly reduced cIAP-1 expression, and this reduction was abolished by proteasomal inhibition in BAECs. Also, knockdown of ARIA demonstrated an effect similar to proteasomal inhibition with respect to not only expression but also subcellular localization of cIAP-1 and cIAP-2. In vivo angiogenesis studied by Matrigel-plug assay, mouse ischemic retinopathy model, and tumor xenograft model was significantly enhanced by ARIA knockdown. Together, our data indicate that ARIA is a unique factor regulating endothelial apoptosis, as well as angiogenesis, presumably through modulating proteasomal degradation of cIAP-1 and cIAP-2 in endothelial cells.

It remains to be determined whether the evidence in Western countries for blockade of the renin-angiotensin System in cardiovascular diseases could be directly applied to East Asian races including the Japanese population as a long-term strategy. The KYOTO HEART Study (KHS) is designed to investigate the add-on effect of valsartan versus conventional anti-hypertensive treatment on cardiovascular morbidity and mortality in Japanese hypertensive patients with uncontrolled blood pressure and with high cardiovascular risk. Over 3000 high-risk Japanese patients with uncontrolled hypertension were randomised to receive either additional treatment with valsartan or conventional non-angiotensin receptor blocker therapies, and the follow-up period will be at least 3 years. The primary end point is a composite of defined cardio- or cerebro-vascular events. Secondary end points include all causes of mortality, worsening of cardiac function, new onset or worsening of arrhythmias or diabetes mellitus. The KHS will provide new evidence for the management of blood pressure in hypertensive patients with high risk.

Viper bites in pregnant women have rarely been reported thus far. Moreover, there is no consensus regarding the treatment of such cases. In this paper, the authors report the successful treatment of viper bite during pregnancy without using antivenom.

Background: A mass-screened neuroblastoma (MSN) shows low-grade malignancy. Although the tumor is small, open laparotomy requires a large incision. Purpose: Extirpation by retroperitoneoscopy (ER) was performed in children with MSN to reduce the surgical stress. Methods: The indications for ER were (1) MSN originating from the adrenal gland and (2) a tumor size of less than 4 cm. Between January 2000 and June 2002, 6 children (mean age: 8.5 ± 0.6 months) underwent ER. Results: All children successfully underwent ER and no conversion of laparoscopy to open surgery was required. The only complication in one patient was a peritoneal tear. Oral intake was possible in all children the day after the operation. No port site metastasis or local recurrence was observed during follow-up (15 to 29 months). Conclusions: Adrenal MSN less than 4 cm were successfully extirpated by ER. This method has the advantage of allowing patients an early return to eating and has no risk of postoperative ileus. ER is an available surgical technique for children with MSN less than 4 cm.

MRI studies using the manual tracing method have shown a smaller-than-normal hippocampal volume in patients with posttraumatic stress disorder (PTSD). However, these studies have yielded inconsistent results, and brain structures other than the hippocampus have not been well investigated. A recently developed, fully automated method called voxel-based morphometry enables an exploration of structural changes throughout the brain by applying statistical parametric mapping to high-resolution MRI. Here we first used this technology in patients with PTSD. Participants were 9 victims of the Tokyo subway sarin attack with PTSD and 16 matched victims of the same traumatic event without PTSD. The voxel-based morphometry showed a significant gray-matter volume reduction in the left anterior cingulate cortex (ACC) in trauma survivors with PTSD compared with those without PTSD. The severity of the disorder was negatively correlated with the gray-matter volume of the left ACC in PTSD subjects. There were no significant differences in other gray-matter regions or any of the white-matter regions between two groups. The present study demonstrates evidence for structural abnormalities of ACC in patients with PTSD. Together with previous functional neuroimaging studies showing a dysfunction of this region, the present findings provide further support for the important role of ACC, which is pivotally involved in attention, emotional regulation, and conditioned fear, in the pathology of PTSD.

In order to determine the influence of early ambulation and other factors on headaches occurring after lumbar myelography we randomised 207 patients (127 men and 80 women) into two groups. Following the investigation, we allowed the 101 patients (65 men and 36 women) in group A to sit or stand freely, while we confined the 106 patients (62 men and 44 women) in group B to bed for 20 hours. The nine patients in group B who could not maintain bed rest were excluded. There was no significant difference between the two groups as regards the prevalence of spinal headache (8.9% in group A v 14.4% in group B). Patients who reported headaches, however, were significantly more likely to be women (18.7%) than men (7.3%), be younger (mean age 45 years v 56 years), have a higher cerebrospinal pressure before removal of fluid (mean values 172 v 137 mm H2O) and a lower systolic (mean values 120 v 134 mmHg) and diastolic blood pressure. We conclude that, although other factors may be associated with headaches, late ambulation is not effective in preventing spinal headaches after lumbar myelography.

