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Summary: Eukaryotic DNA replication licensing is a prerequisite for, and plays a role in, regulating genome duplication that occurs exactly once per cell cycle. ORC (origin recognition complex) binds to and marks replication origins throughout the cell cycle and loads other replication-initiation proteins onto replication origins to form pre-replicative complexes (pre-RCs), completing replication licensing. However, how an asymmetric single-heterohexameric ORC structure loads the symmetric MCM (minichromosome maintenance) double hexamers is controversial, and importantly, it remains unknown when and how ORC proteins associate with the newly replicated origins to protect them from invasion by histones. Here, we report an essential and cell-cycle-dependent ORC “dimerization cycle” that plays three fundamental roles in the regulation of DNA replication: providing a symmetric platform to load the symmetric pre-RCs, marking and protecting the nascent sister replication origins for the next licensing, and playing a crucial role to prevent origin re-licensing within the same cell cycle. : Amin et al. provide in vivo evidence for an essential, cell-cycle-dependent, and likely semi-conservative ORC dimerization cycle that regulates eukaryotic chromosomal DNA replication. ORC dimers provide symmetric platforms to load the symmetric pre-RCs at replication origins. ORC de-dimerization produces two single hexamers to bind and protect the two nascent origins. Keywords: DNA replication, replication licensing, pre-RC formation, cell-cycle control, ORC dimerization

Objective To evaluate our 5-year experience with deep lateral transurethral incisions of bladder neck contracture (TUIBNC), identify risk factors associated with failure of procedure, and assess outcomes of men subsequently treated for concomitant or de novo stress urinary incontinence (SUI). Materials and Methods We reviewed 50 consecutive patients who underwent TUIBNC between June 2007 and January 2012. TUIBNC was standardized to include initial dilation followed by deep transurethral incisions. All patients were evaluated cystoscopically after a 2-month interval; those with recurrent bladder neck contracture (RBNC) underwent a second TUIBNC. For patients with concomitant SUI, we assessed the timing between TUIBNC and subsequent artificial urinary sphincter (AUS) placement and its outcome. Perioperative characteristics were reviewed to identify factors associated with failure. Results Of the 50 patients analyzed, most were refractory, 78% having failed previous TUIBNC. After TUIBNC, 72% required no further surgery for obstruction at a mean follow-up of 12.9 months. Of the 14 who failed initial TUIBNC, 7 underwent repeat TUIBNC with success, representing an overall success rate of 86% after 2 procedures. Significant factors associated with treatment failure were >10 pack/year smoking history (P = .039) and ≥2 previous endoscopic BNC procedures (P = .03). Of 39 men (78%) with concomitant SUI, two-thirds underwent AUS placement after an average of 2.9 months after TUIBNC. Only 2 of 26 (8%) patients required repeat transurethral procedures after AUS placement for RBNC. Conclusion Deep lateral TUIBNC alone is a highly effective treatment modality for RBNC. Smokers and those having 2 or more previous transurethral procedures appear to have greater risk for failure. Subsequent AUS placement can be safely performed with >90% long-term urethral patency.

Oligosaccharyltransferase (OT) catalyzes the glycosylation of asparagine residues in nascent polypeptides in the endoplasmic reticulum. In a previous communication we reported the purification and characterization of this enzyme from chicken oviduct. Here we describe the purification and sequence analysis of OT from human liver microsomes. Oligosaccharyltransferase copurified with three proteins designated 50-kDa, 65-I and 65-II based on their molecular weights by gel electrophoresis. The N-terminal sequence of the 50-kDa component was homologous to the 50-kDa subunit of avian OT. The N-terminal sequences of 65-I and 65-II were identical to the primary structures of human ribophorins I and II, respectively, predicted by cDNA sequencing. The complete amino acid sequence of the 50-kDa subunit of human OT was determined by chemical sequencing of peptides isolated from chemical and enzymatic digests. The 50-kDa subunit of human OT is 98% identical to its canine homolog, 93% identical to its avian homolog, and 25% identical to the β subunit of yeast OT. These data indicate that structural features of oligosaccharyltransferase are conserved in all eukaryotes.

N VIEW of the interest in allergic as well as physiologic phenomena, the question of colonic absorption is important. This report presents data obtained in a study of that question. The products of protein digestion in vitro differ from the original protein by being slightly diffusible. For some time it was assumed that only diffusible protein was absorbed and hence that peptonization was essential. Schloss and Worthen,l however, demonstrated by precipitin and anaphylactic tests, that foreign protein might be absorbed. in an undigested or partially digested state. This has been more recently confirmed by Walzer2 by application of the local passive transfer phenomenon described by Prausnitz and Ktistner.3 Walzer showed that, in adults, oral administration of the antigen gave results quite comparable with those obtained by injection in the local sensitized skin areas. In a previous study4 me have reported similar results in new’born infants. There has remained, however, the question as to the site of this absorption in the intestinal tract. The opinion in many textbooks is that. absorption takes place above the cecum and that only water a.nd crystalloids are absorbed from the large bowel. The contrary evidence of Voit? has apparently been overlooked. Following rectal a.dministration of egg white and salt solution, they found an increase in urinary nitrogen. Since it was, known that practically no peptonization took place in the colon and since the effect of enzymes could be ruled out, absorption probably accounted for their findings. Egg white represents a nonassimilable type of protein in colztrast with its acid albumin fraction. Introduced in the blood stream the former substance is excreted by the kidney. Schloss and Worthenl demonstrated the presenee of egg white in the urine following oral administration. They emphasized the greater absorption from upset or abnormal intestinal t.racts. Colonic absorption is suggested from their findings since with increased peristalsis the chance of absorption from the upper intestinal tract is 1es.s. Yet it has been shown by previous passive transfer studies4 that the majority of healthy yoang infants will absorb egg white antigen after oral administration. The f olloming experiments were designed to see if application of local passive trans

Summary Determinations of the concentration of certain lipoprotein molecules (S f 10–20 class) are reported for forty-six juveniles with diabetes mellitus. Diabetic girls and diabetic boys have higher levels than their normal counterparts. The values for the girls were higher than those for boys. No close correlation was found in this age group between the level of S f 10–20 lipoprotein molecules in the sera and (1) the duration of the diabetic state, (2) the degree of control, (3) the severity of the disease, (4) the analytic serum cholesterol levels, or (5) the dietary intake of fat per unit of body weight.

