No decrease in annual risk of tuberculosis infection in endemic area in Cape Town,South Africa

Objective To estimate the change in annual risk of tuberculosis infection (ARTI) in two neighbouring urban communities of Cape Town, South Africa with an HIV prevalence of approximately 2%, and to compare ARTI with notification rates and treatment outcomes in the tuberculosis (TB) programme. Methods In 1998–1999 and 2005, tuberculin skin test surveys were conducted to measure the prevalence of Mycobacterium tuberculosis infection and to calculate the ARTI. All 6 to 9‐year‐old children from all primary schools were included in the survey. Notification rates and treatment outcomes were obtained from the TB register. Results A total of 2067 children participated in the survey from 1998 to 1999 and a total of 1954 in 2005. Based on a tuberculin skin test cut‐off point of 10 mm, the ARTI was 3.7% (3.4–4.0%) in the 1998–1999 survey and 4.1% (3.8–4.5%) in 2005. The notification rate for pulmonary TB increased significantly from 646 per 100 000 in 1998 to 784 per 100 000 in 2002. In Ravensmead, there was no significant change in ARTI [first survey: 3.5% (3.1–3.9%), second survey: 3.2% (2.9–3.6%)], but in Uitsig the ARTI increased significantly from 4.1% (3.6–4.6%) to 5.8% (5.2–6.5%). The difference in ARTI between the two areas was associated with differences in reported case rates and the proportion of previously treated cases. Conclusion Tuberculosis transmission remains very high in these two communities and control measures to date have failed. Additional measures to control TB are needed.     

The effect of enhanced gap junctional conductance on ventricular conduction in explanted hearts from patients with heart failure

Aim  To investigate ventricular conduction and refractoriness before and after application of rotigaptide, an enhancer of gap junctional conductance, to explanted hearts of patients with heart failure (HF). Methods and results  In six explanted perfused hearts of patients with end-stage HF, activation/repolarization mapping was performed and refractory periods (RPs) and activation recovery intervals (ARIs) were measured before and after application of 50 nM rotigaptide. Rotigaptide caused a decrease of RP from 476 ± 36 to 453 ± 31 ms (P < 0.05), but did not change ARI-dispersion. During premature activation along the fibers rotigaptide decreased the minimal activation time (AT_min) and maximal activation time (AT_max) significantly from 35 ± 12 to 24 ± 9 and from 97 ± 38 to 43 ± 7 ms, respectively. Rotigaptide did not change AT_min and AT_max during activation perpendicular to the fiber direction. After application of rotigaptide conduction curves normalized in five/six recordings when activation was parallel, but destabilized in three/six hearts when activation was perpendicular to fiber direction. The destabilization was associated with local conduction delays rather than with facilitation of conduction. Conclusion  Rotigaptide applied to hearts of patients with end-stage HF shortened RPs normalized conduction curves and increased conduction parallel to fiber direction. However, in 50% of the hearts local slowing of conduction with destabilization of conduction (curves) occurs at sites close to the stimulation site, when activation is perpendicular to fiber direction. Returned for 1. Revision: 14 July 2008 1. Revision received: 26 August 2008 Returned for 2. Revision: 19 September 2008 2. Revision received: 31 October 2008 Returned for 3. Revision: 17 November 2008 3. Revision received: 18 November 2008     

Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model

Background and purpose:

During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate ({"type":"entrez-nucleotide","attrs":{"text":"LY466195","term_id":"1258058612","term_text":"LY466195"}}LY466195) glutamate receptors affected dural vasodilatation induced by α-CGRP, capsaicin and periarterial electrical stimulation in rats, using intravital microscopy.

Experimental approach:

Male Sprague-Dawley rats were anaesthetized and the overlying bone was thinned to visualize the dural artery. Then, vasodilator responses to exogenous (i.v. α-CGRP) and endogenous (released by i.v. capsaicin and periarterial electrical stimulation) CGRP were elicited in the absence or presence of the above antagonists.

Key results:

α-CGRP, capsaicin and periarterial electrical stimulation increased dural artery diameter. Ketamine and MK801 inhibited the vasodilator responses to capsaicin and electrical stimulation, while only ketamine attenuated those to α-CGRP. In contrast, GYKI52466 only attenuated the vasodilatation to exogenous α-CGRP, while {"type":"entrez-nucleotide","attrs":{"text":"LY466195","term_id":"1258058612","term_text":"LY466195"}}LY466195 did not affect the vasodilator responses to endogenous or exogenous CGRP.