PURPOSE: To investigate the mechanism by which traumatic macular hole closes spontaneously. DESIGN: Consecutive observational case series of three patients with unilateral traumatic macular hole who consulted medical staff at the Kansai Medical University between 1997 and 2000. METHODS: Three patients who sustained unilateral blunt trauma to the eye and developed traumatic macular hole were followed with ophthalmic examination, fundus photography, fluorescein angiography, and optical coherence tomography (OCT). RESULTS: Case 1 was an 11-year-old boy. He had neither a macular hole nor prominent macular edema at his first consultation, but a macular hole opened 3 weeks later. OCT showed macular edema and a full-thickness macular hole. The tissue around the edge of the macular hole protruded inward toward the center and finally closed spontaneously 18 weeks later. Case 2 was a 19-year-old man. He had a tiny rough-edged macular hole at his first consultation with a local ophthalmologist. OCT showed macular hole enlargement and worsening of the macular edema during follow up. The macular hole finally closed 4 months after injury. Case 3 was a 15-year-old boy. He had a tiny rough-edged macular hole at his first consultation with a local ophthalmologist. The macular hole finally closed 6 months after injury. CONCLUSION: Macular hole can be a result of severe damage from ocular concussion or damage to the retina. For 6 months following injury, traumatic macular hole should probably be observed rather than surgically repaired, because of the possibility that the macular hole may close spontaneously.

Transient receptor potential cation channel subfamily V member 1 (TRPV1), a member of the calcium-permeable thermosensitive transient receptor potential superfamily, is a sensor of thermal and chemical stimuli. TRPV1 is activated by noxious heat (> 43°C), acidic conditions (pH < 6.6), capsaicin, and endovanilloids. This pain receptor was discovered on nociceptive fibers in the peripheral nervous system. TRPV1 was recently found to be expressed by non-neuronal cells, such as epithelial cells. The oral gingival epithelium is exposed to multiple noxious stimuli, including heat and acids derived from endogenous and exogenous substances; however, whether gingival epithelial cells (GECs) express TRPV1 is unknown. We show that both TRPV1 mRNA and protein are expressed by GECs. Capsaicin, a TRPV1 agonist, elevated intracellular Ca2+ levels in the gingival epithelial cell line, epi 4. Moreover, TRPV1 activation in epi 4 cells accelerated proliferation. These responses to capsaicin were inhibited by a specific TRPV1 antagonist, SB-366791. We also observed GEC proliferation in capsaicin-treated mice in vivo. No effects were observed on GEC apoptosis by epithelial TRPV1 signaling. To examine the molecular mechanisms underlying this proliferative effect, we performed complementary (c)DNA microarray analysis of capsaicin-stimulated epi 4 cells. Compared with control conditions, 227 genes were up-regulated and 232 genes were down-regulated following capsaicin stimulation. Several proliferation-related genes were validated by independent experiments. Among them, fibroblast growth factor-17 and neuregulin 2 were significantly up-regulated in capsaicin-treated epi 4 cells. Our results suggest that functional TRPV1 is expressed by GECs and contributes to the regulation of cell proliferation.

Primary leiomyosarcoma of the broad ligament is a very rare and highly malignant gynecological tumor. The authors report a 61-year-old postmenopausal woman with signs and symptoms of malignant ovarian tumor. Preoperative magnetic resonance imaging (MRI) was interpreted as being suspicious for malignant tumors, such as an ovarian cancer or a leiomyosarcoma of the broad ligament, so laparotomy was performed. Macroscopically, the tumor was revealed with a 18 x 13.7 x 9.5 cm degenerated, multiple cystic part and solid whitish part arising from broad ligament which on histopathology proved to be leiomyosarcoma. To the best of the authors' knowledge, primary leiomyosarcoma of the broad ligament has been documented in 21 reports or so, and no imaging findings are available. Here the authors present the MRI findings of primary leiomyosarcoma of the broad ligament.

