Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by Memantine

The activity of protein phosphatase (PP)-2A, which regulates tau phosphorylation, is compromised in Alzheimer disease brain. Here we show that the transient transfection of PC12 cells with inhibitor-2 (I2PP2A) of PP2A causes abnormal hyperphosphorylation of tau at Ser396/Ser404 and Ser262/Ser356. This hyperphosphorylation of tau is observed only when a sub-cellular shift of I2PP2A takes place from the nucleus to the cytoplasm and is accompanied by cleavage of I2PP2A into a 20 kDa fragment. Memantine, an un-competitive inhibitor of N-methyl-D-aspartate receptors, inhibits this abnormal phosphorylation of tau and cell death and prevents the I2PP2A-induced inhibition of PP2A activity in vitro. These findings demonstrate novel mechanisms by which I2PP2A regulates the intracellular activity of PP2A and phosphorylation of tau, and by which Memantine modulates PP2A signaling and inhibits neurofibrillary degeneration.     

SMS messaging to improve retention and viral suppression in prevention of mother-to-child HIV transmission (PMTCT) programs in Kenya: A 3-arm randomized clinical trial

BackgroundPregnant and postpartum women living with HIV (WLWH) need support for HIV and maternal child health (MCH) care, which could be provided using short message service (SMS).Methods and findingsWe compared 2-way (interactive) and 1-way SMS messaging to no SMS in a 3-arm randomized trial in 6 MCH clinics in Kenya. Messages were developed using the Health Belief Model and Social Cognitive Theory; HIV messages were integrated into an existing MCH SMS platform. Intervention participants received visit reminders and prespecified weekly SMS on antiretroviral therapy (ART) adherence and MCH, tailored to their characteristics and timing. Two-way participants could message nurses as needed. Clinic attendance, viral load (VL), and infant HIV results were abstracted from program records. Primary outcomes were viral nonsuppression (VL ≥1,000 c/ml), on-time clinic attendance, loss to follow-up from clinical care, and infant HIV-free survival. Among 824 pregnant women randomized between November 2015 and May 2017, median age was 27 years, gestational age was 24.3 weeks, and time since initiation of ART was 1.0 year. During follow-up to 2 years postpartum, 9.8% of 3,150 VL assessments and 19.6% of women were ever nonsuppressed, with no significant difference in 1-way versus control (11.2% versus 9.6%, adjusted risk ratio (aRR) 1.02 [95% confidence interval (CI) 0.67 to 1.54], p = 0.94) or 2-way versus control (8.5% versus 9.6%, aRR 0.80 [95% CI 0.52 to 1.23], p = 0.31). Median ART adherence and incident ART resistance did not significantly differ by arm. Overall, 88.9% (95% CI 76.5 to 95.7) of visits were on time, with no significant differences between arms (88.2% in control versus 88.6% in 1-way and 88.8% in 2-way). Incidence of infant HIV or death was 3.01/100 person-years (py), with no significant difference between arms; risk of infant HIV infection was 0.94%. Time to postpartum contraception was significantly shorter in the 2-way arm than control. Study limitations include limited ability to detect improvement due to high viral suppression and visit attendance and imperfect synchronization of SMS reminders to clinic visits.ConclusionsIntegrated HIV/MCH messaging did not improve HIV outcomes but was associated with improved initiation of postpartum contraception. In programs where most women are virally suppressed, targeted SMS informed by VL data may improve effectiveness. Rigorous evaluation remains important to optimize mobile health (mHealth) interventions.Trial registrationClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT02400671","term_id":"NCT02400671"}}NCT02400671.

John Kinuthia and co-workers study one- and two-way text messaging for impact on HIV and maternal health outcomes in women with HIV infection.     

