Pulmonary involvement in Niemann-Pick C type 1.

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder caused by mutations in either NPC-1 or NPC-2 genes, resulting in abnormal intracellular cholesterol trafficking. The estimated prevalence of NPC disease is 1: 120,000-150,000. Lung involvement has been described in only few patients with NPC, mostly NPC2. We describe a series of 12 patients, originating from six families all homozygotes to the p.R404Q (c.1211G > A) mutation of NPC1 gene; nine of them had significant pulmonary manifestations. All patients were followed in our medical center. Nine of the patients had pulmonary involvement, with recurrent pneumonia as the first manifestation in most, followed by recurrent wheezing episodes and subsequent development of interstitial lung disease with chronic need for oxygen support. Seven patients were reported of having interstitial disease by various imaging modalities.Conclusion: Pulmonary involvement in NPC1 is more common than previously reported. It is characterized as primary obstructive and restrictive lung disease and not only as part of neurologic sequel of NPC. It can lead to respiratory insufficiency and death from respiratory failure. What is Known: • Lung involvement has been described in only few patients with NPC. • Most reported NPC cases with pulmonary involvement were of NPC2. What is New: • Pulmonary involvement in NPC1 is more common than previously reported. • Pulmonary involvement in NPC1 should be considered as part of the disease and be thoroughly assessed and managed.

Maternal Asthma Is an Independent Risk Factor for Long-Term Respiratory Morbidity of the Offspring.

OBJECTIVE: The objective of this study was to investigate whether maternal bronchial asthma increases the risk for long-term respiratory morbidity of the offspring. STUDY DESIGN: A population-based cohort study compared the incidence of long-term pediatric hospitalizations due to respiratory disease of the offspring of mothers with and without bronchial asthma. Deliveries occurred between the years 1991 and 2014 in a tertiary medical center. Congenital malformations as well as multiple pregnancies were excluded. Kaplan-Meier's survival curve was used to estimate cumulative incidence of respiratory morbidity. A multivariate generalized estimating equation (GEE) logistic regression model analysis was used to control for confounders. RESULTS: During the study period, 253,808 deliveries met the inclusion criteria; of which 1.3% were born to mothers with bronchial asthma (n = 3,411). During the follow-up period, children born to women with bronchial asthma had a significantly higher rate of long-term respiratory morbidity (odds ratio [OR] = 1.5; 95% confidence interval [CI] = 1.3-1.7; p < 0.001). Specifically, the rate of childhood asthma was higher among offspring of mothers with asthma (OR = 2.3; 95% CI = 1.8-2.9; p < 0.001). Children born to women with asthma had higher cumulative incidence of respiratory morbidity, using a Kaplan-Meier's survival curve (log-rank test; p < 0.001). Using two multivariable GEE logistic regression models, controlling for the time to event, maternal age, and gestational age at delivery, maternal bronchial asthma was found to be an independent risk factor for long-term respiratory disease of the offspring (adjusted OR = 1.6; 95% CI = 1.4-1.9; p < 0.001), and specifically for bronchial asthma (adjusted OR = 2.5; 95% CI = 1.9-3.1; p < 0.001). CONCLUSION: Maternal bronchial asthma is an independent risk factor for long-term respiratory morbidity of the offspring.

High fat/refined carbohydrate diet enhances the susceptibility to spatial learning deficits in rats exposed to intermittent hypoxia.

BACKGROUND: Intermittent hypoxia during sleep (IH), as occurs in sleep disordered breathing (SDB), induces spatial learning deficits associated with regulation of transcription factors associated with learning and memory in the hippocampal CA1 region in rats. high fat refined carbohydrate diet (HF/RC) can induce similar deficits and associated changes in signaling pathways under normoxic conditions. METHODS: Sprague-Dawley adult male rats were fed either with (HF/RC) or low fat/complex carbohydrate diet (LF/CC) starting at post-natal day 30 for 90 days, and were then exposed for 14 days during light phase (12 h/day) to either normoxia (RA) or IH (21% and 10% O2 alternations every 90 s). Place-training reference memory task deficits were assessed in the Morris water maze. Total and ser-133 phosphorylated CREB were assessed in different brain regions by Western blotting and immunostaining in rats exposed to normoxia or IH and to LF/CC or HF/RC. RESULTS: Substantial decreases in CREB phosphorylation occurred in CA1 but not in motor cortex following either IH, HF/RC, and HF/RC + IH. Place-training reference memory task deficits were observed in rats exposed to IH and to HF/RC, and to a much greater extent in rats exposed to HF/RC + IH. CONCLUSIONS: Nutritional factors alter recruitment of transcription factors, possibly via oxidative-related pathways, and modulate the vulnerability of the CA1 region of the hippocampus to the episodic hypoxia that characterizes SDB, thereby enhancing neurocognitive susceptibility in SDB patients.

Intermittent hypoxic exposure during light phase induces changes in cAMP response element binding protein activity in the rat CA1 hippocampal region: water maze performance correlates.

Intermittent hypoxia (IH) during sleep, a characteristic feature of sleep-disordered breathing (SDB) is associated with time-dependent apoptosis and spatial learning deficits in the adult rat. The mechanisms underlying such neurocognitive deficits remain unclear. Activation of the cAMP-response element binding protein (CREB) transcription factor mediates critical components of neuronal survival and memory consolidation in mammals. CREB phosphorylation and DNA binding, as well as the presence of apoptosis in the CA1 region of the hippocampus were examined in Sprague-Dawley male rats exposed to IH. Spatial reference task learning was assessed with the Morris water maze. IH induced significant decreases in Ser-133 phosphorylated CREB (pCREB) without changes in total CREB, starting as early as 1 h IH, peaking at 6 h-3 days, and returning toward normoxic levels by 14-30 days. Double-labeling immunohistochemistry for pCREB and Neu-N (a neuronal marker) confirmed these findings. The expression of cleaved caspase 3 (cC3) in the CA1, a marker of apoptosis, peaked at 3 days and returned to normoxic values at 14 days. Initial IH-induced impairments in spatial learning were followed by partial functional recovery starting at 14 days of IH exposure. We postulate that IH elicits time-dependent changes in CREB phosphorylation and nuclear binding that may account for decreased neuronal survival and spatial learning deficits in the adult rat. We suggest that CREB changes play an important role in the neurocognitive morbidity of SDB patients.

