Recent changes in reproductive phenology of a K-selected aquatic insect predator, Belostoma flumineum Say (Heteroptera, Belostomatidae).

The timing of critical events like mating, migration, and development has noticeably and recently shifted in many populations of diverse organisms. Here, we report a change in the breeding phenology of giant waterbugs, Belostoma flumineum Say (Heteroptera, Belostomatidae), in the northeastern United States. Waterbugs collected in 2005 and 2006 exhibited previously typical patterns of mating and reproduction: two annual reproductive peaks in which overwintered adults mated in the spring and young adults from a new generation mated in the fall. In 2012 and 2015, despite similar sampling effort, we detected no fall breeding activity in the study area. Reproductive behaviour under controlled laboratory conditions was also different between the earlier (2005 and 2006) and recent (2012 and 2015) years: waterbugs collected in recent years exhibited significant delays in reproduction (>30 days) under similar photoperiod and thermal conditions. We discuss potential causes of this dramatic change in reproductive behaviour, such as climate change, as well as possible negative impacts of the absence of fall reproduction on populations of B. flumineum in the study region.

An alternate form of Ku80 is required for DNA end-binding activity in mammalian mitochondria.

Mammalian mitochondrial DNA end-binding activity is nearly indistinguishable from that of nuclear Ku. This observation led to the hypothesis that mitochondrial DNA end-binding activity is in part dependent upon Ku80 gene expression. To test this hypothesis, we assayed for Ku activity in mitochondrial extracts prepared from the xrs-5 hamster cell line that lacks Ku80 mRNA expression. Mitochondrial protein extracts prepared from this cell line lacked the DNA end-binding activity found in similar extracts prepared from wild-type cells. Azacytidine-reverted xrs-5 cells that acquired nuclear DNA end-binding activity also acquired mitochondrial DNA end-binding activity. Western blot analysis of human mitochondrial protein extracts using a monoclonal antibody specific for an N-terminal epitope of Ku80 identified a protein with an apparent molecular weight of 68 kDa. This mitochondrial protein was not detected by a monoclonal antibody specific for an epitope at the C-terminal end of Ku80. Consistently, while both the N- and C-terminal Ku80 monoclonal antibodies supershifted the nuclear DNA end-binding complex on an electrophoretic mobility shift assay, only the N-terminal monoclonal antibody supershifted the mitochondrial DNA end-binding complex. To confirm that the 68 kDa Ku protein was not a consequence of nuclear protein contamination of mitochondrial preparations, highly purified intact nuclei and mitochondria were treated with proteinase K which traverses the pores of intact nuclei but gains limited access into intact mitochondria. Ku80 in purified intact nuclei was sensitive to treatment with this protease, while the 68 kDa Ku protein characteristic of purified intact mitochondria was resistant. Further, immunocytochemical analysis revealed the co-localization of the N-terminal specific Ku80 monoclonal antibody with a mitochondrial-targeted green fluorescence protein. Mitochondrial localization of the C-terminal Ku80 monoclonal antibody was not observed. These data are consistent with the hypothesis that a C-terminally truncated form of Ku80 is localized in mammalian mitochondria where it functions in a DNA end-binding activity.

Mammalian mitochondrial extracts possess DNA end-binding activity.

Mammalian mitochondrial protein extracts possess DNA end-binding (DEB) activity. Protein binding to a 394 bp double-stranded DNA molecule was measured using an electrophoretic mobility shift assay. Mitochondrial DEB activity was highly specific for linear DNA. Inclusion of a vast excess of non-radioactive circular DNA did not disrupt binding to radioactive f394. In contrast, binding was abolished by the inclusion of linear competitor DNA. In mammals, nuclear DEB activity is due to Ku, a hetero-dimer composed of the Ku70 and Ku86 proteins. To determine whether mitochondrial DEB activity was also due to Ku, protein extracts were prepared from the Chinese hamster XR-V15B cell line, which lacks this protein. As anticipated, nuclear extracts prepared from these cells lacked DEB activity. In contrast, mitochondrial extracts prepared from these cells had wild-type levels of DEB activity, demonstrating that this latter activity is not a consequence of nuclear contamination. Although the nuclear and mitochondrial DEB activities are independent of each other, they are nevertheless closely related, since mitochondrial DEB activity was 'supershifted' by both anti-Ku70 and anti-Ku86 antisera. The nuclear DEB protein Ku plays an essential role in nuclear DNA double-strand break repair. The DEB activity described herein may therefore play a similar role in mitochondrial DNA repair.

Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition.

Precursor-B-cell receptor (pre-BCR) signaling and spleen tyrosine kinase (SYK) recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacological and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR(+) B-ALL, but not other B-ALL subsets, on this signaling pathway. We demonstrate that SYK, PI3K/AKT, FOXO1 and MYC are important downstream mediators of pre-BCR signaling in B-ALL. Furthermore, we define a characteristic immune phenotype and gene expression signature of pre-BCR(+) ALL to distinguish them from other B-ALL subsets. These data provide comprehensive new insight into pre-BCR signaling in B-ALL and corroborate pre-BCR signaling and SYK as promising new therapeutic targets in pre-BCR(+) B-ALL.

Time-dependent changes in cocaine-seeking behavior and extracellular dopamine levels in the amygdala during cocaine withdrawal.

Cocaine and cocaine-associated cues elicit craving in addicts and reinstate cocaine-seeking behavior in rats. Craving and cocaine-seeking behavior may be mediated by withdrawal-induced changes in dopamine (DA) neurotransmission in the amygdala. To examine whether there are concomittant changes in cocaine-seeking behavior and extracellular DA levels during withdrawal, experimental rats were trained to self-administer cocaine (0.75 mg/kg i.v.). After 14 daily 3-hour training sessions, animals underwent either a 1-day, 1-week, or 1-month withdrawal period. Extracellular DA levels were assessed during baseline, extinction, cue reinstatement, and cocaine (15 mg/kg i.p.) reinstatement of cocaine-seeking behavior (i.e., defined as the difference in nonreinforced lever presses on an active minus inactive lever). Cocaine-seeking behavior became more intense during the course of cocaine withdrawal. Additionally, basal and cocaine-induced extracellular DA levels were enhanced after the 1-month withdrawal period. We suggest that the former may reflect a persistent elevation in tonic extracellular DA levels in the amygdala, whereas the latter may reflect a persistent elevation in phasic extracellular DA levels.

Knowledge of and reported asthma management among South Australian general practitioners.

AIM: This study, carried out in 1989, set out to assess general practitioners' knowledge of asthma management and their reported management practices. METHOD: Of 153 randomly selected South Australian general practitioners 127 (83%) completed a questionnaire designed to explore issues relating to the management of asthma. RESULTS: The survey revealed substantial differences between general practitioners in their knowledge and management practices including the assessment of the severity of asthma, the need for objective monitoring, that is by the use of spirometry and peak flow meters, and the use of medication. Overall, the sampled general practitioners believed that patient-related factors were the main barriers to effective treatment of asthma. CONCLUSION: The findings of this study suggest that ideal asthma management was not being attained. More research is required to ascertain why such variability among practitioners exists and how best to remedy these differences.

Pain: theories and a new approach to treatment.

Various theories of pain are reviewed in an attempt to understand its mode of action. The therapeutic effects of a new, noninvasive form of treating pain, utilizing electrical units which selectively stimulate the sensory nerves, are discussed.PATIENTS WITH PAIN OF VARYING DEGREES OF SEVERITY AND OF MANY DIFFERENT ETIOLOGIES WERE TREATED WITH A NEW FORM OF TREATMENT: transcutaneous electrical nerve stimulation (TENS). The authors' results have shown this method to be highly successful in the treatment of patients, most of whom had been treated unsuccessfully with conventional medical and surgical approaches.TENS affords a new dimension in the current concept of treating pain.

