Population Pharmacokinetics and Antimalarial Pharmacodynamics of Piperaquine in Patients With Plasmodium vivax Malaria in Thailand.

Dihydroartemisinin-piperaquine is an effective drug in the treatment of Plasmodium falciparum and P. vivax malaria. The objective of this study was to evaluate the population pharmacokinetics and pharmacodynamics of piperaquine in patients with P. vivax malaria in Thailand after a standard regimen of dihydroartemisinin-piperaquine to determine whether residual piperaquine prevents or delays the emergence of P. vivax relapse. Sparse blood samples were collected from 116 patients. Piperaquine pharmacokinetics were described well by a three-compartment distribution model. Relapsing P. vivax malaria was accommodated by a constant baseline hazard (8.94 relapses/year) with the addition of a surge function in a fixed 3-week interval and a protective piperaquine effect. The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection. This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

The presence of leukocytes in ex vivo assays significantly increases the 50-percent inhibitory concentrations of artesunate and chloroquine against Plasmodium vivax and Plasmodium falciparum.

Plasmodium species ex vivo sensitivity assay protocols differ in the requirement for leukocyte removal before culturing. This study shows that the presence of leukocytes significantly increases the 50% inhibitory concentration (IC50) of P. vivax and P. falciparum to artesunate and chloroquine relative to results with the paired leukocyte-free treatment. Although leukocyte removal is not an essential requirement for the conduct of ex vivo assays, its use has important implications for the interpretation of temporal and spatial antimalarial sensitivity data.

Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific and South East Asian regions, 2007-2008.

Long-term surveillance of antimicrobial resistance in Neisseria gonorrhoeae has been conducted in the World Health Organization (WHO) Western Pacific Region (WPR) to optimise antibiotic treatment of gonococcal disease since 1992. In 2007 and 2008, this Gonococcal Antimicrobial Surveillance Programme (GASP) was enhanced by the inclusion of data from the South East Asian Region (SEAR) and recruitment of additional centres within the WPR. Approximately 17,450 N. gonorrhoeae were examined for their susceptibility to one or more antibiotics used for the treatment of gonorrhoea by external quality controlled methods in 24 reporting centres in 20 countries and/or jurisdictions. A high proportion of penicillin and/or quinolone resistance was again detected amongst isolates tested in North Asia and the WHO SEAR, but much lower rates of penicillin resistance and little quinolone resistance was present in most of the Pacific Island countries. The proportion of gonococci reported as 'resistant', 'less susceptible' or 'non-susceptible' gonococci to the third-generation cephalosporin antibiotic ceftriaxone lay in a wide range, but no major changes were evident in cephalosporin minimal inhibitory concentration (MIC) patterns in 2007-2008. Altered cephalosporin susceptibility was associated with treatment failures following therapy with oral third-generation cephalosporins. There is a need for revision and clarification of some of the in vitro criteria that are currently used to categorise the clinical importance of gonococci with different ceftriaxone and oral cephalosporin MIC levels. The number of instances of spectinomycin resistance remained low. A high proportion of strains tested continued to exhibit a form of plasmid mediated high level resistance to tetracyclines. The continuing emergence and spread of antibiotic resistant gonococci in and from the WHO WPR and SEAR supports the need for gonococcal antimicrobial resistance surveillance programs such as GASP to be maintained and potentially expanded.

Novel animal models for studying complex brain disorders: BAC-driven miRNA-mediated in vivo silencing of gene expression.

In schizophrenia, glutamic acid decarboxylase 1 (GAD1) disturbances are robust, consistently observed, cell-type specific and represent a core feature of the disease. In addition, neuropeptide Y (NPY), which is a phenotypic marker of a sub-population of GAD1-containing interneurons, has shown reduced expression in the prefrontal cortex in subjects with schizophrenia, suggesting that dysfunction of the NPY+ cortical interneuronal sub-population might be a core feature of this devastating disorder. However, modeling gene expression disturbances in schizophrenia in a cell type-specific manner has been extremely challenging. To more closely mimic these molecular and cellular human post-mortem findings, we generated a transgenic mouse in which we downregulated GAD1 mRNA expression specifically in NPY+ neurons. This novel, cell type-specific in vivo system for reducing gene expression uses a bacterial artificial chromosome (BAC) containing the NPY promoter-enhancer elements, the reporter molecule (eGFP) and a modified intron containing a synthetic microRNA (miRNA) targeted to GAD1. The animals of isogenic strains are generated rapidly, providing a new tool for better understanding the molecular disturbances in the GABAergic system observed in complex neuropsychiatric disorders such as schizophrenia. In the future, because of the small size of the silencing miRNAs combined with our BAC strategy, this method may be modified to allow generation of mice with simultaneous silencing of multiple genes in the same cells with a single construct, and production of splice-variant-specific knockdown animals.

Occurrence of synchronous invasive lobular breast carcinoma and poorly differentiated ovarian carcinoma in a single peritoneal deposit.

The synchronous occurrence of breast and ovarian cancers within individual omental metastases has not been reported in the available medical literature. We report such a finding in a patient with previously diagnosed invasive lobular carcinoma of the right breast. After 5 years of surveillance and disease-free interval, there was development of ovarian cancer, ascites and peritoneal metastases. Ultrasound-guided biopsy of a peritoneal metastasis confirmed dual histology from breast and ovarian carcinoma. Despite the presence of a prolonged disease-free survival from the primary breast cancer, the subsequent finding of advanced ovarian cancer highlights the potential diagnostic and therapeutic dilemmas which persist in the management of these patients.