Increasing prevalence of penicillin-resistant pneumococcal infections in children in southern Israel: implications for future immunization policies.

Although penicillin-resistant pneumococci (PR-PnC) are recognized as an increasing problem worldwide, data on the prevalence of these strains among pediatric patients are incomplete. The present study was conducted in southern Israel (1) to investigate the frequency of PR-PnC in invasive and middle ear infections in pediatric patients and (2) to assess the impact of resistance on the potential role of the candidate conjugate vaccines in preventing childhood PR-PnC infections. A total of 120 blood or cerebrospinal fluid isolates from 1987 to 1993 and 78 ear isolates from 1992 to 1993 were serogrouped and tested for susceptibility to antibacterial agents. The prevalence of PR-PnC among invasive isolates increased from 16% in the years 1987 to 1991 to 36% in 1992 to 1993 (P = 0.019). This increase was noted mainly for intermediately resistant strains (minimal inhibitory concentration, 0.12 to 1.0 micrograms/ml) whereas the prevalence of highly resistant strains was 3 and 2% for the 2 periods, respectively. The prevalence of PR-PnC among ear isolates in 1992 to 1993 was 42%. Resistance to other antimicrobial agents (one or more of the following: tetracycline, erythromycin, clindamycin and chloramphenicol) was found in 16 (8%) isolates, and multiple resistance (resistance to > or = 3 antibacterial agents) was found in 9 (5%) isolates. Sixty-five (99%) of the 66 resistant isolates belong to Serogroups 6, 14, 19 and 23. The prevalence of these 4 serogroups rose from 37% in 1987 to 1991 to 66% in 1992 to 1993 (P = 0.043). This rise was mainly because of Serogroup 23, the prevalence of which rose from 3% in 1987 to 1991 to 23% in 1992 to 1993 (P < 0.001). Eighty-five percent of all isolates belonging to Serogroup 23 were resistant to penicillin. Because Serogroups 6, 14, 19 and 23 are among the commonest pediatric pneumococcal strains, the newly developed conjugate pneumococcal vaccines contain these 4 serogroups. The selection of antibiotic-resistant strains has thus led to a change in the spectrum of serotypes causing invasive disease and to a situation of potential increase in vaccine coverage for the proposed pneumococcal conjugate vaccines.

[Penicillin resistance of pneumococci from invasive pediatric infections].

Susceptibility to antibiotics of 199 isolates of Streptococcus pneumoniae from blood and cerebrospinal fluid of children hospitalized during 1987-1993 was tested. Of 119 isolates, 18% were resistant to penicillin. The prevalence in 1992-93 was double that in 1987-89. The increase in minimal inhibitory concentrations (MIC) of penicillin was associated with an increase in MIC of other beta-lactams. There was also resistance to other antibiotics: trimethoprim-sulfamethoxazole, erythromycin and chloramphenicol. Most of the resistant isolates belonged to serogroups 6, 14, 19 and 23. When planning vaccine policies, resistant types should be taken into consideration.

Circulating cytokines in patients undergoing tonsillectomy with fibrin glue.

OBJECTIVE: Fibrin glue is used as a haemostatic agent or as a sealant. The aim of this study is to objectively evaluate the efficacy of the use of fibrin glue Quixil - a human surgical sealer - in tonsillectomy, for the reduction of post-operative inflammatory response. STUDY DESIGN: A prospective randomized single-blind study. METHODS: The study was performed on 40 consecutive patients undergoing adenotonsillectomy (T&A). Patients were randomly assigned to one of two sub-groups: a study group and a control group. The tonsillar beds of patients in the study group were coated with fibrin glue (Quixil, OMRIX biopharmaceuticals) at the end of the operation; the patients in the control group were treated for hemostasis without the use of fibrin glue. Complete blood counts and circulating pro-inflammatory cytokines (assayed by specific immunoassay - ELISA) were assessed in samples drawn pre- and 16 h post-tonsillectomy. RESULTS: Forty patients (aged 5.8 ± 2.4 years) were consecutively enrolled; 45% (18) of the patients were treated with fibrin glue, 55% (22) were not. Compared to controls, Quixil-treated patients demonstrated a reduction in post-tonsillectomy circulating leukocytes (29.2% vs. 45.4%, p<0.05), neutrophiles (28.3% vs. 42.1%, p<0.05), IL-6 (+1% vs. +42%, p<0.05), and TNF-alpha (+8% vs. +26%, p<0.05. CONCLUSIONS: Intra-operative fibrin glue therapy is associated with decreased immediate inflammatory response following T&A. Further studies are warranted to assess long-term outcome. LEVEL OF EVIDENCE: 1B.

Near fatal acute colchicine intoxication in a child. A case report.

UNLABELLED: An 8-year-old child with familial Mediterranean fever exhibited signs of colchicine intoxication while receiving prophylactic doses of the drug. She developed gastrointestinal, central nervous system, cardiovascular and haematological disturbances. Over 2 months she had been drinking high doses of natural grapefruit juice which, combined with long-term colchicine therapy and a viral upper respiratory tract infection, increased her susceptibility to the drug. CONCLUSION: To the best of our knowledge, this is the first time colchicine intoxication in this age group has been described in the English literature.