Adaptive mutation: general mutagenesis is not a programmed response to stress but results from rare coamplification of dinB with lac

In a particular genetic system, selection stimulates reversion of a lac mutation and causes genome-wide mutagenesis (adaptive mutation). Selection allows rare plated cells with a duplication of the leaky lac allele to initiate clones within which further lac amplification improves growth rate. Growth and amplification add mutational targets to each clone and thereby increase the likelihood of reversion. We suggest that general mutagenesis occurs only in clones whose lac amplification includes the nearby dinB+ gene (for error-prone DNA polymerase IV). Thus mutagenesis is not a programmed response to stress but a side effect of amplification in a few clones; it is not central to the effect of selection on reversion.     

Quantification of Human T-lymphotropic virus type I (HTLV-I) provirus load in a rural West African population: no enhancement of human immunodeficiency virus type 2 pathogenesis, but HTLV-I provirus load relates to mortality

Human T-lymphotropic virus type I (HTLV-I) provirus load was examined in a cohort of a population in Guinea-Bissau among whom human immunodeficiency virus (HIV) type 2 is endemic. Geometric mean of HIV-2 RNA load among HTLV-I-coinfected subjects was significantly lower than that in subjects infected with HIV-2 alone (212 vs. 724 copies/mL; P=.02). Adjusted for age, sex, and HIV status, the risk of death increased with HTLV-I provirus load; mortality hazard ratio was 1.59 for each log10 increase in HTLV-I provirus copies (P=.038). There is no enhancing effect of HTLV-I coinfection on HIV-2 disease, but high HTLV-I provirus loads may contribute to mortality.     

Clonal success of piliated penicillin nonsusceptible pneumococci

Antibiotic resistance in pneumococci is due to the spread of strains belonging to a limited number of clones. The Spain(9V)-3 clone of sequence type (ST)156 is one of the most successful clones with reduced susceptibility to penicillin [pneumococci nonsusceptible to penicillin (PNSP)]. In Sweden during 2000-2003, a dramatic increase in the number of PNSP isolates was observed. Molecular characterization of these isolates showed that a single clone of sequence type ST156 increased from 40% to 80% of all serotype 14, thus causing the serotype expansion. Additionally, during the same time period, we examined the clonal composition of two serotypes 9V and 19F: all 9V and 20% of 19F isolates belonged to the clonal cluster of ST156, and overall approximately 50% of all PNSP belonged to the ST156 clonal cluster. Moreover, microarray and PCR analysis showed that all ST156 isolates, irrespective of capsular type, carried the rlrA pilus islet. This islet was also found to be present in the penicillin-sensitive ST162 clone, which is believed to be the drug-susceptible ancestor of ST156. Competitive experiments between related ST156 serotype 19F strains confirmed that those containing the rlrA pilus islet were more successful in an animal model of carriage. We conclude that the pilus island is an important biological factor common to ST156 isolates and other successful PNSP clones. In Sweden, a country where the low antibiotic usage does not explain the spread of resistant strains, at least 70% of all PNSP isolates collected during year 2003 carried the pilus islet.     

Uterus and ovaries in girls and young women with Turner syndrome evaluated by ultrasound and magnetic resonance imaging

Objective To determine uterine and ovarian size in Turner syndrome (TS) and to compare uterine and ovarian size evaluated by transabdominal ultrasound (US) and magnetic resonance imaging (MRI) in girls with TS and two groups of controls. Design A cross‐sectional study. Patients Forty‐one girls with TS (17·0 ± 3·3 years, range 11·2–24·9 years), 50 healthy age‐matched controls (16·9 ± 3·2 years, range 12·5–25·0 years) and 107 Tanner‐stage‐matched controls (15·0 ± 3·2 years, range 10·1–24·2). Measurements Uterine and ovarian volume by US and MRI. Results Ovaries were detected in 37% in TS by US and in 55% in TS by MRI (P = 0·1). Total ovarian volume was lower in TS compared to both groups of controls (TS vs C‐US: median 1·1 ml (range 0·1–29·3) vs 11·52 ml (1·9–77·9), P = 0·001, TS vs C‐MRI: 1·0 ml (0·1–34·2) vs 13·2 ml (2·4–30·1), P < 0·0005). Mean difference in total ovarian volume measured by MRI and US in patients with TS was 2·3 ± 3·8 ml (P = 0·01). Mean uterine volume by MRI was lower in TS compared to controls (29·5 ± 25·1 vs 54·3 ± 23·3 ml, P < 0·0005). Uterine volume by US was lower in TS at Tanner stage B5 compared to controls (TS vs C: 33·6 ± 18·2 vs 50·2 ± 18·0 ml, P = 0·007). Conclusions A larger ovarian volume was detected by MRI in TS compared to US. This finding is important with the advancements of performing ovarian biopsies for cryopreservation and later reimplantation. Mean uterine volumes by MRI and US in fully matured TS were lower compared to controls despite appropriate hormonal replacement therapy in TS.     

