A role for TENM1 mutations in congenital general anosmia.

Congenital general anosmia (CGA) is a neurological disorder entailing a complete innate inability to sense odors. While the mechanisms underlying vertebrate olfaction have been studied in detail, there are still gaps in our understanding of the molecular genetic basis of innate olfactory disorders. Applying whole-exome sequencing to a family multiply affected with CGA, we identified three members with a rare X-linked missense mutation in the TENM1 (teneurin 1) gene (ENST00000422452:c.C4829T). In Drosophila melanogaster, TENM1 functions in synaptic-partner-matching between axons of olfactory sensory neurons and target projection neurons and is involved in synapse organization in the olfactory system. We used CRISPR-Cas9 system to generate a Tenm1 disrupted mouse model. Tenm1(-/-) and point-mutated Tenm1(A) (/A) adult mice were shown to have an altered ability to locate a buried food pellet. Tenm1(A) (/A) mice also displayed an altered ability to sense aversive odors. Results of our study, that describes a new Tenm1 mouse, agree with the hypothesis that TENM1 has a role in olfaction. However, additional studies should be done in larger CGA cohorts, to provide statistical evidence that loss-of-function mutations in TENM1 can solely cause the disease in our and other CGA cases.

Unwanted sexual contact on campus: a comparison of women's and men's experiences.

While sexual victimization continues to be a problem on college campuses, recent attention has been drawn to understanding gender differences in victimization rates and consequences. To date, these studies remain relatively few in number. The current study surveyed 651 male and female undergraduate students about unwanted sexual experiences during 1 academic year. Comparison of men and women revealed expected differences in incidence rates, with women reporting higher rates of unwanted contact. Within the subsample of reported victims, however, there was gender similarity in terms of the context of unwanted sexual experiences. Analyses also revealed the negative consequences of these experiences for both men and women and low rates of disclosure regardless of gender. Across the full sample of students surveyed, there were interesting gender differences in knowledge of campus support services, with women more likely to have attended a prevention program and to have indicated greater knowledge of rape crisis services.

Efficient induction of immune tolerance to coagulation factor IX following direct intramuscular gene transfer.

BACKGROUND: The formation of inhibitory anti-factor IX (anti-FIX) antibodies is a major complication of FIX protein replacement-based treatment for hemophilia B. It is difficult to treat patients with anti-FIX antibodies. Gene therapy is emerging as a potentially effective treatment for hemophilia. Direct i.m. injection of adeno-associated virus (AAV) is a safe and efficient procedure for hemophilia B gene therapy. However, the development of anti-FIX antibodies following i.m. of AAV may impede its application to patients. OBJECTIVE: We aimed to investigate induction of immune tolerance to human FIX (hFIX) by i.m. of AAV1, further validating i.m. of AAV1 for hemophilia B gene therapy. METHODS AND RESULTS: Cohorts of hemostatically normal and hemophilia B mice with diverse genetic and MHC backgrounds received i.m. of AAV-hFIX. Human FIX antigen and anti-hFIX antibodies were examined. I.m. of 1 x 10(11) vector genomes (VG) of AAV2 elicits formation of anti-hFIX antibodies comparable to those by hFIX protein replacement. I.m. of 1 x 10(11) VG of AAV1 results in expression of therapeutic levels of hFIX (up to 950 ng mL(-1), mean = 772 ng mL(-1), SEM +/- 35.7) and hFIX-specific immune tolerance in C57BL/6 mice. CONCLUSIONS: A single i.m. of AAV1 can result in efficient expression of therapeutic levels of hFIX and induction of hFIX tolerance in hemostatically normal and hemophilic B mice. Our results substantiate the prospect of i.m. of AAV1 for hemophilia B gene therapy and FIX tolerance induction.

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele.

INTRODUCTION: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. METHODS: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. RESULTS: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. CONCLUSIONS: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

The effects of intraoperative fenoldopam on renal blood flow and tubular function following suprarenal aortic cross-clamping.