Abnormalities of blood coagulation at high altitude

Immediately on arrival of man at 3,600 m altitude there was a tendency towards hypercoagulation with increase in the platelet count, factor X, factor XII, thrombotest activity and thrombin clotting time with compensatory increase in fibrinolysis and reduction in factor VIII. During continuous stay there was a regression of the hypercoagulation state with reduction in platelet count, platelet factor 3, clot retraction, factor X, factor XII, thrombotest activity and persistence of increased fibrinolytic activity. The main difference in the hypercoagulation state in high-altitude pulmonary oedema and the corresponding highaltitude controls was the absence of a compensatory increase in fibrinolysis and increase in factor VIII. The main difference in the hypercoagulation state in highaltitude pulmonary hypertension and the corresponding high-altitude controls was an increase in platelet adhesiveness, platelet factor 3, factor V and factor VIII. The outstanding difference between high-altitude pulmonary oedema and highaltitude pulmonary hypertension was in the fibrinolytic activity and thrombin clotting time which were reduced in pulmonary oedema but were increased in pulmonary hypertension.

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Zusammenfassung Unmittelbar nach der Ankunft von Männern in 3.600 m Höhe zeigte sich eine Hyperkoagulation mit Anstieg der Plättchenzahl, Faktor X und Faktor XII, Thrombotest-Aktivität und Thrombin-Gerinnungszeit mit kompensatorischem Anstieg der Fibrinolyse und Verminderung von Faktor VIII. Bei längerem Aufenthalt ging der Hyperkoagulationszustand zurück mit verminderter Plättchenzahl, Plättchenfaktor 3, Thrombusretraktion, Faktor X, Faktor XII, Thrombotest-Aktivität und Verbleiben oder Anstieg der fibrinolytischen Aktivität. Der Hauptunterschied in der Hyperkoagulationsphase von Personen mit Lungenoedem und Gesunden in der Höhe war das Fehlen eines kompensatorischen Anstieges der Fibrinolyse und Faktor VIII. Der Hauptunterschied in der Hyperkoagulationsphase von Personen mit pulmonalem Hochdruck und Gesunden in der Höhe war ein Anstieg der Klebrigkeit der Plättchen, Plättchenfaktor 3, Faktor V und Faktor VIII. Die fibrinolytische Aktivität und die Thrombin-Gerinnungszeit waren bei Lungenoedem vermindert und bei pulmonalem Hochdruck erhöht.

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Resume A l'arrivée à 3.600 m d'altitude, on constate chez des sujets d'expérience une hypercoagulation accompagnée d'une hausse du nombre de plaquettes, du facteur X et du facteur XII, de l'activité du thrombotest et du temps de réaction de la thrombine. En compensation, on note une hausse de la fibrinolyse et une baisse du facteur VIII. Un séjour prolongé en altitude a pour conséquence une normalisation des réactions sanguines. Dans la phase d'hypercoagulation, la principale différence observée entre les personnes souffrant d'oedème pulmonaire et les personnes en bonne santé a été que, chez les premières, on n'a pas constaté de hausse compensatoire de la fibrinolyse ni de baisse du facteur VIII. Dans cette même phase, les personnes souffrant d'hypertension pulmonaires se distinguent des gens en bonne santé par le fait que les plaquettes collent entre elles et par une augmentation du facteur de plaques 3, du facteur V et du facteur VIII. L'activité fibrinolytique et le temps de coagulation de la thrombine sont diminués par l'oedème et augmentés par l'hypertension pulmonaire.

     

Adverse changes in fibrinolysis,blood coagulation and platelet function in high altitude pulmonary oedema and their role in its pathogenesis

Blood coagulation studies were undertaken in patients of highaltitude pulmonary oedema at 3, 700 m, comparable controls, and sea level subjects to determine the possible causal connection between changes in fibrinolytic activity, blood coagulation factors, and formation of thrombi within the alveolar capillaries, venules and some branches of pulmonary arteries. The following changes have been observed: Fibrinolytic acitivty was reduced. Plasma fibrinogen and factor VIII were increased. Factor XII was decreased. Platelet adhesiveness and platelet factor 3 were increased and electrophoretic mobility of platelets reduced. The integrity of platelet plasma membrane and release reaction remained intact. Both arterial and venous ADP levels were low and there was evidence of excessive utilisation of ADP in the pulmonary bed. The findings suggest that sludging of RBCs and formation of thrombi possibly result from these changes, impede the pulmonary blood flow, and aggravate the disease.

