Palladium mediated 11C-cyanation and characterization in the non-human primate brain of the novel mGluR5 radioligand [11C]AZD9272

IntroductionThe aims of the present positron emission tomography (PET) study were to set up a system for ¹¹C-cyanation labeling of the selective mGluR5-antagonist [¹¹C]AZD9272 and to perform the first in vivo characterization of [¹¹C]AZD9272 binding in cynomolgus monkeys.Methods[¹¹C]AZD9272 was labeled using palladium mediated ¹¹C-cyanation. Altogether seven PET measurements were performed in three cynomolgus monkeys including baseline and co-injection experiments with unlabelled AZD9272 (0.04 and 0.4 mg/kg). Radiometabolites in plasma were measured using HPLC.Results[¹¹C]AZD9272 was prepared in over 50% incorporation yield from hydrogen [¹¹C]cyanide in a total synthesis time of 45–50 min. The radiochemical purity of the radioligand in its final formulation was high (> 99%) and the mean specific radioactivity was 47 GBq/ μmol (1278 Ci/mmol, n = 7) calculated at end of bombardment (EOB). In the baseline measurements 10% of the total injected radioactivity was present in monkey brain at five minutes after i.v. injection. The radioactivity concentration was high in the caudate, cingulate gyrus and thalamus whereas it was moderate in the temporal cortex and lower for the cerebellum. After co-injection with cold AZD9272 the binding of [¹¹C]AZD9272 was reduced in a dose-dependent fashion. Analysis of radiometabolites showed relatively slow metabolism and resulted only in hydrophilic radiometabolites.ConclusionA fast and efficient method was developed to label AZD9272 with ¹¹C. PET-examination in Cynomolgus monkeys showed that [¹¹C]AZD9272 entered the brain to a high extent, that binding was saturable and that the regional radioactivity pattern was in accordance with the known distribution of mGluR5. The results support further examination of [¹¹C]AZD9272 binding in human subjects.     

Do Direct Current Electric Fields Enhance Micturition in the Spinal Cat?

ABSTRACT

Changes in micturition behavior and motoneuron ultrastructure were studied in spinal cats to determine the effects of direct current (DC) electric field treatment. Adult cats received a complete injury at T8. A treatment group with an implanted 15 pA DC source and electrodes positioned near the lesion site was compared with non-treatment groups that were either operated or unoperated. Both bladder emptying with Crede and the withdrawal reflex were improved in the treatment group compared with the non-treatment group. Urodynamic procedures showed that high urethral resistance and pelvic floor activity following spinal injury was partially reduced in the stimulated cat, indicating inhibition of the urethral sphincter. The ultrastructural analysis of Onuf’s nucleus suggested a similar synaptic input in all three groups. In conclusion, possible activation of inhibitory processes and/or neural plasticity best explain the early improvement of bladder function seen following electrical stimulation. (J Spinal Cord Med 19:225–233)     

Prevalence of surgical-site infections and patterns of antimicrobial use in a large tertiary-care hospital in Ho Chi Minh City, Vietnam.

BACKGROUND: Few studies have been conducted in Vietnam on the epidemiology of healthcare-associated infections or antimicrobial use. Thus, we sought to determine the prevalence of and risk factors for surgical-site infections (SSIs) and to document antimicrobial use in surgical patients in a large healthcare facility in Vietnam. METHODS: We conducted a point-prevalence survey of SSIs and antimicrobial use at Cho Ray Hospital, Ho Chi Minh City, a 1,250-bed inpatient facility. All patients on the 11 surgical wards and 2 intensive care units who had surgery within 30 days before the survey date were included. RESULTS: Of 391 surgical patients, 56 (14.3%) had an SSI. When we compared patients with and without SSIs, factors associated with infection included trauma (relative risk [RR], 2.65; 95% confidence interval [CI95], 1.60 to 4.37; P < .001), emergency surgery (RR, 2.74; CI95, 1.65 to 4.55; P < .001), and dirty wounds (RR, 3.77; CI95, 2.39 to 5.96; P < .001). Overall, 198 (51%) of the patients received antimicrobials more than 8 hours before surgery and 390 (99.7%) received them after surgery. Commonly used antimicrobials included third-generation cephalosporins and aminoglycosides. Thirty isolates were identified from 26 SSI patient cultures; of the 25 isolates undergoing antimicrobial susceptibility testing, 22 (88%) were resistant to ceftriaxone and 24 (92%) to gentamicin. CONCLUSIONS: Our data show that (1) SSIs are prevalent at Cho Ray Hospital; (2) antimicrobial use among surgical patients is widespread and inconsistent with published guidelines; and (3) pathogens often are resistant to commonly used antimicrobials. SSI prevention interventions, including appropriate use of antimicrobials, are needed in this population.     

