Altered aquaporins in the brains of mice submitted to intermittent hypoxia model of sleep apnea

Rostral fluid displacement has been proposed as a pathophysiologic mechanism of both central and obstructive sleep apnea. Aquaporins are membrane proteins that regulate water transport across the cell membrane and are involved in brain edema formation and resolution. The present study investigated the effect of intermittent hypoxia (IH), a model of sleep apnea, on brain aquaporins.     

The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease

The course of autosomal dominant polycystic kidney disease (ADPKD) varies among individuals, with some reaching ESRD before 40 years of age and others never requiring RRT. In this study, we developed a prognostic model to predict renal outcomes in patients with ADPKD on the basis of genetic and clinical data. We conducted a cross-sectional study of 1341 patients from the Genkyst cohort and evaluated the influence of clinical and genetic factors on renal survival. Multivariate survival analysis identified four variables that were significantly associated with age at ESRD onset, and a scoring system from 0 to 9 was developed as follows: being male: 1 point; hypertension before 35 years of age: 2 points; first urologic event before 35 years of age: 2 points; PKD2 mutation: 0 points; nontruncating PKD1 mutation: 2 points; and truncating PKD1 mutation: 4 points. Three risk categories were subsequently defined as low risk (0–3 points), intermediate risk (4–6 points), and high risk (7–9 points) of progression to ESRD, with corresponding median ages for ESRD onset of 70.6, 56.9, and 49 years, respectively. Whereas a score ≤3 eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%, a score >6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%. This new prognostic score accurately predicts renal outcomes in patients with ADPKD and may enable the personalization of therapeutic management of ADPKD.     

Pregnancy outcomes among farming households of Nueva Ecija with conventional pesticide use versus integrated pest management

A retrospective cohort study was conducted to compare pregnancy outcomes in farming households that used pesticides conventionally with those that practiced integrated pest management (IPM) in Nueva Ecija, Philippines, in the period 1998-1999. Conventional pesticide users (CPUs) were defined as pesticide appliers who used pesticides routinely and regularly, whereas users of IPM were those who used pesticides as necessary, and on economically injured crop areas only. The data sets were subjected to the chi-square test of association, Fisher's exact probability test, and logistic regression analysis. At a significance level at 0.05, spontaneous abortion occurred significantly more often among the 345 CPU households than among the 331 IPM households (adjusted risk ratio 6.17). Likewise, birth defects were significantly more common in the CPU group (adjusted risk ratio 4.56). Thus, people of reproductive age who plan to have children should avoid any use of pesticides.     

Therapy of infections in neutropenic patients: Results with gentamicin in combination with cephalothin or chloramphenicol

Gentamicin in combination with cephalothin (Gent-Ceph) or with chloramphenicol (Gent-Chloro) was utilized in the treatment of 55 infections occurring in 49 cancer patients. Responses were obtained in 78% of the infections treated with Gent-Ceph and in 64% of those treated with Gent-Chloro. Pneumonia and septicemia were the most common infections in this study. Among the cases of pneumonia, 64% responded to Gent-Ceph and 67% to Gent-Chloro. Among the cases of septicemia, 88% responded to Gent-Ceph and 50% to Gent-Chloro. All of the identified organisms producing infection were gram-negative bacilli. Of these, E. coli was the most common. All organisms were resistant to cephalothin in vitro, and only 41% of them were resistant to chloramphenicol. However, resistant organisms responded significantly better to the Gent-Ceph combination (p < 0.025). Also, response to therapy among patients with severe neutropenia (< 100 neutrophils/mm³) was better for those patients treated with Gent-Ceph (p = 0.07). The combination of gentamicin with cephalothin or with chloramphenicol did not increase the frequency of side effects expected from gentamicin alone. No significant hematological toxicity was seen among those patients treated with chloramphenicol. Gentamicin in combination with cephalothin or chloramphenicol is an effective and safe antibiotic combination against gram-negative bacilli infections occurring in cancer patients. The efficacy of Gent-Ceph in patients with severe neutropenia is particularly advantageous.     

Clinical and morphological correlations in acute promyelocytic leukemia

Thirty adults with acute leukemia and greater than 20% bone marrow infiltrate by promyelocytes were studied. Eighteen patients had acute promyelocytic leukemia (APML) as defined by the presence of malignant promyelocytes, and the remaining 12 patients had acute myelocytic leukemia (AML) with an elevated percentage of normal promyelocytes. Malignant promyelocytes were characterized by abundant, abnormal, cytoplasmic granules, by Auer rods in meshwork pattern, and by splinter cytoplasmic granulations and dilatation of the cisternae of endoplasmic reticulum. Patients with APML had, in general, greater than 35% bone marrow infiltrate by promyelocytes. The degree of bone marrow infiltrate by these cells correlated with the clinical status of the patients. Diffuse intravascular coagulation with bleeding occurred in 61% of patients with APML, and the bone marrows of these patients had greater than 50% promyelocytes. No coagulation abnormalities were seen among patients with elevated bone marrow promyelocytes infiltrate and without APML. Coagulation abnormalities in patients with APML were only corrected by controlling the leukemia itself. When this occurred, patients with APML had an excellent rate of complete remission, and the duration of remission and survival were comparable to the results obtained in adults with AML.     

