The primary stone event: a new hypothesis involving a vascular etiology

PURPOSE: We detail a new hypothesis regarding a vascular phenomenon as the primary event in the formation of urolithiasis. MATERIALS AND METHODS: A complete MEDLINE search was performed to examine the existing literature regarding the etiology of nephrolithiasis. In addition, urinary calculi were retrieved from 11 patients undergoing percutaneous nephrolithotomy and analyzed for total and esterified cholesterol content. RESULTS: A review of the literature on stone disease revealed many factors inconsistent with the current paradigm of the initiation of nephrolithiasis. These arguments can be based and classified on epidemiological, clinical, physiological, anatomical, and molecular data. In our stone analysis free and esterified cholesterol were found in varying quantities between 0.058 and 2.258 microg/mg stone and 0.012 and 0.777 microg/mg stone, respectively. Esterified cholesterol was found to comprise 75% of total serum cholesterol. In urinary stones esterified cholesterol accounted for 14% to 16% of total cholesterol and the esterified-to-free cholesterol ratio appeared to be related to stone composition. CONCLUSIONS: Numerous inconsistencies exist between current theories of the initial event in nephrolithiasis formation and empirical observational data on stone disease. Our review of the literature and our study of the cholesterol content of renal stones support a new theory regarding the initial stone forming event. We base this novel hypothesis on multiple epidemiological, physiological, anatomical and clinical observations. Further studies are required to confirm this hypothesis and its clinical usefulness.     

DNR directives are established early in mechanically ventilated intensive care unit patients

Purpose

Setting treatment goals in the intensive care unit (ICU) often involves resuscitation decisions. Our objective was to study the rate of establishing do-not-resuscitate (DNR) directives, determinants, and outcomes of those directives for mechanically ventilated patients.

Methods

In a multicentre observational study, we included consecutive adults with no DNR directives within 24 hr of ICU admission who were mechanically ventilated for at least 48 hr. We identified the rate with which DNR directives were established, and factors associated with these directives.

Results

Among 765 patients, DNR directives were established for 231 (30.2%) patients; 143 (62.1%) of these were established within the first week. Factors independently associated with a DNR directive were: patient age [> 75 yr (hazard ratio [HR] 2.3, 95% confidence interval 1.5–3.4], 65 to 74yr(HR 1.8, 1.2–2.7), 50 to 64 yr (HR 1.4, 1.0–2.2) relative to < 50 yr); medical rather than surgical diagnosis (HR 1.8, 1.3–2.5); multiple organ dysfunction score (HR 1.7 for each five-point increment, 1.4–2.0); physician prediction of ICU survival [< 10% (HR 15.0, 6.7–33.6)], 10 to 40% [(HR 5.0, 2.3–11.2), 41 to 60% (HR 4.0, 1.8–9.0) relative to > 90%]; and physician perception of patient preference to limit life support (no advanced life support [(HR 5.8, 3.6–9.4) or partial advanced life support (HR 3.2, 2.2–4.6) compared to full measures].

Conclusion

One third of mechanically ventilated patients had DNR directives established early during their ICU stay after the first 24 hr of admission. The strongest predictors of DNR directives were physician prediction of low probability of survival, physician perception of patient preference to limit life support, organ dysfunction, medical diagnosis and age.     

Studies on the differentiation of dopaminergic traits in human neural progenitor cells in vitro and in vivo

The development of cell replacement therapies for the treatment of neurodegenerative disorders such as Parkinson's disease (PD) may depend upon the successful differentiation of human neural stem/progenitor cells into dopamine (DA) neurons. We show here that primary human neural progenitors (HNPs) can be expanded and maintained in culture both as neurospheres (NSPs) and attached monolayers where they develop into neurons and glia. When transplanted into the 6-hydroxydopamine-lesioned rat striatum, undifferentiated NSPs survive longer (60% graft survival at 8-16 weeks vs. 30% graft survival at 8-13 weeks) and migrate farther than their attached counterparts. While both NSP and attached cells continue to express neuronal traits after transplantation, the spontaneous expression of differentiated transmitter-related traits is not observed in either cell type. However, following predifferentiation in culture using a previously described cocktail of reagents, approximately 25% of HNPs can permanently express the DA enzyme tyrosine hydroxylase (TH), even following replating and removal of the DA differentiation cocktail. When these predifferentiated HNPs are transplanted into the brain, however, TH staining is not observed, either because expression is lost or TH-expressing cells preferentially die. Consistent with the latter view is a decrease in total cell survival and migration, and an enhanced glial response in these grafts. In contrast, we found that the overall survival of HNPs is improved when cells engraft near blood vessels or CSF compartments or when they are placed into an intact unlesioned brain, suggesting that there are factors, as yet unidentified, that can better support the development of engrafted HNPs.     