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Zusammenfassung An Patienten mit Lungenödem und vergleichbaren Kontrollen in 3700 m Höhe und Personen in Meereshöhe wurden Blutgerinnungsstudien vorgenommen, um die möglichen kausalen Beziehungen zu bestimmen zwischen den Veränderungen der fibrinolytischen Aktivität, den Gerinnungsfaktoren und der Bildung von Thromben im arteriellen und venösen Teil der Alveolarkapillaren und einiger Äste der Pulmonalarterien. Folgende Änderungen wurden gefunden: die fibrinolytische Aktivität war vermindert; Plasmafibrinogen und Faktor VIII waren erhöht; Faktor XII war vermindert; Plättchenklebrigkeit und Plättchenfaktor 3 waren erhöht und die elektrische Beweglichkeit der Plättchen herabgesetzt. Die Plasmamembran der Plättchen und die Release-Reaktion bleiben unbeschädigt. Der arterielle und venöse ATP-Spiegel waren niedrig und es zeigten sich Hinweise auf vermehrte ATP-Utilisation in den Pulmonargefässen. Die Ergebnisse deuten darauf hin, dass als Folge der Veränderungen die Erythrozyten träge werden und sich Thromben bilden. Dies hemmt den pulmonalen Blutstrom und verstärkt die Krankheit.

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Resume On a mesuré les différentes propriétés de coagulation du sang de patients atteints d'oedème pulmonaire et de gens en santé (contrôle) et cela aussi bien à 3700 m d'altitude qu'au bord de la mer. Ces essais ont été effectués pour déterminer les relations de cause à effet possibles entre les changements de l'activité fibrinolytique et des facteurs de coagulation du sang d'une part, la formation de thromboses dans les capillaires alvéolaires, les veinules et diverses branches des artères pulmonaires d'autre part. On a alors pu observer les modifications suivantes chez les personnes du premier groupe (malades) : l'activité fibrinolytique est réduite, la fibrinogène du plasma et le facteur VIII sont augmentés, le facteurs XII est diminué, l'adhésivité des plaquettes et le facteur 3 des plaquettes sont augmentés et la mobilité électrophorétique des plaquettes est réduite. L'intégrité des membranes plasmatiques des plaquettes et la réaction de décontraction sont restées inchangées. Le niveau de l'ADP aussi bien artériel que veineux a été très bas ce qui démontre une surconsommation au niveau des poumons. Les résultats obtenus laissent à penser que, par suite des modifications mentionnées, les érythrocytes perdent de leur vitalité et que des thromboses se forment. Ceci a pour conséquence de ralentir le flot sanguin pulmonaire et d'aggraver la maladie.

     

Rat immunoreactive cholecystokinin (CCK): characterization using two chromatographic techniques

Acid and neutral extracts of rat cerebral cortex and upper small intestine were prepared and the endogenous concentrations of cholecystokinin-like immunoreactivity (CCK-LI) measured by three new CCK-specific radioimmunoassays. The characterization of the immunoreactive CCK molecular forms was undertaken using gel permeation chromatography in the presence of 6 M urea to minimise problems relating to peptide adsorption or aggregation. Reverse-phase high-performance liquid chromatography (HPLC) was also performed on the rat tissue extracts. Rat cortex contained 268 +/- 12 pmol/g CCK-LI, and over 90% resembled the sulphated CCK-8, which was preferentially extracted at neutral pH. In contrast, the rat upper small intestine (97 +/- 8 pmol/g of CCK-LI) contained less than 20% CCK-8, the majority of immunoreactive CCK being of larger molecular size and being preferentially extracted at acid pH. In the small intestine the predominant molecular form(s) was intermediate in size between CCK-33 and CCK-8. Large amounts of CCK-33 and of a molecular form larger than CCK-33 were also detected. It is concluded that post-translational cleavage of CCK differs in rat brain and gut.     

Studies on biologically active complexes of cobalt(II) and nickel(II) with dithiooxamide-derived ligands.

A number of cobalt(II) and nickel(II) complexes with novel dithiooxamide ligands derived from precursors such as benzonitrile, benzosulfonamide, benzaldehyde, benzoic acid, and phenol have been synthesized and characterized on the basis of their elemental analysis molar conductance, magnetic moment, H NMR and electronic and IR spectral data. These ligands and their complexes have been screened for their antibacterial activities against bacterial species Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, and Tuberculi bacilli. The studies indicate that in comparison to the ligands their metal complexes are more potent and antibacterial.