Differences in sleep-induced hypoxia between A/J and DBA/2J mouse strains

In obstructive sleep apnea, hypoxic ventilatory sensitivity may affect the degree of hypoxic stress and sleep disruption that occurs in response to upper airway obstruction. We induced (1) sleep-induced hypoxia (SIH) or (2) sleep fragmentation (SF) without hypoxia for 5 days (12-hour light/dark cycle) in two inbred mouse strains with low (A/J) and high (DBA/2J) hypoxic ventilatory sensitivities. During SIH, the time to arousal (26.4 +/- 1.1 vs. 21.3 +/- 1.5 seconds, p<0.025) and the severity of hypoxic exposure (nadir FIO2: 11.5 +/- 0.4 vs. 13.6 +/- 0.1%, p<0.002) was greater in A/J than DBA/2J mice. Furthermore, A/J mice had a greater frequency of hypoxic events (640 +/- 29 vs. 368 +/- 33 events per 24 hours, p<0.001) and total sleep time (47.5 +/- 2.8% vs. 26.5 +/- 2.4% per 24 hours, p<0.0001) during SIH than DBA/2J mice. In contrast, the event characteristics and total sleep time during SF were the same in both strains. Furthermore, in the light phase, both strains showed a longer (p<0.01) time to arousal during SIH and SF compared with the dark phase. We conclude that genetic background can influence respiratory events and sleep architecture during SIH and that the arousal threshold is subject to circadian variation. Our data imply that individuals with low hypoxic sensitivity may be at a greater risk for hypoxia-related complications of obstructive sleep apnea.     

Salivary glands and the aging process: mechanistic aspects, health-status and medicinal-efficacy monitoring

Xerostomia is a major complaint of many elderly individuals, and although they seek medical help, it usually provides no adequate relief. This complaint is considered a major clinical problem, since not less than 25% to 50%-60% of the population over the age of 65 complain of xerostomia. By definition, Xerostomia is a subjective feeling and in up to one-third of the cases does not reflect a real reduction in salivary flow rate but rather the subjective feeling of a dry mouth. Moreover, only a minute portion of the patients suffer from xerostomia with a known aetiology such as radiotherapy or Sjögren's syndrome, while in the majority of the cases, the aetiology is assumed to be related to age, disease, various medications and drugs or is simply idiopathic. The current review focuses on age-related histological, sialometrical and sialochemical changes and on the possible mechanisms which underlie these changes. Finally, directions for further exploring the subject are suggested.     

Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor.

Myelodysplastic syndromes (MDS) are characterized by chronic refractory cytopenias resulting in increased risk of infection, bleeding, and conversion to acute leukemia. In an effort to improve these cytopenias we have treated 18 patients over a 6- to 8-week period with increasing daily subcutaneous doses of recombinant human granulocyte colony-stimulating factor (G-CSF). Sixteen patients responded with improvement in neutrophil counts. On cessation of treatment these counts returned to baseline values over a 2- to 4-week period. To maintain these improved blood counts 11 patients were treated with G-CSF for more prolonged periods. Ten patients again responded with an increase in total leukocyte counts (1.6- to 6.4-fold) and absolute neutrophil counts (ANC) (3.6- to 16.3-fold), with responses persisting for 3 to 16 months. A significantly decreased risk of developing bacterial infections was noted during periods with ANC greater than 1,500/mm3 as compared with periods of time with ANC less than 1,500/mm3. Two anemic patients had a greater than 20% rise in hematocrit over the study period, and 2 additional patients had a decrease in red blood cell transfusion requirements during G-CSF treatment. Bone marrow myeloid maturation improved in 7 of 9 maintenance phase patients. Three patients progressed to acute myeloid leukemia during treatment. The drug was generally well-tolerated and no severe toxicities were noted. These data demonstrated that G-CSF administered to MDS patients by daily subcutaneous administration was well-tolerated and effective in causing persistent improvement of the neutrophil levels and marrow myeloid maturation. These effects were associated with a decreased risk of infection and, in some patients, with decreased red blood cell transfusion requirements.     

Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality

We investigated the feasibility of unrelated stem cell transplantation in 21 patients with advanced stage II/III multiple myeloma after a reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m(2)), melphalan (100-140 mg/m(2)), and antithymocyte globulin (ATG; 10 mg/kg on 3 days). The median patient age was 50 years (range, 32-61 years). All patients had received at least one prior autologous transplantation, in 9 cases as part of an autologous-allogeneic tandem protocol. No graft failure was observed. At day 40 complete donor chimerism was detected in all patients. Grade II to IV acute graft-versus-host disease (GVHD) was seen in 8 patients (38%), and severe grade III/IV GVHD was observed in 4 patients (19%). Six patients (37%) developed chronic GVHD, but only 2 patients (12%) experienced extensive chronic GVHD. The estimated probability of nonrelapse mortality at day 100 was 10% and at 1 year was 26%. After allografting, 40% of the patients achieved a complete remission, and 50% achieved a partial remission, resulting in an overall response rate of 90%. After a median follow-up of 13 months, the 2-year estimated overall and progression-free survival rates are 74% (95% CI, 54%-94%) and 53% (95% CI, 29%-87%), respectively. A shorter progression-free survival was seen in patients who already experienced relapse to prior autograft (26% versus 86%, P =.04). Dose-reduced conditioning with pretransplantation ATG followed by unrelated stem cell transplantation provides durable engraftment and donor chimerism, reduces substantially the risk of transplant-related organ toxicity, and induces high remission rates.     