Posttraumatic growth has been demonstrated to occur following the diagnosis and treatment of cancer. Still unknown is whether patients expect such growth, how growth is perceived at early points in time that follow the cancer experience, and whether patient reports of growth are corroborated by others. Participants were 87 patients and 55 collaterals who reported their anticipation of growth pretreatment and their perceived growth at a 9-month follow-up. Patients' expectations for their own growth were significantly higher than collaterals' expectations for theirs. When anticipated growth was compared to later reported growth, patients overanticipated growth across all domains and collaterals underanticipated growth.

The term "chemobrain" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment. As breast cancer survivors now commonly reach late life, it is not known whether previous exposure to chemotherapy may affect long-term risk for cognitive impairment. To help address this concern, this study tested whether successfully surviving chemotherapy earlier in life was associated with later differences in brain metabolic function as an older adult compared to controls. This question was examined using positron emission tomography measures of brain glucose metabolism in elderly women cancer survivors.Breast cancer survivors (N = 10), currently free of recurrent cancer and without a diagnosis of a cognitive disorder, were compared to matched healthy controls (N = 10). All subjects were imaged at rest with [(18)F]fluorodeoxyglucose. Images were analyzed semi-quantitatively using the Alzheimer's Discrimination Tool and a volume of interest-based approach derived from co-registered magnetic resonance imaging.Relative [(18)F]fluorodeoxyglucose uptake (normalized to global) was significantly lower in the survivors compared with control subjects in bilateral orbital frontal regions, consistent with differences between the groups in cognition and executive function (i.e., Trail Making Test, Part B and mini-mental state examination) and despite no significant differences with respect to age, education, intelligence, or working memory. None of the survivors and only one control manifested a global positron emission tomography score consistent with an Alzheimer's disease metabolic pattern.Breast cancer survivors treated with chemotherapy may manifest long-term changes in brain glucose metabolism indicative of subtle frontal hypometabolism, a finding consistent with results from neuropsychological testing and other imaging modalities.

The authors conducted this retrospective study to evaluate the efficacy of radiotherapy (RT) for high-risk patients with adenocarcinoma (AC) compared with chemotherapy (CT) after radical hysterectomy.There were 263 patients with AC and 58 with adenosquamous cell carcinoma (ASCC). Of these 321 patients, 151 received adjuvant treatment. Of these 151 patients, 69 received radiotherapy (RT) alone, including concurrent chemoradiotherapy (CCRT) with weekly cisdiamminedichloroplatinum (CDDP), 64 patients received CT alone, and 18 patients received concomitant RT and CT (RT + CT).The five-year overall survival (OS) was 70.9% for patients receiving RT, 79.2% for CT, and 66.2% for RT + CT. Adjuvant treatment did not affect the incidence or the pattern of recurrence. The incidence of lymph node involvement was 9.0% in Stage Ib1, 23.9% in Stage Ib2, 30.8% in Stage IIa, and 41.2% in Stage IIb.Adjuvant CT may be effective for high-risk patients with cervical adenocarcinoma.

Although the trafficking of newly synthesized VEGFR2 to the plasma membrane is a key determinant of angiogenesis, the molecular mechanisms of Golgi to plasma membrane trafficking are unknown. Here, we have identified a key role of the kinesin family plus-end molecular motor KIF13B in delivering VEGFR2 cargo from the Golgi to the endothelial cell surface. KIF13B is shown to interact directly with VEGFR2 on microtubules. We also observed that overexpression of truncated versions of KIF13B containing the binding domains that interact with VEGFR2 inhibited VEGF-induced capillary tube formation. KIF13B depletion prevented VEGF-mediated endothelial migration, capillary tube formation and neo-vascularization in mice. Impairment in trafficking induced by knockdown of KIF13B shunted VEGFR2 towards the lysosomal degradation pathway. Thus, KIF13B is an essential molecular motor required for the trafficking of VEGFR2 from the Golgi, and its delivery to the endothelial cell surface mediates angiogenesis.

Some colorectal adenomas show non-polypoid features endoscopically, e.g. nodule-aggregation or lateral spreading. To understand the developmental mechanism of non-polypoid adenomas better, we evaluated apoptosis indices in the upper and lower parts of 26 colorectal adenomas of non-polypoid appearance using TUNEL or single-stranded DNA (ssDNA) immunohistochemical staining. Regression analysis showed an extremely strong positive correlation between the apoptosis index (AI) values generated using each method. The AI of the lower section of lesion (4.54 ± 1.86) was significantly higher than that of the upper part (1.21 ± 1.47). In conclusion, ssDNA immunostaining is as useful as the TUNEL method in the evaluation of apoptosis in colorectal adenomas. It seems that vertical growth in non-polypoid adenomas is inhibited by apoptosis allowing horizontal growth to dominate and resulting in the characteristic, laterally spreading morphology.