On intracutaneous injection, the serums from certain infants with eczema give an immediate wheal formation. In about 30 patients with eczema, studied by passive transfer, 10, or over 30 per cent, showed this phenomenon. This toxicity is not related to enteral absorption of offending allergens nor to alteration of the colloidal properties by heat or cold. It resembles the effect of the theoretical "histamine-like" substance described by Lewis in studying the response of the skin to trauma, but other conditions in which there was extensive skin injury failed to show similar toxicity in the serum.

T HE observation of infants and children would seem to offer an opportunity to study the nature of certain diseases in relatively pure or uncomplicated st,ates. The cumulative results from diverse insults to the human organism, which confuse t,he adult picture, usually are absent in the young. Hereditary factors, on the other hand, are more obvious and the usual home relations afford information more accurate with regard to familp history and less subjcctivc with regard to symptomatology. Hence,, it has been expected that in the field of juvenile allergy etiologic factors and prevent,ive measures could be discovered more readily. The problem of etiology and prcvcntion is not, however, easily solved. The marked la.bility of infants as a group affords no gauge for t)he reactions which may bc seen in older children or adults. All too frequently natural processes, or at least factors beyond the knowledge and intent of medical treatmcni! will alter the nature and severity of the later manifestations considerably. (Nervous and psychogenic fact)ors may complie:lte the adolescent period.) The defense mechanisms with which allergy is somewhat allied are poorly established in infants. In early infant)there may be protection from some diseases because of transmission of maternal immunit,y, but this is of short duration. The inherent immune bodies (judged by precipitins, etc.) are developed with age. Although exireme variability in the acquisition of immunity may be noted, time is an element of great import. The most recent discussions of the relationship of immunity and allergy are those of Schick,l who in contrast wit,h Rich and his coworkers2 would emphasize the similarity of the mechanism in allergy and immunity. The skin of the young infant must undergo changes before it affords adequate protect,ion. Early the skin is extremely sensitive to tho physical agents, light, heat, cold and trauma, just as it is poorly rcsistant to infectious organisms. It would seem that a condition analogous to ‘ ‘ st,reet immunit!’ ’ might be concerned with some allergies. But regardless of that possibility, the skin, from which we frequently expect information concerning specific allergic tests, is notably unre

Treating the serum from patients giving positive skin tests with saturated ammonium sulphate, the essential antibody fraction is precipitated with the globulins. The albumin fraction is without sensitizing power, as judged by passive transfer, while the precipitated globulins when dialyzed and redissolved are potent. While passive transfer offers a poor means of estimating the titer of this antibody, it is apparently possible to concentrate the substance. It is found associated with the pseudoglobulin, ∗ ∗We use the term "associated with pseudoglobulin" feeling that the exact chemical nature of antibodies is still a matter of discussion. not with the euglobulin, and the nonessential lipoidal substances may be eliminated by prolonged cold-storage of the serum before treatment with ammonium sulphate. In many respects the antibody substance behaves like the antitoxin of diphtheria, save in its relative heat lability.

1.1. The skin of younger children and infants gives a greater response to trauma than does that of older individuals. This may be due to liberation of a toxic substance in the skin cells. 2.2. Clinically this finding may interfere with the interpretation of specific allergy tests, particularly when the intracutaneous method is used. 3.3. Specific skin reactions dependent on an antibody presence (reagin of Coca) are rare in infants under four months, regardless of sensitivity or contact with allergen. With increasing age, the antibody likewise increases, apparently following a general immunologic law. 4.4. Skin tests may become negative following these conditions: 4.1.(a) Severe allergic reactions. 4.2.(b) Graded therapy. 4.3.(c) Freedom from contact. 4.4.(d) Epinephrin administration. Skin reaction may also fail because of faulty preparations of the test substances (allergens) or because of inability of the individual to form the skin test antibody, even though he is clinically sensitive.

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Summary Determinations of the concentration of certain lipoprotein molecules (S f 10–20 class) are reported for 147 normal children ranging in age from birth to 15 years. These molecules previously have been shown to be associated with atherosclerosis. Similarity of values was found for normal male and female children. Boys had significantly lower values than those previously determined for normal male adults, but the levels for girls approximate the range for young normal female adults. No correlation was present between the concentrations of these lipoproteins in the sera of newborn infants and their mothers. No significant correlation was noted between the total serum cholesterol and the level of the S f 10–20 class. The data presented would indicate that children can tolerate a much higher intake of fat per unit of body weight than adults without showing comparable increases in concentration of the S f 10–20 molecules.

Summary In some children having severe hypothyroidism resembling that of the true cretins, many of the epiphyses develop abnormally and have the following characteristics: There are multiple loci of calcification; the calcification is slow; abnormal epiphyses occur in many parts of the skeleton; the distribution usually is bilateral; the process occurs generally in the capital epiphyses; and there may never be normal structure without treatment. When thyroid extract is used normal epiphyses develop in as short a time as six to twelve months. Dysgenesis is frequently mistaken for the chondrodystrophy of Calve-Legg-Perthes disease.