The effect of prazosin on patients with symptoms of benign prostatic hypertrophy.

OBJECTIVE: To evaluate the effect of prazosin on the symptoms of benign prostatic hypertrophy for patients of general practitioners. SETTING AND PATIENTS: Eighty-two general practitioner patients from 317 who were identified as being eligible for inclusion in the trial. They were randomly allocated to receive either prazosin or placebo for the first 3 month arm then crossed-over for the second 3 months. RESULTS: Seventy-six patients completed the trial. An analogue scale of patient rating of symptoms showed a statistically significant decrease in symptoms for patients taking prazosin when compared with patients taking placebo, regardless of the order in which they had been administered. A total symptom score and an obstructive symptom score for benign prostatic hypertrophy showed a statistically significant difference between the two treatments at 4 weeks. A difference was still apparent at 8 and 12 weeks but it was not statistically significant. No difference was detected for irritative symptoms. CONCLUSION: Prazosin may have a limited place in the management of benign prostatic hypertrophy.

Assessing case records using monitor criteria developed from consensus guidelines.

OBJECTIVE: To develop criteria to enable the monitoring of general practitioner (GP) case records using consensus guidelines for conditions commonly managed in general practice and to measure how well the case records of a non random sample of GPs conformed to these criteria. METHOD: An iterative process was used to develop criteria from consensus guidelines for 19 conditions. Criteria were also developed to enable monitoring of the structure and content of the patient case record. A non random sample of GPs in Adelaide was approached to allow measurement of the content of their case records against these criteria. This measurement was undertaken by allied health professionals. An overall percentage score of conformity with the criteria was created for 10 acute, and six chronic conditions and for the patient case record review. These were rank ordered and Kendall's rank order correlation coefficients were used to compare the results in these three areas of practice. RESULTS: Criteria were successfully developed for each condition. Thirty-one GPs had their patient case records assessed. There was substantial variability between these practitioners in their conformity to the criteria. Kendall's rank order coefficients found statistically significant correlation between the results for acute and chronic conditions, and between acute conditions and the patient case record review section. CONCLUSION: It is feasible to develop criteria that enable measurement of the conformity of GP case records to these criteria. The overall level of conformity, together with the substantial variability found between practitioners suggest that there is a need for GPs to address this area of their practice.

Reported diabetes mellitus management among South Australian general practitioners.

Diabetes mellitus is a chronic disease commonly managed in general practice. This article reviews the findings of a questionnaire survey of 173 randomly chosen South Australian general practitioners and their reported management in the areas of detection, diagnosis, assessment, monitoring and GP knowledge. Substantial differences between respondents were found in all areas, suggesting the need for improved educational methods aimed at all general practitioners.

Signs, symptoms, and the new descriptors.

Data from 143 consultations in general practice were assessed by factors relevant to the four-category descriptive system developed by the Royal Australian College of General Practitioners. It seems that there is no relationship between consultation length, apparent symptom seriousness or the occurrence of a physical examination. Suggestions are offered for improving the clarity of consultation descriptor categories.

Development of consensus guidelines for conditions commonly managed in general practice. Royal Australian College of General Practitioners.

OBJECTIVE: Initially, the project objective was to develop audit protocols for commonly managed conditions in general practice. However, as the nature of the project evolved these objectives changed to developing consensus guidelines. METHOD: An iterative process was undertaken using mail-outs to gain items for potential inclusion in an audit protocol. This resulted in a change of direction to management guidelines. Consensus, as to the validity of inclusion of items in each guideline, was then achieved by continuing to use an iterative process. RESULTS: Guidelines for 30 presenting complaints were developed. Because a number of differential diagnoses were possible for each complaint, a total of 105 guidelines were developed. A total of 263 general practitioners participated. CONCLUSION: The concept of discriminant actions was developed. It was agreed that this described the clinical decision making that occurs in the general practices of participating practitioners. It is feasible to use an iterative method undertaken by mail to develop consensus guidelines for conditions that are commonly managed by general practitioners.