Purpose: To investigate the age and sex dependence of the bone mineral status of human lumbar vertebrae with special regard to differences between cortical and trabecular bone. Material and Methods: The study group comprised 125 normal Japanese healthy volunteers (54 males and 71 females), and was subdivided into adult male and female groups (subjects younger than 40 years), intermediate male and female groups (ages ranging between 41 and 64 years) and old male and female groups (subjects older than 65 years). The cortical bone mineral status was estimated using a single-energy quantitative CT (SE-QCT) technique, whereas trabecular bone mineral density (BMD) was estimated using a dual-energy (DE-QCT) technique. Results: A considerable gender difference in the age-related cortical bone status was found. There was a significant reduction of the mean values of the cortical volume and BMD in the old female group compared with those obtained in the old male group. Conclusion: The results suggest that in men, cortical and trabecular bone volume decrease very little with age. In women, cortical volume and BMD and trabecular BMD decrease with age while trabecular bone volume does not. The study showed that all variables had higher values in men than in women and that the difference increased with age.

Objective: To investigate the relationship between cerebral cortical function and white matter myelination in the visual pathway in the evaluation of normal brain development.Methods: The authors performed quantitative analysis of white matter myelination detected with conventional T1-weighted spin echo (SE) MRI and brain functional MRI (fMRI) using echoplanar imaging with photic stimulation in 27 neurologically normal infants (age range, 0 to 22 weeks).Results: An age-dependent gradual increase in signal intensity was observed in optic radiation on the T1-weighted SE images, indicating progression of white matter myelination. A rapid age-dependent reverse in signal response was observed on fMRI. Infants older than 8 weeks showed a stimulus-induced signal decrease in the visual cortex, whereas infants younger than 7 weeks showed a signal increase.Conclusions: A rapid inversion of response revealed by fMRI with photic stimulation in infants suggests a change in oxygen consumption during neuronal activation, which is related to rapid synapse formation and accompanying increased metabolism. fMRI can detect dynamic metabolic changes during brain maturation, which is a different developmental process from white matter myelination. The metabolic changes detected by fMRI provide a milestone for the evaluation of normal brain development.

Telomerase plays a key role in the maintenance of chromosomal stability in tumors, but the mechanism regulating telomerase activity is still unclear. Recent studies have suggested that c-myc may be vital for regulation of hTERT mRNA expression and telomerase activity. In this study, we investigated the changes of telomerase activity and telomerase-related genes induced by herbimycin A in K562 human chronic myelogeous leukemic cells. Telomerase activity showed a biphasic pattern in herbimycin A-treated K562 cells. Initially, the telomerase activity decreased along with the decline of cells in S and G2/M phases, but it recovered slightly at the end of treatment. Expression of mRNA for the telomerase catalytic subunit (hTERT) was decreased before the decline of telomerase activity, and increased slightly before the reactivation of telomerase activity. During herbimycin A treatment, both c-myc and cyclin D1 mRNA showed transient downregulation before the increase of G1 cells. Herbimycin A treatment caused the downregulation of both telomerase activity and hTERT mRNA in cyclin D1-transfected K562 cells, while telomerase activity was partially restored in c-Myc-transfected cells. In contrast, hTERT-transfected K562 cells maintained a high level of telomerase activity during herbimycin A treatment. Neither the template RNA component of telomerase (hTERC) nor telomerase-associated protein (TEP-1) were altered in any of the transfected K562 cells. These results indicate that telomerase activity is mainly regulated by hTERT, and that c-Myc protein is one of the positive regulators of hTERT in leukemic cells but is not enough to counteract the downregulation of telomerase activity by herbimycin A completely.

