Specular microscopy of hard contact lens wearers

Wide-field specular microscopy, slit-lamp examination, and pachometry were performed on 22 successful hard contact lens wearers and 22 controls matched for age, race, sex, and refractive error. A minimum of 600 cells per control and 1200 per contact lens wearer were manually digitized from the specular photomicrographs. Frequency distributions of cell areas were compared between the two groups using the parameters of mean, median, standard deviation, coefficient of variation, skewness and kurtosis. Slit-lamp examination was normal and there was no significant difference in corneal thickness between the patient group and the control group. Comparison of mean, median, and standard deviation also revealed no significant difference, but skewness (P less than .001), kurtosis (P less than .001) and coefficient of variation (P less than .004) were greater in the hard contact lens wear group. Hard contact lens wearing time correlated with increasing pleomorphism (P less than .05). Specular microscopy also revealed morphologic changes including deep stromal striae, intra- and extracellular "blackout" areas, and clustering of extremely small and large cells. The possible relationship between endothelial hypoxia and structural stromal changes are discussed.     

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial

BackgroundThe use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.ObjectiveTo evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.Design, setting, and participantsIMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.InterventionPatients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.Outcome measurements and statistical analysisThe secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.Results and limitationsFifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.ConclusionsThe atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.Patient summaryPatients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.     

Awake intubation of the adult trachea using the Bullard laryngo-scope

Awake intubation using the Bullard laryngoscope can be comfortably and easily performed in the adult. Five cases are presented in which tracheal intubation was performed under topical anaesthesia with light intravenous sedation. In each case, topical anaesthesia was performed by insertion of a Guedel oral airway, with lidocaine ointment applied to the inferior and posterior surfaces. In one case, Bullard intubation was successful where direct laryngoscopy and multiple attempts at bronchoscopic intubation by three different operators had failed. We conclude that the Bullard laryngoscope can be easily used in awake patients and may be a useful alternative where other methods for awake intubation have failed.     

Hormone and fertility drug use and the risk of neuroblastoma: a report from the Children's Cancer Group and the Pediatric Oncology Group.

Previous epidemiologic studies have suggested an association between maternal sex hormone use during pregnancy, including infertility medication, and an increased risk of neuroblastoma in the offspring. The authors conducted a case-control interview study from 1992 to 1996 that included 504 children less than 19 years of age whose newly diagnosed neuroblastoma was identified by two national collaborative clinical trials groups in the United States and Canada, the Children's Cancer Group and the Pediatric Oncology Group. Controls, matched to cases on age, were identified by random digit dialing. No association was found for use of oral contraceptives before or during pregnancy (first trimester odds ratio (OR) = 1.0, 95% confidence interval (CI): 0.5, 2.1). The odds ratio was slightly elevated for history of infertility (OR = 1.4, 95% CI: 0.9, 2.1) and ever use of any infertility medication (OR = 1.2, 95% CI: 0.7, 2.2). Specifically, ever use of clomiphene was associated with a 1.6-fold increased risk (95% CI: 0.8, 3.0) but not periconceptionally or during the index pregnancy. A suggestive pattern was found for gender of the offspring, with an increased risk for males but not for females after exposure to oral contraceptives or clomiphene. This study did not find consistent and large increased risks for maternal use of hormones, but the suggestion of an association for male offspring requires further consideration.     

Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR

Cystic fibrosis (CF) is caused by mutations in the gene encodinga chloride channel called the CF transmembrane conductance regulator(CFTR). A single mutation in this gene, deletion of three nucleotidesthat leads to the absence of phenylalanine 508 (i.e., F508),is found on 70% of all CF chromosomes. To explore the molecularmechanism(s) responsible for defective chloride transport inpatients with CF, we have studied the processing, localization,and function of wild type (W.T.), F508 and G551D CFTR (a GDmissense mutation at position 551) in retrovirus transducedL cells. Cell transduced with W.T. CFTR expressed a 170 kd CFTRprotein that was endoglycosidase H (Endo H) resistant, localizedto the plasma membrane, and generated a cAMP-mediated anionconductance (G_Cl) when stimulated with standard concentrationsof forskolin (5 µM), cpt cAMP (400 µM) and IBMX(100 µM). The G551D CFTR was indistinguishable from W.T.CFTR with respect to post-translational processing and localization,but it did not produce a cAMP-activated G_CI in response to thestandard stimulation cocktail. However, raising the IBMX concentrationto 4 mM produced Gc, in G551D expressing cells. Cells transducedwith F508 CFTR expressed an Endo H sensitive CFTR protein (140kd) that was found in a cytosolic, perinuclear location. Thesecells did not respond to the standard cocktail, but 20% of cellsincreased G_CI when the cocktail contained 4 mM IBMX. Incubationof cells at 26°C for 48 hours prior to analysis elicitedresponses in F508 expressing cells at low IBMX concentrations,but had no effect on the responses of cells expressing W.T.or G551D CFTR. The response of F508 to 26°C was associatedwith plasma membrane localization of CFTR protein. These resultssuggest that there are two mechanisms whereby CFTR mutationslead to loss of cAMP-responsive GCI. First, shown by G551D CFTR,the protein can be processed and targeted to the plasma membranecorrectly, but lack full responsiveness to stimulation by cAMP.Second, as examplified by F508 CFTR, a partially functionalprotein which is not targeted to its correct cellular locationcan also lead to loss of the cAMP, responsive G_CI.     

Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of sudden death in apparently healthy young individuals. In less than half of kindreds with HCM, the disease is linked to the beta-myosin heavy-chain gene locus (MYH7). We have recently described two missense MYH7 gene mutations [Arg-403 to Gln (R403Q) and Leu-908 to Val (L908V)] and found that the mutant message is present in skeletal muscle soleus) and that the mutant beta-myosin obtained from soleus muscle has abnormal in vitro motility activity. Having identified a second kindred with the R403Q mutation, and 3 other kindreds with two additional mutations (G741R and G256E), we performed histochemical analysis of soleus muscle biopsies from 25 HCM patients with one of these four mutations. Light microscopic examination of the NADH-stained biopsies revealed the presence of central core disease (CCD) of skeletal muscle, a rare autosomal dominant nonprogressive myopathy characterized by a predominance of type I "slow" fibers and an absence of mitochondria in the center of many type I fibers. CCD was present in 10 of 13 patients with the L908V mutation, 5 of 8 patients with the R403Q mutation, 1 of 3 patients with the G741R mutation, and 1 patient with the G256E mutation. Mild-to-moderate myopathic changes with muscle fiber hypertrophy were present in 16 patients. Notably, CCD was present in 2 adults and 3 children with the L908V mutation who did not have cardiac hypertrophy. In contrast, soleus muscle samples from 5 patients from 4 kindreds in which HCM was not linked to the MYH7 locus showed no myopathy or CCD. Soleus muscle biopsies from 5 control subjects also showed normal histology. This work demonstrates that (i) MYH7-associated HCM is often a disease of striated muscle but with predominant cardiac involvement and (ii) a subset of HCM patients with MYH7 gene missense mutations have CCD.     

Differential effects of MK-801, NMDA and scopolamine on rats learning a four-member repeated acquisition paradigm

The glutamatergic (NMDA) and cholinergic neurotransmitter systems have been extensively implicated as neurochemical mediators of learning processes. These two systems may differentially affect learning; for example, although both the cholinergic antagonist scopolamine and the NMDA antagonist MK-801 reduced overall accuracy of rats in a 3-member repeated acquisition paradigm, the nature of the underlying error patterns produced by the two drugs differed significantly: rats administered scopolamine produced a pattern of skipping errors, while administration of MK-801 predominantly increased perseverative errors (Cohn et al., 1992). The present experiment extended that study to examine whether a more complex task, i.e. a 4-member repeated acquisition paradigm, would alter the nature of the error patterns resulting from administration of each drug, and whether NMDA itself would increase accuracy on the repeated acquisition paradigm. MK-801 (0.05-0.3mg/kg i.p.) significantly decreased overall accuracy in a dose-dependent manner, and the rats produced a pattern of errors similar, although not identical to, that noted in the 3-member paradigm, including perseverative errors early in the sequence, but additional skipping errors at later points in the sequence. MK-801 dramatically decreased correct initiation of a sequence following an error at any point in the sequence. NMDA (10.0-30.0mg/kg) itself did not facilitate sequence acquisition, i.e. it did not affect overall accuracy. However, it was the only drug to increase the frequency of correctly reinitiating a sequence following an incorrect first or an incorrect second sequence member. Like MK-801, scopolamine (0.5-3.0mg/kg i.p.) also produced a decline in overall accuracy which was again achieved primarily through increased skipping errors. Scopolamine did not, however, interfere with correctly reinitiating a sequence either after successful completion of a sequence, or after an error. These findings suggest that cholinergic and glutamatergic compounds exert their effects on learning through different behavioral mechanisms.     

Men''s disclosure of HIV test results to male primary sex partners.

We evaluated disclosure of human immunodeficiency virus (HIV) antibody status to a main sex partner and the impact on the relationship in men who have sex with men and who are enrolled in the Acquired Immunodeficiency Syndrome (AIDS) Community Demonstration Projects cohorts. Eighty-nine percent of both seronegative and seropositive men disclosed the results to their main sex partner. Seventy percent of the seronegative men and 82% of the seropositive men who did so reported that the relationship remained "as strong as ever" after 6 months. Most men who did not disclose their test results to their main partner reported being "single" after 6 months.