Pharmacology of Amikacin in Humans

Amikacin is a new aminoglycoside antibiotic which is active in vitro against most isolates of gram-negative bacilli. A dose of 300 mg/m(2) intramuscularly produced a highest mean serum concentration of 25.4 mug/ml with a mean serum concentration of 3.1 mug/ml at 8 h. The same dose intravenously produced a highest mean serum concentration of 52.4 mug/ml with a mean serum concentration of 2.1 mug/ml at 8 h. The mean urinary excretion during the first 6 h was 75 and 66%, respectively. When amikacin was administered at a dose of 150 mg/m(2) every 6 h, there was evidence of some drug accumulation. A loading dose of 150 mg/m(2) administered intravenously over 30 min followed by 200 mg/m(2) administered as a continuous infusion every 6 h maintained serum concentrations of 8 mug/ml. No major toxicity was observed with any of these drug regimens.     

CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22

Interleukin (IL)-22–producing group 3 innate lymphoid cells (ILC3) promote mucosal healing and maintain barrier integrity, but how microbial signals are integrated to regulate mucosal protection offered by these cells remains unclear. Here, we show that in vivo depletion of CX₃CR1⁺ mononuclear phagocytes (MNPs) resulted in more severe colitis and death after infection with Citrobacter rodentium. This phenotype was rescued by exogenous IL-22, which was endogenously produced by ILC3 in close spatial proximity to CX₃CR1⁺ MNPs that were dependent on MyD88 signaling. CX₃CR1⁺ MNPs from both mouse and human tissue produced more IL-23 and IL-1β than conventional CD103⁺ dendritic cells (cDCs) and were more efficient than cDCs in supporting IL-22 production in ILC3 in vitro and in vivo. Further, colonic ILC3 from patients with mild to moderate ulcerative colitis or Crohn’s disease had increased IL-22 production. IBD-associated SNP gene set analysis revealed enrichment for genes selectively expressed in human intestinal MNPs. The product of one of these, TL1A, potently enhanced IL-23– and IL-1β-induced production of IL-22 and GM-CSF by ILC3. Collectively, these results reveal a critical role for CX₃CR1⁺ mononuclear phagocytes in integrating microbial signals to regulate colonic ILC3 function in IBD.Mononuclear phagocytes (MNPs) are sentinels of the intestinal lamina propria, capable of responding to microbial products, and play a crucial role in orchestrating intestinal lymphocyte homeostasis. MNPs can be subdivided based on their expression of CD103 or CX₃CR1, and each group has been ascribed critical functions in maintaining intestinal homeostasis (Bogunovic et al., 2009; Merad et al., 2013). CD103⁺ cells, which can be further subdivided based on the expression of CD11b, differentiate from a common DC precursor and are thought to be the conventional, migratory myeloid DCs (Varol et al., 2010). CD103⁺ CD11b⁻ DCs require Irf8, Id2, and Batf3 for their development and are thought to play a critical role in cross-priming virus- and tumor-specific CTLs (Hildner et al., 2008; Merad et al., 2013). Loss of these cells, however, does not alter intestinal T cell homeostasis or lead to spontaneous inflammation (Edelson et al., 2010). CD103⁺CD11b⁺ DCs, in contrast, require Notch2 signaling, produce IL-23 in response to flagellin-induced TLR5 activation, resulting in IL-22 production by ILC3, and have additionally been proposed to support Th17 polarization (Lewis et al., 2011; Kinnebrew et al., 2012). These cells can produce retinoic acid, which promotes the expression of the gut-homing receptor CCR9 and synergizes with TGFβ to induce regulatory T cells (Sun et al., 2007). One recent study suggests that Notch2-dependent CD103⁺ CD11b⁺ DCs regulate protection from C. rodentium–induced colitis (Satpathy et al., 2013). However, specific depletion of CD103⁺ CD11b⁺ intestinal DCs revealed that these cells are not the MNP subset required for protection against C. rodentium or IL-22 production (Welty et al., 2013).In contrast to CD103⁺ cDCs, CX₃CR1⁺ MNPs differentiate from monocyte precursors (Varol et al., 2010). Although these cells were previously thought to be tissue-resident and to promote local T_reg differentiation (Hadis et al., 2011), recent data from our group showed that they can up-regulate CCR7 and migrate to secondary lymphoid organs, suggesting a broader role in orchestrating immunity (Diehl et al., 2013). Notably, we observed that interaction with microbiota limits the migration of these cells to mesenteric LNs (MLNs; Diehl et al., 2013), and an increase in CX₃CR1⁺ cells has been described in the lamina propria during mouse (Zigmond et al., 2012) and human colitis (Kamada et al., 2008). A recent study reported that fractalkine receptor (CX₃CR1) expression supports innate cell–dependent clearance of C. rodentium infection (Manta et al., 2013), but a functional role for CX₃CR1⁺ MNPs in regulating colitis-associated ILC3 remains unclear. To evaluate this question, we employed novel mouse models to enable selective depletion of CX₃CR1⁺ MNPs in vivo. Our results reveal a critical role for CX₃CR1⁺ MNPs from both mouse and human tissue in supporting IL-22 induction in ILC3 in vitro and in vivo. Moreover, we identify the ability of TL1A produced by MNPs to potently enhance IL-23– and IL-1β–induced production of IL-22 and GM-CSF by ILC3.