It has been shown that either dual-chamber or atrial pacing may be better than ventricular single-chamber pacing, but the long-term effect of dual-chamber pacing on cardiac sympathetic activity is unclear. The aim of this study was to assess the effect of long-term dual-chamber pacing on cardiac sympathetic activity, compared with atrial pacing and unpaced individuals. We studied 11 patients with dual-chamber pacemakers (Group D), nine with atrial single-chamber pacemakers (Group A) over the long term (mean 44 +/- 36 months) and 10 normal individuals without cardiac pacing. All underwent myocardial 123I-metaiodobenzylguanidine (MIBG) imaging to assess cardiac sympathetic activity. The heart-to-mediastinum (H/M) MIBG uptake ratio and the MIBG washout rate from the myocardium were calculated. Echocardiography was performed in all patients with cardiac pacing to assess left ventricular function. In Group D, the H/M ratio on delayed images was significantly lower than that of Group A (1.82 +/- 0.51 vs 2.56 +/- 0.50, P < 0.001) and normal individuals (2.65 +/- 0.35, P < 0.05). The myocardial MIBG washout rate of Group D was significantly higher than that of either Group A (52 +/- 13% vs 36 +/- 8%, P < 0.01) or normal individuals (31 +/- 7%, P < 0.05). Neither the H/M ratio nor MIBG washout rate differed significantly between patients in Group A and normal individuals. Furthermore, the echocardiographic parameters did not differ significantly between the two pacing groups. We conclude that long-term ventricular pacing, even in the presence of atrioventricular synchrony, accelerates cardiac sympathetic activity without deteriorating left ventricular function.

The serous adenocarcinoma (SA) and clear cell adenocarcinoma (CCA) of endometrium have been shown to be associated with high relapse rate and poor survival. It is not clear whether prognostic significance of these specific cell types of tumor is independent of retroperitoneal lymph node metastasis and other histopathologic prognostic factors in endometrial carcinoma.We examined 240 consecutive patients with clinical stage I to stage III endometrial carcinoma who were treated prospectively with radical surgery and/or platinum-based chemotherapy. Surgery included extended hysterectomy, bilateral salpingo-oophorectomy, and systematic pelvic and paraaortic lymph node dissection. Prognostic significance of various histopathologic factors was determined by Cox regression analysis.SA/CCA were more frequently associated with deep myometrial invasion, high nuclear grade (G3), lymph-vascular space invasion (LVSI), and pelvic lymph node metastasis when compared to endometrioid adenocarcinoma (EMA). Of 216 clinically staged stage I or II disease, seven of 12 cases of SA/CCA had extrauterine disease. This incidence was much higher than that for EMA (46/204) (p0.01). A multivariate Cox regression analysis revealed that cell type, grade, LVSI, and paraaortic node metastasis (PANM) were independent prognosticators.Prognosis of patients with endometrial carcinoma depends on cell type, grade, LVSI, and PANM. Poor prognosis for patients with SA/CCA is independent of lymph node metastasis and other histopathologic prognostic factors. The SA/CCA should be strictly discriminated from EMA.

Introduction Acetylcholine (ACh) is a well known neurotransmitter in the central nervous system, but determining its level in cerebrospinal fluid (CSF) is very difficult and the origin of CSF ACh is still unknown. In this study, we attempted to measure CSF ACh by a specific and sensitive radioimmunoassay (RIA) from patients with neurologic diseases. Material and methods Patients with cerebral infarction (n = 7), Parkinson's disease (n = 6), spinocerebellar degeneration (n = 6), Alzheimer's disease (n = 3), amyotrophic lateral sclerosis (n = 3) and disc herniation with no central nervous involvement (n = 8) participated to determine the CSF ACh levels. Results Of these 33 patients, the mean ACh level in CSF was 282.2 +/- 61.7 fmol/ml (mean +/- SE, range 20-1505.8 fmol/ml). The mean ACh level of spinocerebellar degeneration group was lower than others, but not statistically significant. Conclusion We conclude that an amount of ACh detectable by RIA is certainly present in CSF.

The immunopathogenesis of autoimmune hepatitis (AIH), and the role of T cells in the onset and maintenance of this disease, are still unclear. Since T cells expand clonally after stimulation by an antigen, it is important to analyze the behavior of T cells at a clonal level. We have established recently a novel system, using reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent single-strand conformation polymorphism (SSCP) that allows the identification of clonal accumulation of T cells in a lymphocyte population. Using this system, we demonstrated that oligoclonal T cells were accumulated in the liver of patients with AIH, and that identical T-cell clonotypes were detected in two different regions of the liver, although these features were also observed in cases with viral hepatitis. Only in cases with AIH, however, nearly all identical T cells were found to belong to CD8+ subset and there were very few CD4+ T cells in this population. Our results suggest that common antigens presented to CD8+ T cells in the context of HLA class I molecule are distributed diffusely in the liver of AIH. These findings also suggest that antigens recognized by CD4+ T cells may be relatively heterogeneous in the liver with AIH.