This study evaluated the effect of fenoldopam, a selective dopamine (DA1) agonist, on renal blood flow and renal tubular function following renal ischemia induced by suprarenal aortic cross-clamping. Twenty anesthetized research pigs received either fenoldopam (10 micro g/kg/min; n = 10) or saline ( n = 10) beginning 20 min before suprarenal aortic cross-clamping and continuing for 20 min after clamp release, for a total infusion time of 160 min (120-min cross-clamp). Recordings of renal blood flow, mean arterial pressure, and heart rate were taken at baseline, during cross-clamping, and immediately postclamp. Ischemic renal injury was evaluated by serum creatinine and by histologic grading of acute tubular necrosis. Treatment with fenoldopam increased renal blood flow in comparison to that in the control group ( p = 0.03). The mean creatinine increase from baseline at 6 hr and 18 hr after cross-clamp removal for the fenoldopam-treated group was significantly less than that in the control group ( p < 0.001). On histologic evaluation, the mean score for the degree of tubular necrosis was significantly higher in the control group ( p = 0.02), indicating less derangement of tubular morphology in the fenoldopam group. This study demonstrated that the intraoperative use of a continuous infusion of fenoldopam during suprarenal aortic cross-clamping results in increased renal blood flow, less postoperative rise in creatinine, and better preservation of tubular histology in the pig model.

Acute embolic occlusion of the distal aorta.

PURPOSE: Acute occlusion of the abdominal aorta requires rapid diagnosis and intervention to prevent loss of life or limb. The overall mortality due to embolic occlusion is reported to be over 30%. The most common source of emboli is the heart, secondary to atrial fibrillation or myocardial infarction. METHODS: A patient is herein presented who arrived at the emergency department 6 hours after onset of classic signs of acute arterial occlusion. RESULTS: She had a saddle embolus of the distal abdominal aorta with extension of the clot into both iliac and femoral arteries. CONCLUSIONS: Heparin therapy and embolectomy successfully reestablished blood flow. The etiology, presentation and management of aortoiliac occlusion is discussed.

Parent perspectives of occupational therapy using a sensory integration approach.

This qualitative study explored parents' points of view regarding their children's participation in occupational therapy using a sensory integration approach. Data were collected through parent interviews and were analyzed using grounded theory methods. The parents' perceptions of the benefits of therapy for their children were categorized into three interrelated constructs: abilities, activities, and reconstruction of self-worth. For themselves, parents valued understanding their children's behavior in new ways, which facilitated a shift in expectations for themselves and their children, having their parenting experience validated, and being able to support and advocate for their children. Implications for family-centered intervention and future research are proposed.

Temperature, routine activities, and domestic violence: a reanalysis.

It was hypothesized that base rate differences in the number of complaints made during daylight and nighttime hours were responsible for a previously reported, nonlinear relationship between temperature and domestic violence. This hypothesis was tested by subjecting calls for service in 1987 and 1988 in Minneapolis, to moderator-variable regression analyses with controls for time of day, day of the week, season, and their interactions as well as linear trend, major holidays, public school closings, the first day of the month, and other weather variables. Temporal variables explained 75% of the variance in calls for service. As hypothesized, the base rate artifact was responsible for an apparent downturn in violence at high temperatures: Fewer complaints were received during afternoon hours, because they happen to be the warmest time of the day. The results were interpreted in terms of routine activity theory.

Tibial bypass using complex autologous conduit: patency and limb salvage.

Over an 8-year period, we performed 93 lower extremity bypasses using complex autologous conduits, which included (1) contralateral greater saphenous vein (GSV), (2) composite GSV, (3) superficial femoral vein, (4) lesser saphenous vein, (5) cephalic or basilic veins, and (6) composite-sequential (PTFE and vein) grafts. These grafts represented 16% of all infrainguinal bypasses during this period, and all grafts were performed to treat limb-threatening ischemia. Survival, patency, and limb salvage were examined by the life-table method. Primary graft patency was 46 and 38% at 3 and 5 years. Assisted-primary patency was 62 and 59%, and secondary graft patency rates were 68 and 64% at 3 and 5 years. Twenty-nine bypasses (31%) required revision to restore or maintain patency. The 3-year limb salvage rate was significantly better when revision was performed for graft stenosis than for graft thrombosis (90% vs. 46%, p < 0.05). Overall limb salvage rate was 73% at 5 years. The mortality rate was 5.4% and the 5-year survival was 51%. Complex autologous tibial bypasses provided acceptable long-term limb salvage in patients with severe ischemia and inadequate ipsilateral GSV. The increased operating time and complexity required did not produce prohibitive operative risks. Postoperative graft surveillance in these complex vein bypasses allowed revision in many cases before graft occlusion occurred and significantly improved long-term limb salvage.