Tenosynovial giant cell tumour of the neck.

We report the case of a diffuse tenosynovial giant cell tumour to be found adjacent to the thyroid gland. These tumours, also known as extra-articular pigmented villonodular synovitis, are found more commonly in the fingers, wrist, knee thigh and foot, rarely in the head and neck. These tumours are prone to local recurrence, require a high clinical index of suspicion and if they have atypical features may be extremely difficult to obtain a histological diagnosis.

Case report 734. Fibroma of tendon sheath eroding 3rd metatarsal bone.

A case is presented of a 37-year-old man with an extrinsic lesion originating in the soft tissue adjacent to the 3rd metatarsal and smoothly eroding the adjacent bone. The operatively confirmed diagnosis of fibroma of tendon sheath was surprising, giant cell tumour of tendon sheath eroding bone being considerably more common; these two lesions are normally impossible to distinguish radiologically.

An immunohistological study of leukocyte localization in benign and malignant breast tissue.

Using morphometric and immunohistological techniques, we investigated the distribution of T lymphocytes and subsets, B lymphocytes, macrophages and plasma cells in sections of human breast tissue. In normal lobules and ducts, leukocytes were found in greater density in the epithelium than in the stroma. The intra-epithelial cells consisted largely of suppressor/cytotoxic T lymphocytes with a smaller number of macrophages; inducer T cells were seen in only 1 out of 10 subjects and were present in very low numbers. In the stroma, there were roughly equal numbers of suppressor/cytotoxic cells, macrophages and plasma cells containing IgA or IgM. Small numbers of stromal inducer lymphocytes were seen in only 2 cases. Although the density of suppressor/cytotoxic cells in the epithelium was considerably greater than in the stroma, macrophages were present in roughly similar density in both locations. In carcinoma, the ratio of epithelial to stromal leukocyte density was reversed, due to a marked reduction in intra-epithelial cells and to an increase in those in the stroma. Between 10% and 30% of lymphocytes expressed activation markers in contrast to the normal breast in which virtually all were negative. Inducer lymphocytes were identified in 9/10 carcinomas. The possible relationship of inducer cells to breast carcinoma and pre-neoplasia is discussed and warrants further investigation. No alteration in stromal plasma cell numbers was observed.

BCG vaccination of children against leprosy: fourteen-year findings of the trial in Burma.

The value of BCG vaccination in preventing leprosy among children was studied in an area of high leprosy endemicity in Burma through a controlled trial; one group of 13 066 children received BCG and another group of 13 176 served as controls. The overall protective effect of BCG, which was only about 20% over the 14-year period, was found to vary with the batch of vaccine, as well as age, sex, and contact status of the children. BCG protection was found to be independent of the initial tuberculin status of the children. The protective effect of BCG against the lepromatous type of leprosy could not be measured because of the low incidence. Protection was observed throughout the fourteen years of the study except for the first year. The results are compared with those of three other major BCG trials in leprosy. The trial has shown that BCG provides only a very modest level of protection and that BCG vaccination is not likely to be an important solution for leprosy control.

Epidemiological information on leprosy in the Singu area of Upper Burma.

In the course of a WHO trial designed to evaluate the possible protective action of BCG vaccine against leprosy, a longitudinal epidemiological study of the whole population was carried out in an area of very high endemicity in Burma from 1964 to 1976. Two mass surveys of the whole population with an interval of 4 years and annual re-examination of the 28 000 children (0-14 years) in the BCG trial were carried out. The data collected yielded important information about general prevalence and yearly incidence of the disease as well as on sex, age, and classification of cases. The general prevalence rate declined from 32.6 per 1000 in the first survey to 25.2 per 1000 in the second. The number of cases among males was significantly higher than among females. Incidence rate among contacts of already known cases was 9.8 per 1000 person-years. The estimated yearly incidence among non-contacts was 5.9 per 1000. Prevalence rates reached a peak in the 20-39-year age group. The prevalence rate of multibacillary patients also reached a peak in the same age bracket. It is stressed that a further period of epidemiological surveillance will be essential in order to have a correct estimate of the expected number of new infections, especially multibacillary cases, in the 20-39-year group. The value of this information is considered unique for planning and programming of future control activities.

Case detection rates for Central Burma (1962-1972).

A short description of the leprosy control program in Burmpa is given and the decrease of the case detection rates during thhe period 1962-1972 are presented to show the effects of control measures in the program emphasizing the importance of early case detection through annual examination of household contacts and school children, regular treatment and health education.

BCG vaccination of children against leprosy: nine-year findings of the controlled WHO trial in Burma.

The leprosy incidence rates so far in the vaccinated and unvaccinated children aged 5-9 and 10-14 years are similar. The BCG-vaccinated children aged 0-4 years at intake had an incidence rate lower than that of children in the control group. BCG vaccination did not protect household contacts or children aged 5-14 years not exposed in the household, and did not influence the distribution of the forms of leprosy in the cases detected. The lepromin reaction in relation to the age at intake was consistently stronger in the vaccinated children than in those of the control group; the younger the age group the more pronounced was the difference, which was only slight in the age group 10-14 years at intake. If the results of the late lepromin reaction are related to the age at onset (when the children are older than at intake), the differences between the BCG and the control groups tend to decrease. It does not seem that the BCG-vaccinated children suffer from a less serious form of leprosy than the nonvaccinated children (most of them nonreactors to tuberculin).