Serum amyloid type a may be a predictor of restenosis

Background: Elevation of acute phase proteins [C-reactive protein (CRP) and serum amyloid type A (SAA)] has been demonstrated in unstable angina with an adverse clinical prognosis. Hypothesis: The study was undertaken to determine the effect of angioplasty on the levels of SAA and the correlation with postangioplasty restenosis. Methods: In a university-affiliated tertiary medical center, a prospective case study was undertaken in 55 patients who underwent successful percutaneous transluminal coronary angioplasty (PTCA) of a single coronary lesion for angina pectoris. Three groups of patients were clinically characterized according to Braunwald's classification of anginal syndrome: Group A: class III; Group B: class I; Group C: stable angina. Serum amyloid type A was measured by an ELISA method before PICA and after 24 h, 1, and 3 months. Patients were followed clinically for 12 months. A thallium stress perfusion scan was performed 3 months after PTCA and coronary angiography was repeated in patients with an abnormal thallium perfusion scan. Results: Serum amyloid type A levels >100 m?/ml could identify Group A patients with a high sensitivity and specificity (r = 0.85 and 0.86, respectively). Of the patients studied. 75% increased their SAA level 24 h after angioplasty. An increase of SAA by >100% was associated with an increased risk of restenosis, with a relative risk of 6.4 (p < 0.05). Conclusion: Increased levels of SAA characterize patients with unstable angina pectoris with a high specificity and sensitivity. Levels of SAA that increase > 100% 24 h after angioplasty may serve as a marker of restenosis.     

Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model

Chronic graft versus host disease (cGVHD) is a major complication that can develop after bone marrow transplantation. It involves an immune-mediated attack by transplanted donor lymphocytes, and often results in inflammatory damage of host target organs. Immune hyporesponsiveness induced by oral antigen administration has been recently shown to prevent the development of cGVHD in a murine model. The aim of this study was to evaluate whether tolerance induction in bone marrow transplant (BMT) recipients after transplantation, toward their pretransplant antigens, can alleviate preexisting cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ by minor histocompatibility antigens. Transplantation resulted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral tolerance was induced by feeding recipient BALB/c mice with proteins extracted from BALB/c splenocytes for 11 days after B10.D2 splenocyte transplantation. Tolerance induction was evidenced by a significant reduction in mixed lymphocyte response of effector splenocytes from tolerant BALB/c mice transplanted with B10.D2 splenocytes against BALB/c target splenocytes. Oral tolerance decreased skin collagen deposits. Reduction of collagen alpha1(I) gene expression and skin collagen were shown by in situ hybridization and histochemistry, respectively. Liver and bowel biopsy specimens revealed less inflammation. Serum IL-10 levels were higher in tolerant mice than in controls, whereas IFNgamma was significantly reduced. Oral tolerance of BMT recipients toward their pretransplant antigens after splenocyte transplantation down-regulated the immune attack by transplanted cells, thus ameliorating cGVHD.     

Understanding Utilization of Outpatient Clinics for Children with Special Health Care Needs in Southern Israel

To understand the pattern of utilization of ambulatory care by parents of children with special health care needs (CSHCN) and to explore parental challenges in coping with health maintenance of their infants after discharge from a neonatal intensive care unit (NICU). CSHCN require frequent utilization of outpatient ambulatory clinics especially in their first years of life. Multiple barriers are faced by families in disadvantaged populations which might affect adherence to medical referrals. Our study attempts to go beyond quantitative assessment of adherence rates, and capture the influence of parental agency as a critical factor ensuring optimal utilization of healthcare for CSHCN. A prospective, mixed-methods, cohort study followed 158 Jewish and Bedouin-Arab infants in the first year post discharge from NICU in southern Israel. Rates of utilization of ambulatory clinics were obtained from medical records, and quantitative assessment of factors affecting it was based on structured interviews with parents at baseline. Qualitative analysis was based on home visits or telephone in-depth interviews conducted about 1 year post-discharge, to obtain a rich, multilayered, experiential perspectives and explained perceptions by parents. Adherence to post-discharge referrals was generally good, but environmental, cultural, and financial obstacles to healthcare, magnified by communication barriers, forced parents with limited resources to make difficult choices affecting utilization of healthcare services. Improving concordance between primary caregivers and health care providers is crucial, and further development of supportive healthcare for CSHCN in concordance with parental limitations and preferences is needed.     

Alternative donor hematopoietic stem cell transplantation for mature lymphoid malignancies after reduced-intensity conditioning regimen: similar outcomes with umbilical cord blood and unrelated donor peripheral blood

We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignancies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received an allogeneic unrelated donor transplant using umbilical cord blood (n=104) or mobilized peripheral blood stem cells (n=541) after a reduced-intensity conditioning regimen. Unrelated cord blood recipients had more refractory disease. Median follow-up time was 30 months. Neutrophil engraftment (81% vs. 97%, respectively; P<0.0001) and chronic graft-versus-host disease (26% vs. 52%; P=0.0005) were less frequent after unrelated cord blood than after matched unrelated donor, whereas no differences were observed in grade II–IV acute graft-versus-host disease (29% vs. 32%), non-relapse mortality (29% vs. 28%), and relapse or progression (28% vs. 35%) at 36 months. There were also no significant differences in 2-year progression-free survival (43% vs. 58%, respectively) and overall survival (36% vs. 51%) at 36 months. In a multivariate analysis, no differences were observed in the outcomes between the two stem cell sources except for a higher risk of neutrophil engraftment (hazard ratio=2.12; P<0.0001) and chronic graft-versus-host disease (hazard ratio 2.10; P=0.0002) after matched unrelated donor transplant. In conclusion, there was no difference in final outcomes after transplantation between umbilical cord blood and matched unrelated donor transplant. Umbilical cord blood is a valuable alternative for patients with lymphoid malignancies lacking an HLA-matched donor, being associated with lower risk of chronic graft-versus-host disease.     

Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.