Conclusions and implications:

Although GYKI52466 has not been tested clinically, our data suggest that it would not inhibit migraine via vascular mechanisms. Similarly, the antimigraine efficacy of {"type":"entrez-nucleotide","attrs":{"text":"LY466195","term_id":"1258058612","term_text":"LY466195"}}LY466195 seems unrelated to vascular CGRP-mediated pathways and/or receptors. In contrast, the cranial vascular effects of ketamine and MK801 may represent a therapeutic mechanism, although the same mechanism might contribute, peripherally, to cardiovascular side effects.     

99th Dahlem Conference on Infection,Inflammation and Chronic Inflammatory Disorders: Neonatal immune function and vaccine responses in children born in low‐income versus high‐income countries

There is increasing evidence that the functional state of the immune system at birth is predictive of the kinetics of immune maturation in early infancy. Moreover, this maturation process can have a major impact on early vaccine responses and can be a key determinant of risk for communicable and non‐communicable diseases in later life. We hypothesize that environmental and genetic factors that are often typical for poor‐resource countries may have an important impact on prenatal immune development and predispose populations in low‐income settings to different vaccine responses and disease risks, compared to those living in high‐income countries. In this paper we aimed to summarize the major differences between neonatal and adult immune function and describe what is known so far about discrepancies in immune function between newborns in high‐ and low‐income settings. Further, we discuss the need to test the immunological feasibility of accelerated vaccination schedules in high‐risk populations and the potential of variation in disease specific and non‐specific vaccine effects.     

A critical appraisal of prognostic and predictive factors for common lung cancers

The outlook for patients with lung cancer remains poor despite advances in the understanding of the pathology and biology of this disease. To optimize treatment protocols prognostic data are essential. The current era with molecular research on mRNA expression analysis and proteomics will lead to a plethora of new molecular markers, which are likely to be correlated, at least in part, with each other and with disease activity, progression and survival. However, although the number of prognostic factors analysed in published systematic reviews on lung cancer is large, the scope of these factors in individual studies is often narrow. In daily practice prognostic factors other than general TNM staging are not implemented. To assess the efficacy of new prognostic factors for the management of individual patients with non-small cell lung cancer, studies with clinically relevant modelling are required. In this review arguments are provided to use a model combining radiological and histopathological growth rate, histopathological diagnosis and molecular characteristics as markers for metastatic capacity, tumour volume doubling time and expected response to targeted therapy. This may reveal time-related predictive information useful for treatment guidance of the individual patient.     

Major affective disorders and schizophrenia: a common molecular signature?

Psychiatric disorders, including affective disorders (AD) and schizophrenia (SZ) are among the most common disabling brain diseases in Western populations and result in high costs in terms of morbidity as well as mortality. Although their etiology and pathophysiology is largely unknown, family-, twin-, and adoption studies argue for a strong genetic determination of these disorders. These studies indicate that there is between 40 and 85% heritability for these disorders but point also to the importance of environmental factors. Therefore, any research strategy aiming at the identification of genes involved in the development of AD and SZ should account for the complex nature (multifactorial) of these disorders. During the last decade, molecular genetic studies have contributed a great deal to the identification of genetic factors involved in complex disorders. Here we provide a comprehensive review of the most promising genes for AD and SZ, and the methods and approaches that were used for their identification. Also, we discuss the current knowledge and hypotheses that have been formulated regarding the effect of variations on protein functioning as well as recent observations that point to common molecular mechanisms.     

Antibacterial treatment needed for severe early childhood caries

OBJECTIVES: To assess the effects of a single 10% povidone iodine application as an adjunct to extensive surgical procedures in the clinical treatment of children with early childhood caries. METHODS: Twenty-two children scheduled for dental treatment under general anesthesia were randomized into either an intervention group (10% povidone iodine), or a control group (phosphate buffered saline). Either povidone iodine or phosphate buffered saline was applied to teeth and soft tissues after prophylaxis and all operative dental procedures, followed by 1.23% acidulated phosphate fluoride gel. Saliva samples taken at baseline, and after 1 hour, 3 weeks and 3 months were assayed for mutans streptococci, lactobacilli and total viable bacteria. Caries lesions were recorded at baseline and at one year. RESULTS: Mutans streptococci and lactobacilli levels in the povidone iodine group were significantly reduced relative to baseline at 1 hour, 3 weeks and 3 months. At one year at least 60% of subjects had new caries lesions in each group, and there was no significant difference in caries increment between the two groups. CONCLUSIONS: Even prophylaxis, fluoride gel application and complete surgical treatment of caries at baseline were insufficient to prevent new caries in over 60% of the patients in these high caries risk infants. Although the one-time treatment with povidone iodine reduced mutans streptococci and lactobacilli levels for up to 3 months this therapy failed to additionally reduce future caries formation over one year, indicating that repeated antibacterial treatments will be needed to control high levels of cariogenic bacteria.     