Ocular manifestations of adult T-cell leukemia/lymphoma (ATL) are rare events. However, several ocular lesions which resulted from human T-cell leukemia virus type I (HTLV-I) infection have been reported, including direct infiltration of ATL cells, cytomegalovirus retinitis, and HTLV-I-associated uveitis (HAU). The aim of this study was to characterize ocular involvement in ATL and to correlate these lesions with HTLV-I proviral DNA integration. Three patients with acute-type ATL and ocular lesions were evaluated hematologically and ophthalmologically. Analysis of HTLV-I proviral DNA was carried out with a standard Southern blot technique using DNA from abnormal lymphocytes in peripheral blood. Two patients developed intraocular lesions located within intermediate and/or posterior segments which were caused by infiltration of ATL cells. Ocular lesions in one patient, which were localized to the anterior-intermediate segment, closely resembled those of HAU. Analysis of HTLV-I proviral DNA revealed multiple integrations in all three patients. The present study indicated heterogeneity in ocular manifestations of ATL. Multiple HTLV-I proviral DNA integrations may be associated with intraocular involvement in this disease.

Although the number of global clinical trials (GCTs) conducted in multiple countries including Japan has increased recently, it is not clear how much these GCTs help in reducing the lag in drug development (LDD: difference between the submission dates for new drug applications (NDAs) in the United States and Japan). We examined the effects of various clinical development strategies on LDD because the development period depends on what types of clinical trials were conducted for the Japanese NDA. Although various drug development strategies are available, deciding early on an appropriate strategy is a key to minimizing the LDD in Japan. The inclusion of GCTs in the clinical development strategy is also important; simultaneously, the smaller sample size of the Japanese population should be taken into consideration. Furthermore, reinforcement of Japan's capability to lead drug development may also be important in providing innovative drugs to Japanese patients without any significant LDD. Clinical Pharmacology & Therapeutics (2014); 95 5, 533–541. doi:10.1038/clpt.2013.223

The objective of this study was to investigate ethnic differences in the glyoxylate reductase/hydroxypyruvate reductase (GRHPR) gene in patients with primary hyperoxaluria type 2 (PH2). GRHPR was genotyped in Japanese patients with PH2 and all GRHPR mutations described to date were reviewed in terms of geographic and ethnic association. We identified a novel mutation, a two-nucleotide deletion (c.248_249delTG) in exon 3 creating a premature 'stop' at codon 91. Also, we found that the c.864_865delTG mutation was associated with the rs35891798 single-nucleotide polymorphism. The allelic frequencies of the c.103delG, c.494GA, c.403_404+2 delAAGT, and c.864_865delTG mutations in PH2 patients were 37.8%, 15.6%, 10.0%, and 10.0%, respectively. All patients with the c.103delG mutation were Caucasian. Patients with the c.494GA mutation and 78% (7/9) of those with the c.403_404+2 delAAGT mutation were from the Indian subcontinent, whereas those with the c.864_865delTG mutation were Chinese or Japanese. Molecular analysis of GRHPR of four Japanese PH2 patients identified a novel mutation (c.248_249delTG in exon 3). Caucasians with PH2 should be screened for the c.103delG mutation; patients from the Indian subcontinent for c.494GA; and patients of East Asian origin (particularly) for c.864_865delTG. The prevalence of the latter mutation in PH2 patients from East Asia was 75.0%.

The purpose of this study was (1) to construct Quality of Life Scale for Elderly (QOLS-E), which was to evaluate the older person's physical, social, and psychological states synthetically, and (2) to find out which factors most influenced the person's psychological satisfaction. Two groups of people, 42 in total who were between 65 and 90 years old, participated in the study, with 25 living in the nursing home, and 17 in the hospital. Although the factor structure of QOLS-E was reasonable, the reliabilities were not very high, meaning further research was necessary to improve the scale. Multiple regression showed that Satisfaction with Activities of Daily Life was apt to be related to psychological satisfaction. Also, enjoying a hobby and positive relationships with institutional staff members appeared important for other facets of psychological satisfaction. As for subscales of psychological satisfaction, enjoying a hobby was significantly related to Acceptance of Own Life, and number of diseases to Mental Stability. Another subscales of QOLS-E, Satisfaction with Family Relationships, was also related to Acceptance of Own Life.