Botulinum toxin in blepharospasm and oromandibular dystonia: comparing different botulinum toxin preparations

Amongst all regions of the body, the craniocervical region is the one most frequently affected by dystonia. Whilst blepharospasm – involuntary bilateral eye closure – is produced by spasmodic contractions of the orbicularis oculi muscles, oromandibular dystonia may cause jaw closure with trismus and bruxism, or involuntary jaw opening or deviation, interfering with speaking and chewing. Both forms of dystonia can be effectively treated with botulinum toxin injection. This article summarizes injection techniques in both forms of dystonia and compares doses, potency and efficacy of different commercially available toxins, including Botox®, Dysport®, Xeomin® and Myobloc®/NeuroBloc®.     

Endoskopische therapie benigner anastomosenstenosen im kolon- und rektumbereich durch elektroinzision und ballondilatation

Zusammenfassung 21 Patienten mit postoperativ aufgetretenen Anastomosenstenosen wurden mittels Elektroinzision in Kombination mit einem Ballondilatator behandelt. Der Schweregrad des Beschwerdebilds korrelierte direkt mit dem Ausmaß der Lumeneinengung (Grad I: Durchmesser 13 mm, n = 12; Grad II: Durchmesser 7 mm, n = 6; Grad III: Durchmesser 4 mm, n = 3). Nach einer endoskopischen Therapie waren alle Patienten mit einer erst- und zweitgradigen Anastomosenstenose beschwerdefrei. Drittgradige Stenosen konnten in 2 Fällen klinisch weitgehend mit verbleibenden gelegentlichen abdominalen Krämpfen und Meteorismus gebessert werden. Ein Patient mit Stenosegrad III profitierte von der Therapie nicht. Die durchschnittliche Dilatationsfrequenz betrug 1,5mal, Komplikationen wie Blutung und Perforation traten nicht auf. Tierexperimentell erhobene Befunde erklären Anastomosenstenosen Durch eine vermehrte, submuköse Kollagenfasereinlagerung mit nachfolgender Narbenbildung im Anastomosenbereich. Die Effektivität der Therapiekombination Elektroinzision und Ballondilatation begründet sich in einer Aufweitung des Narbenrings, ohne eine erneute Kollagenfaserbildung zu induzieren.

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Endoscopic therapy of benign anastomotic stenosis of the colorectal region by electroincision and balloon dilatation

21 patients with a severe anastomotic stenosis in the colorectal region were treated with hydraulic balloon dilatation and endoscopic electroincision. The severity of symptoms directly correlates with the extent of stenosis (degree I Ø 13 mm, n = 12; degree II Ø 7 mm, n = 6; degree III Ø 4 mm, n = 3). All patients with a stenosis of degree I and II were symptom-free after the endoscopic therapy. In 2 of 3 cases the symptoms of stenosis of degree III could clinically be improved after the treatment. The average frequence of dilatation was 1.5 ×, complications such as bleeding or perforation were not registered. Animal studies explain anastomotic stenosis through an increased submucosal formation of collagen fibers followed by formation of scars in the anastomosis. The efficiency of electroincision and balloon dilatation is based on an increased diameter in the anastomotic region without increased formation of new collagen fibers.

     

Mucinous tubular and spindle cell carcinoma of kidney is probably a variant of papillary renal cell carcinoma with spindle cell features