A pattern of decline in general practice obstetric care in Adelaide.

Some educational, training and politico-economic reasons for the decline in GP obstetrics in Adelaide, South Australia, are described. It is recommended that similar studies be done in other centres in Australia to evaluate the general nature of the findings.

Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration.

Syk is a protein tyrosine kinase that couples B-cell receptor (BCR) activation with downstream signaling pathways, affecting cell survival and proliferation. Moreover, Syk is involved in BCR-independent functions, such as B-cell migration and adhesion. In chronic lymphocytic leukemia (CLL), Syk becomes activated by external signals from the tissue microenvironment, and was targeted in a first clinical trial with R788 (fostamatinib), a relatively nonspecific Syk inhibitor. Here, we characterize the activity of two novel, highly selective Syk inhibitors, PRT318 and P505-15, in assays that model CLL interactions with the microenvironment. PRT318 and P505-15 effectively antagonize CLL cell survival after BCR triggering and in nurse-like cell-co-cultures. Moreover, they inhibit BCR-dependent secretion of the chemokines CCL3 and CCL4 by CLL cells, and leukemia cell migration toward the tissue homing chemokines CXCL12, CXCL13, and beneath stromal cells. PRT318 and P505-15 furthermore inhibit Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering. These findings demonstrate that the selective Syk inhibitors PRT318 and P505-15 are highly effective for inhibition of CLL survival and tissue homing circuits, and support the therapeutic development of these agents in patients with CLL, other B-cell malignancies and autoimmune disorders.

Computerized record system for Irish contraception clinics.

PIP: In Ireland, where contraception and planned parenthood are political issues, the 2 Irish Family Planning Association (IFPA) clinics in Dublin have administered a new record system to new clients. Information from the client at interview and medical examination, details of the treatment prescribed are entered on a chart designed for computerization. About 6000 new clients each year attend the clinics. On the first visit a 3 page chart is completed. The top copy remains in the clinic and the carbon copy is transferred to the computer. The client's name and address appear only on the copy remaining in the clinic. Most boxes require completion only if a positive answer is indicated. Past contraception, complications and any referrals to specialist clinics or hospital outpatient clinics may be entered easily. A condensed follow-up page is used for subsequent visits. Possibly significant correlations of side-effects with specific contraceptives might emerge that would otherwise be overlooked. The program began in January, 1979.^ieng

Interethnic variations in the presence of Schneiderian first rank symptoms.

Differences in the presence of Schneiderian First Rank Symptoms in first admission schizophrenic patients were examined in five subcultural groupings treated in the same facilities. Examination of the case notes of 212 patients revealed that first rank symptoms were most prevalent in the UK immigrant group and least frequently present in the Greek immigrant group. First rank symptoms were more prevalent in patients admitted recently, admitted voluntarily, and amongst those who had at least some command of English.

Hypoglycaemia secondary to pancreatic islet cell adenoma.

The detailed case histories of 5 patients with hypoglycaemic episodes secondary to islet cell adenoma of the pancreas are presented. Clinical recognition of this syndrome remains the major problem but a full and detailed medical history is usually strongly suggestive of the correct diagnosis. The clinical diagnosis is confirmed by the repeated demonstrated that: 1) Symptomatic episodes produced by fasting are in fact due to hypoglycaemia (plasma glucose level less than 2.5 mmol/litre) 2) Such episodes are relieved by glucose administration 3) Concomitant hyperinsulinaemia is present (serum insulin greater than 8 micro-units/ml in the fasting state). Surgical resection of the adenoma produces a complete cure but the identification of the lesion at operation may be difficult and preoperative means of accurate localisation may be needed.