Dystrophin is associated with several novel sarcolemmal proteins, including a laminin-binding extracellular glycoprotein of 156 kD (alpha-dystroglycan) and a transmembrane glycoprotein of 50 kD (adhalin). Deficiency of adhalin characterizes a severe autosomal recessive muscular dystrophy prevalent in Arabs. Here we report for the first time two mongoloid (Japanese) patients with autosomal recessive muscular dystrophy deficient in adhalin. Interestingly, adhalin was not completely absent and was faintly detectable in a patchy distribution along the sarcolemma in our patients. Although the M and B2 subunits of laminin were preserved, the B1 subunit was greatly reduced in the basal lamina surrounding muscle fibers. Our results raise a possibility that the deficiency of adhalin may be associated with the disturbance of sarcolemma-extracellular matrix interaction leading to sarcolemmal instability.

Fifty-seven patients with locally advanced, clinical stage TC, adenocarcinoma of the prostate underwent treatment consisting of surgery, external beam radiation therapy and, in selected patients, early hormonal ablation and/or systemic chemotherapy. Surgical morbidity from radical retropubic prostatectomy and limited pelvic lymph node dissection was acceptable with an early complication rate of 11%. Followup ranged from 3.5 to 19.9 years (median 5.4 years). Actuarial 5 and 7.5 years survival rates for all patients was 91.2% and 77.6%, respectively. Of the 57 study patients 19 (33%) were alive with no evidence of disease, including a prostate specific antigen (PSA) less than 0.4 ng/ml at all times during follow-up. The estimated 5 year probability of clinical recurrence was 18.6% and the 5 year probability of clinical and PSA recurrence (> 0.4 ng/ml) was 54.5%. Local recurrence occurred in only 3 patients. This included 2 (4%) patients who received adjuvant radiotherapy. Our results suggest that patients with locally advanced prostate cancer can be successfully treated with low morbidity using a combination of radical prostatectomy and planned adjuvant radiotherapy.

Setting: As an alternative to biochemical analysis, microplate DNA-DNA hybridization was applied for rapid diagnosis of mycobacterial infection. Objective: To assess how rapidly and correctly the microplate hybridization method can progress from clinical sample to final species identification of mycobacteria. Design: Clinical samples (pooled sputa or bronchial lavage fluid) were obtained from patients. Depending on the estimated bacterial amounts, genetic identification was performed either directly or following primary culture. Extracted DNA labeled by photobiotin was hybridized in microdilution wells with type-strain DNAs from 4 species (Mycobacterium tuberculosis, M. avium, M. intracellulare, and M. kansasii), then identified on the basis of genetic relatedness, which was quantitated by colorimetric detection. Results: With samples containing more than 108 colony-forming units [CFU](5 cases), species identification was successfully performed on the day of sample preparation. With samples of not more than 107 CFU (14 cases), although 4–21 days' primary culture were necessary, species were also correctly identified by the microplate method. Furthermore, M. avium and M. intracellulare were distinctly identified. All the results precisely corresponded to those of biochemical analysis, which took 4–12 weeks to complete identification. Conclusion: We consider that microplate DNA-DNA hybridization is a dependable technique for rapid diagnosis of mycobacterial infection.

We report two sisters with congenital myotonic dystrophy (CDM) born to a normal mother and an affected father. The congenitally affected daughters had symptoms from birth. The age of onset of DM in the father was 39 years. Analysis of the CTG trinucleotide expansion in this family showed increase in the repeat length with increasing severity, with the smallest expansion in the grandfather and the largest expansion in the younger of the two CDM sisters. This family shows that exceptionally it is possible for CDM to be inherited paternally and refutes the hypothesis that CDM is exclusively of maternal origin. This contradicts several of the previous hypotheses concerning the mechanisms by which the CDM phenotype arises.

Arteriovenous malformation at the cerevicomedullary junction is a rare disorder, usually presenting with subarachnoid hemorrhage. The diagnosis is difficult because of its anatomical location. In addition, the ventral location of these arteriovenous malformations makes surgical treatment difficult. We describe three cases surgically treated with a transcondylar approach. The usefulness of digital subtraction angiography and magnetic resonance imaging is discussed. The technique of the transcondylar approach is also described, including C1 hemilaminectomy, unroofing of the transverse foramen of C1 to obtain control of the vertebral artery, and partial resection of the occipital condyle and lateral atlantal mass by extradural drilling. This approach provides direct access to the ventral portion of the cervicomedullary junction.