The host defense peptide LL‐37 is detected in human parotid and submandibular/sublingual saliva and expressed in glandular neutrophils

The human host defense peptide, LL‐37, is an important player in the first line of defense against invading microorganisms. LL‐37 and its precursor, hCAP18, have been detected in unstimulated whole saliva but no reports showing hCAP18/LL‐37 in isolated, parotid, and/or submandibular/sublingual saliva have been presented. Here, we measured the levels of hCAP18/LL‐37 in human parotid and submandibular/sublingual saliva and investigated the expression of hCAP18/LL‐37 in parotid and submandibular gland tissue. Parotid and submandibular/sublingual saliva was collected from healthy volunteers, and the levels of hCAP18/LL‐37 in saliva were analyzed by dot blot, ELISA, and western blotting. Cellular expression of hCAP18/LL‐37 in human parotid and submandibular glands was investigated by immunohistochemistry. Immunoreactivity for hCAP18/LL‐37 was detected in both parotid and submandibular/sublingual saliva of all individuals. The concentration of hCAP18/LL‐37 was similar in parotid and submandibular/sublingual saliva, and was determined by densitometric scanning of each dot and normalization to the total protein concentration of each sample, and by ELISA. Double immunohistochemistry revealed that intravascular neutrophils of both parotid and submandibular glands express hCAP18/LL‐37. For the first time, we demonstrate hCAP18/LL‐37 in isolated human parotid and submandibular/sublingual saliva and expression of hCAP18/LL‐37 in glandular intravascular neutrophils, indicating that neutrophils of the major salivary glands contribute to the LL‐37 content of whole saliva.     

Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory

D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [¹¹C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.Dopamine (DA) plays a key role in several cognitive processes (1–4). Reductions of D1 and D2 DA receptors (D1DRs and D2DRs) in aging (5–7) have been linked to age-related cognitive deficits (8, 9). The D1DR system has been related to functions supported by the prefrontal cortex (PFC), such as working memory and executive functions (10–12), which may reflect the relatively high density of D1DRs in the PFC (13). However, the role of D2DRs is far less clear. D2DRs are present in the PFC at very low densities (13), and evidence supporting a role for the D2DR system in working memory and executive functions is elusive (10). Pharmacological (14, 15) and PET studies assessing striatal D2DR availability (or binding potential to nondisplacable tissue uptake; BP_ND) with [¹¹C]raclopride (16, 17) have yielded mixed findings in relation to cognition. It has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions (10, 18, 19). Supporting these claims, positive links between D2DR BP_ND and episodic memory are commonly observed (20–23). PET imaging of hippocampal D2DR BP_ND also provides support for this hypothesis, although some studies indicate that hippocampal D2DRs may be related to both episodic memory and PFC-based executive functions (22, 23), including verbal working memory (24). Medial temporal lobe regions have been implicated in working memory (25, 26), and D2DR-mediated modulation may be exerted via hippocampal–cortical pathways (27). In addition, a [¹¹C]raclopride task-activation PET study demonstrated contributions of striatal D2DRs to a verbal working-memory task (11).Taken together, the specific role of the D2DR system in cognition remains unclear, likely due to the fact that past studies included small and age-heterogeneous samples and lacked comprehensive test batteries that allowed systematic comparison of the role of D2DRs in different cognitive functions. Here we present results from the Cognition, Brain, and Aging (COBRA) study that include assessment of episodic memory, working memory, and processing speed, in combination with [¹¹C]raclopride PET and MRI of 181 healthy adults between 64 and 68 y of age (28). The main analyses concerned caudate D2DR–cognition associations, as this striatal region has been implicated in cognitive functioning (11, 12, 29, 30). Subsequently, whole-brain analyses were conducted to examine extrastriatal (especially hippocampal) D2DRs in relation to cognition. Finally, resting-state functional connectivity patterns were analyzed in relation to D2DR BP_ND, with special focus on interactions between the ventral caudate (31) and medial temporal cortex regions (32, 33).     

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Summary. Serum concentrations of tumour necrosis factor alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-γ), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr⁻) bacteraemias after 2 h (TNF-α, IL-lra and IFN-γ), 4h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-α value was higher in the Gr⁻ group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr⁺, 14pg/ ml; range 7-60 pg/ml; P < 0 05) and blood culture negative episodes (BCN, 8pg/ml; range 0-87pg/ml; P<0 05).
Furthermore, the peak values of TNF-α, IL-lra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the ^Gr- group in comparison to the Gr⁺ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in ^Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.     

Imported rocket salad partly responsible for increased incidence of hepatitis A cases in Sweden, 2000-2001

An increased incidence of domestic hepatitis A without any obvious source of infection in Sweden and a small outbreak in late spring 2001 led to the undertaking of a case-control study. Consumption of imported rocket salad was clearly associated with disease (odds ratio 9.1, 95% confidence interval 1.5 to 69). The importation of vegetables from countries where hepatitis A is endemic to countries where this disease is not endemic continues to be a public health problem.