A SERCA2 pump with an increased Ca2+ affinity can lead to severe cardiac hypertrophy, stress intolerance and reduced life span

Abnormal Ca(2+) cycling in the failing heart might be corrected by enhancing the activity of the cardiac Ca(2+) pump, the sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) isoform. This can be obtained by increasing the pump's affinity for Ca(2+) by suppressing phospholamban (PLB) activity, the in vivo inhibitor of SERCA2a. In SKO mice, gene-targeted replacement of SERCA2a by SERCA2b, a pump with a higher Ca(2+) affinity, results in cardiac hypertrophy and dysfunction. The stronger PLB inhibition on cardiac morphology and performance observed in SKO was investigated here in DKO mice, which were obtained by crossing SKO with PLB(-/-) mice. The affinity for Ca(2+) of SERCA2 was found to be further increased in these DKO mice. Relative to wild-type and SKO mice, DKO mice were much less spontaneously active and showed a reduced life span. The DKO mice also displayed a severe cardiac phenotype characterized by a more pronounced concentric hypertrophy, diastolic dysfunction and increased ventricular stiffness. Strikingly, beta-adrenergic or forced exercise stress induced acute heart failure and death in DKO mice. Therefore, the increased PLB inhibition represents a compensation for the imposed high Ca(2+)-affinity of SERCA2b in the SKO heart. Limiting SERCA2's affinity for Ca(2+) is physiologically important for normal cardiac function. An improved Ca(2+) transport in the sarcoplasmic reticulum may correct Ca(2+) mishandling in heart failure, but a SERCA pump with a much higher Ca(2+) affinity may be detrimental.     

The risk of being fearful or fearless of falls in older people: an empirical validation

PURPOSE: To investigate the risk of being fearful or fearless of falls in older people. METHODS: Using a force plate, postural control in different sensory and rhythmic conditions was measured in 263 community-dwelling older people. Other assessments included fear of falling, and handgrip strength. Fall incidence was assessed at baseline and during a one-year follow-up period. RESULTS: Logistic regression analysis revealed that increased lateral sway in near-tandem stance with eyes open (OR = 5.33; p < 0.01) and a worse performance on anteroposterior rhythmic weight shifts (OR = 0.65; p < 0.05) were related to falls. Univariate analyses revealed that older people with inappropriate high fear of falling according to their fall incidence had worse balance capacities on the rhythmic weight shifts (p < 0.05) but had similar static balance and physical capacities. Older people with inappropriate low fear of falling had a better hand grip (p < 0.05) but equally worse balance capacities than the comparison group. CONCLUSIONS: The results indicate the importance of lateral stability in relation to falls. They also suggest a substantial impact of inappropriate fear of falling on physical performance. Inappropriate high fear of falling may result in worse performance during dynamic balance tests, whereas older people with inappropriate low fear seem to overrate their capacities because of higher strength.     

Rehabilitation of stroke patients needs a family-centred approach

Purpose. To highlight the importance of the spouse in stroke rehabilitation. Stroke not only affects the patients, but also their families, but rehabilitation practice is still primarily focused on the patient only.

Method. Analysis of the position of the spouse and possible consequences of stroke for the spouse, based on the literature.

Results. Three roles of spouses are described: (i) the role of caregiver, as the spouse often provides extensive and comprehensive care for the patient; (ii) the role of client, as this informal care may lead to physical and emotional strain; and (iii) the role of family member, as the stroke affects the interpersonal relationships within the family system, not least the emotional and sexual relationship between the partners. This analysis provides an understanding of problems experienced by spouses as roles conflict and identifies topics for assessment and interventions directed at the spouse in the acute phase, rehabilitation phase and chronic phase of stroke.

Conclusion. We support a family-centred approach in which the strengths and needs of all family members, the patient with stroke included, are considered throughout all phases of the rehabilitation process.