PURPOSE: To assess the feasibility of demonstrating cardiac motion with 313.6-msec single-shot turbo-fast low-angle shot magnetic resonance imaging. MATERIALS AND METHODS: Effects of motion on single-shot images were evaluated with a phantom moving at known velocity. Single-shot images were obtained in eight healthy volunteers and four cardiac patients and compared with conventional cine images. RESULTS: The moving phantom was visualized at the location where zero phase-encoded data were sampled. When the velocity was within the physiologic range of left ventricular wall motion (< 11 cm/sec), the full width at half maximum of the object on a 64 x 64-matrix image with a 4.9-msec repetition time was comparable with that of a stationary phantom. The left ventricular cross-sectional area determined with single-shot imaging showed good correlation with results of conventional cine imaging (r = .96) in healthy volunteers. CONCLUSION: Single-shot imaging can be used for simple and quick assessment of cardiac fun...

Thirty-nine pregnant women with idiopathic thrombocytopenic purpura (ITP) were studied in order to evaluate the influence of therapies for maternal ITP on fetal passive immune thrombocytopenia (PIT). Neonatal platelet counts were also compared with platelet counts, amount of PAIgG, and presence of circulating antiplatelet antibody in maternal blood. Eight of 41 neonates (19.5%) presented PIT without neonatal mortality. A higher incidence of PIT was observed in women with prior splenectomy than in women without splenectomy (66.7% vs 11.4%). Neither a therapeutic effect nor an increased risk of PIT was observed with steroids or gammaglobulin administration. No correlation was found between neonatal platelet counts and maternal platelet counts or maternal PAIgG, while positive cases for circulating antiplatelet antibody assay presented a higher incidence of PIT than negative cases. Additionally, a higher incidence of PIT was observed in women with a history of previous PIT than in women with a history of normal delivery. Prior splenectomy, presence of antiplatelet antibody in maternal blood, and a history of previous PIT seem to be risk factors for fetal PIT.

A 41 year old man with parkinsonism and pyramidal signs is described. He was non-responsive to levodopa and dopamine receptor agonists but dramatically responded to trihexyphenidyl. In this patient, brain MRI showed bilateral hyperintensities along the corticospinal tracts on T2 weighted images. PET studies showed a decrease in (18)F-6-fluorodopa uptake in the putamen contralateral to the more affected limbs and normal D(2) receptor binding in the putamen. The PET and MRI findings and responsiveness to antiparkinsonian agents suggested degeneration of nigrostriatal dopaminergic neurons, striatal output pathways, and corticospinal tracts.

Introduction The purpose of this study was to evaluate the long term results of 19 painful dislocated hips in patients with spastic cerebral palsy (CP) who were treated with hip arthrodesis and internal fixation. Patients and methods The study included 19 patients with spastic CP with a mean age of 17 years and five months (min 10+11 and max 30+8) at the time of surgery. There were 11 tetraplegics, 5 diplegics, 2 diplegics with athetosis, and one hemiplegic. Functionally, 4 patients were community ambulators, 2 were household, and 13 were non-ambulators. Six patients had previous hip procedures prior to arthrodesis. The main surgical indications were pain and too much joint destruction to reconstruct the hip. The mean follow-up period was 11 years and one month. Results All patients showed bone union and pain relief, and postural improvement was seen in almost all patients. Four patients needed revision, with implant change and bone graft for delayed union. In two cases, the hip arthrodesis ended up being converted into a Castle procedure due to difficulties in positioning and/or increasing spinal deformity. Conclusion Hip arthrodesis is a reasonable option in treating painful spastic subluxated and dislocated hips in CP, primarily in unilateral cases and in patients with ambulatory ability.

The present study examined the long-term cognitive implications of cancer treatment among breast cancer survivors aged 65 years and older to better understand the long term implications of cancer treatment.Fifty-seven women survivors were compared with 30 healthy older female adult comparisons, matched in terms of age and education, with no history of cancer. Cancer survivors were also compared on the basis of treatment intervention, involving chemotherapy (n = 27) versus local therapy through surgery and radiation (n = 30).As a group, the breast cancer survivors scored lower on measures of general cognitive function, working memory, psychomotor speed, and executive function when compared with the normal comparisons. Among the cancer survivors, those who received local therapy scored lower than the other survivors and normal comparisons on measures of verbal learning, visual perception and construction, as well as visual attention and short-term retention.Our findings suggest that cognitive outcomes may involve greater age-related deficits among older cancer survivors compared with matched healthy subjects.