Swallowing dysfunction after chemoradiation for advanced squamous cell carcinoma of the head and neck

BACKGROUND: Swallowing dysfunction is a common side effect of chemoradiation. METHODS: Twelve patients with stage III or IV squamous cell carcinoma of the head and neck were enrolled. Videofluorographic swallowing studies were performed before initiation of chemoradiation to provide baseline swallowing function data. Postchemoradiation videofluorographic swallowing studies were performed from 1 to 14 weeks after the completion of treatment (mean, 8 weeks). RESULTS: Changes in swallowing physiology after treatment included decreased base of tongue to posterior pharyngeal wall contact (p =.0010) and reduced pharyngeal contraction (p =.0313), resulting in impaired bolus transport through the pharynx. In addition, decreased laryngeal elevation (p =.0039), decreased laryngeal vestibule closure (p =.0078), and laryngeal penetration (p =.0078) were present. Bolus volume did not have a significant effect on swallowing ability. Aspiration was observed in four patients. CONCLUSIONS: Organ preservation treatment impairs movement of structures essential for normal swallowing. Prophylactic swallowing exercises may benefit these patients.     

Positron emission tomography with 18F-fluorodeoxyglucose to predict pathologic response after induction chemotherapy and definitive chemoradiotherapy in head and neck cancer

BACKGROUND: Conventional imaging is limited in identifying persistent disease after organ-preserving therapy for patients with advanced squamous cell carcinoma of the head and neck (SCCHN). We studied the accuracy of positron emission tomography (PET) with (18)F-fluoro-2-deoxy-D-glucose (FDG-PET) in restaging disease in patients with SCCHN after they had undergone induction chemotherapy (ICT) followed by chemoradiotherapy (CRT). METHODS: Forty patients with advanced SCCHN were treated with ICT followed by CRT. FDG-PET imaging was performed to assess for residual cancer at the primary site and in nodal metastases. Two nuclear medicine physicians interpreted PET scans in random sequence. Test characteristics were calculated with pathologic analysis or clinical recurrence as the standard. RESULTS: After induction chemotherapy, PET imaging had a sensitivity of 100% and specificity of 65% for detecting persistent disease at the primary tumor site. After ICT and CRT were completed, the sensitivity and specificity of PET imaging were 67% and 53%, respectively, for detecting occult disease in cervical lymph nodes. CONCLUSIONS: FDG-PET imaging showed some correlation with pathologic response after ICT and CRT in patients with advanced SCCHN. The use of FDG-PET warrants further investigation in this setting.     

Avidity of antibodies to cytomegalovirus in HIV-seropositive patients with and without CMV retinitis

Antibodies of high avidity may protect the fetus from CMV infection, but the association of avidity with other CMV infections is unknown. To determine if anti-CMV antibody avidity is altered in HIV-seropositive patients, either untreated or treated with HAART, and to determine if alterations in avidity are associated with CMV retinitis, we obtained sera from 164 CMV-seropositive adults: 68 were HIV-seronegative healthy adults and 96 were HIV seropositive. Of the HIV-positive, 57 had no current or prior evidence of CMV retinitis (29 were being treated with HAART, and 28 were receiving no therapy when sampled), and 39 had either active CMV retinitis or were immunorestored by HAART with quiescent CMV retinitis. IgG antibody avidity was determined for each serum run in duplicate using an EIA assay and 5M urea as a dissociating agent. After correction for the significantly higher levels of IgG antibodies to CMV in the HIV-seropositive sera as compared to the normal healthy individuals, both HIV-infected and HIV-uninfected individuals had nearly identical average avidity indices (avidity index = 76). There was also no significant difference in average avidity index between HAART-treated and untreated patients, or between patients with active and immunorestored, quiescent CMV retinitis). These results indicate antibody avidity is unaltered in HIV disease and does not play an important role in the pathogenesis of AIDS-related CMV disease.     

Pharmacoeconomics: the cost of prophylactic migraine treatments

Migraine preventive medications considered effective reduce headache frequency by 50 percent in approximately 50 percent of treated patients. In spite of similar effectiveness, these medications vary tremendonsly in their prices. Knowledge of medication prices and employing cost-effective strategies may greatly reduce treatment costs.