Mucinous tubular and spindle cell carcinoma is a rare and newly described type of renal cell carcinoma (RCC) with a relatively indolent behavior. However, its histogenetic origin or line of differentiation remains unclear. Twelve cases of mucinous tubular and spindle cell carcinoma were identified and retrieved from the files of 3 institutions. Detailed morphological features, as well as their immunohistochemical profile established with markers of proximal renal tubules (RCC marker antigen, CD15, and alpha-methylacyl-CoA racemase) and of distal renal tubules (kidney-specific cadherin and cytokeratin 7), were studied. The age range of the patients was 35 to 73 years with a median of 56 years. The male to female ratio was 1:3. All of the patients were alive with follow-up between 4 and 38 months. All the tumors were confined to the kidney with a mean tumor size of 6.9 cm (range, 1.8-17 cm). The tumors were composed of variable proportions of tubular and spindle cell areas with focal to prominent mucinous or myxoid stroma. Foamy macrophages were seen in 10 cases and were prominent in 4 cases. A focal compressed tubulopapillary growth pattern was seen in 10 cases. The tumor cells were uniformly cuboidal with ovoid to round nuclei and inconspicuous nucleoli (Furhman nuclear grade 3 in 6 cases). Focal necrosis was seen in 3 cases. Immunostains showed that tumors were positive for RCC marker antigen (11/12), alpha-methylacyl-CoA racemase (11/12), CD15 (8/12), CD10 (2/12), kidney-specific cadherin (1/12), and cytokeratin 7 (11/12). Its morphological features as well as a strong preferential expression of proximal tubule markers suggest that this tumor is a type of RCC with proximal tubular differentiation, which appears closely related to or represents a morphological variant of papillary RCC.     

Variations in the core promoter/pre-core region in HBV genotype C in Japanese and Northern Vietnamese patients

Hepatitis B virus (HBV) subgenotypes Cs (C1) and Ce (C2) are common in East Asia. To investigate the genomic difference of HBV genotype C between two separated regions, 50 subgenotype Cs-infected Vietnamese and 70 subgenotype Ce-infected Japanese patients were enrolled for analysis. The patients were categorized to either a hepatocellular carcinoma group (HCC) or a non-HCC group including liver cirrhosis, chronic hepatitis, and asymptomatic carriers. HBV serology, HBV-DNA level, and variations in core promoter/pre-core region were examined. Phylogenetic analysis based on the full genome sequences and nucleotide sequences partly in the S gene and in the P gene revealed that all Japanese strains (70/70) were subgenotype Ce, and nearly all of the Vietnamese strains (50/51) were subgenotype Cs, excluding one subgenotype C5. C1858 and G1775 were common in the Vietnamese (64% and 40%) but not in the Japanese (0%). The prevalence of C/A1753 in Vietnamese was higher than that in the Japanese (32% vs. 17.1%), however the frequency of A1896 in the Japanese was significantly higher (32.9% vs. 12%, P < 0.05). Most of the Vietnamese patients with HCC had a high level of HBV-DNA, the Japanese HCC had a relatively low level. In the Vietnamese, C/A1753 and C1858 were associated closely with T1762A1764, higher HBV-DNA levels and higher HCC incidence. The multivariate analysis revealed that male, T1653 and C/A1753 were independent risk factors for HCC. The subgenotypes and unique mutations of HBV genotype C in the Vietnamese and Japanese differed, and C/A1753 and C1858 variants might play a role in the pathogenesis of liver disease in Vietnamese patients.     

CD4 cell and CD8 cell-mediated resistance to HIV-1 infection in exposed uninfected intravascular drug users in Vietnam

OBJECTIVE: To identify mechanisms of resistance to HIV-1 infection in exposed uninfected individuals. DESIGN: We examined in-vitro cell susceptibility to HIV-1 infection in highly exposed Vietnamese intravascular drug users (IDU) who, despite a history of more than 10 years of drug use and a high prevalence of other blood-borne viral infections, remain apparently HIV uninfected. METHODS: Forty-five exposed uninfected IDU and 50 blood donors were included in the study. Peripheral blood mononuclear cells (PBMC) or CD4 cell susceptibilities to HIV infection were evaluated using three HIV-1 isolates with different tropisms. Polymerase chain reaction analysis of HIV-1-DNA replication intermediates was used to characterize the restriction of HIV-1 replication in CD4 cells. Homologous CD8 cells were mixed with infected CD4 cells to evaluate their role in virus suppression. RESULTS: We observed a relative resistance to PBMC infection with HIV-1 in 21 out of 45 exposed uninfected IDU, but only in five out of 50 unexposed controls (P < 0.001). PBMC resistance was related either to an inhibition of HIV-1 replication in CD4 cells or to CD8 cell-mediated viral suppression. HIV-1 replication in CD4 cells was restricted at the early stages of the viral cycle. CONCLUSION: Reduced PBMC susceptibility to HIV-1 infection was associated with resistance to infection in exposed uninfected IDU. Distinct mechanisms are involved in in-vitro resistance and may contribute to the apparent protection from HIV-1 transmission in this systemically exposed population.