From waiting to relating: parents' experiences in the waiting room of an occupational therapy clinic.

OBJECTIVE: The purpose of this study was to gain an understanding ofparents'perceptions of outcomes of occupational therapy intervention using a sensory integration approach. METHOD: Interviews with parents regarding their childrens participation in occupational therapy were analyzed using grounded theory. RESULTS: The parents' experiences of sitting in the waiting room while their children received occupational therapy emerged as a powerful outcome theme. Through their interactions with other parents, this particular group of parents gave and received naturally occurring support for parenting children with sensory integrative dysfunction. Additionally, by virtue of repeated experiences of waiting, parents moved to positions of liminality, shared weekly rituals, engaged in downward social comparison, and reframed their views of their children. CONCLUSION: Implications are proposedfor expanding the definition of family-centered intervention; attending to the meaning of the cultural world of practice; and directing future research related to how a physical setting, such as a waiting room, might shape naturally occurring support and social interaction.

Distributive and procedural justice in seven nations.

The paper examines the impact of distributive justice and procedural justice variables on judgments in seven countries (Bulgaria, France, Hungary, Poland, Russia, Spain, and the United States). Subjects were presented with each of two experimental vignettes: one in which the actor unsuccessfully appeals being fired from his job and one in which the actor unsuccessfully goes to an employment agency to seek a job; they were asked to rate the justness of the outcome and how fairly the actor had been treated. The vignettes manipulated deservingness and need of the actor (distributive justice factors) and impartiality and voice in the hearing (procedural justice factors). Four hypotheses were tested: first, a distributive justice hypothesis that deservingness would be more important than need in these settings; second, a procedural justice hypothesis that the importance of voice and impartiality vary depending on the nature of the encounter and the forum in which it is resolved; third, because of their recent socialist experience, Central and Eastern European respondents make greater use of need information and less use of deservingness information than Western respondents; and fourth, that distributive justice and procedural justice factors interact. The distributive justice hypothesis is supported in both vignettes. The procedural justice hypothesis receives some support. Impartiality is more important in the first vignette and voice is more important in the second vignette. The interaction hypothesis was not supported in the first vignette, but does receive some support in the second vignette. The cultural hypothesis is not supported in either vignette. The implications for distributive and procedural justice research are discussed.

Exposure of the anterior spine: technique and experience with 66 patients.

PURPOSE: Anterior spinal fusion has become an increasingly popular technique used by orthopedic surgeons for a variety of lower spine pathology. At our institution urologists have assisted as retroperitoneal surgeons in achieving exposure of the appropriate spinal disk space. We report our experience with anterior spinal fusion in 66 patients. MATERIALS AND METHODS: Since 1991 we have performed 66 exposures using the flank, modified Gibson, thoracoabdominal, paramedian and midline transperitoneal approaches. Exposure of each level has subtle technical issues which are reviewed. RESULTS: During the study 34 men and 32 women 24 to 74 years old (mean age 43.8) underwent discectomy and anterior fusion of the spine. Access from T12 through L5-S1 interspace was required, and exposure of multiple spinal levels was necessary in 27. There was 1 death from massive pulmonary embolism in a patient with widely metastatic lung cancer. Retrograde ejaculation was reported by 2 men. There have been no episodes of deep or superficial wound infection and no ureteral or major vascular injuries. CONCLUSIONS: As surgeons of the retroperitoneum urologists have an important role in providing our orthopedic colleagues with safe, adequate exposure to the anterior surface of the spine during discectomy and anterior fusion.

Violence is a curvilinear function of temperature in Dallas: a replication.

Data on weather and aggravated assaults were obtained to determine whether the curvilinear relationship between temperature and violence previously observed in Minneapolis, Minnesota (E. G. Cohn & J. Rotton, 1997), could be replicated. The data consisted of calls for services received by police in Dallas between January 1, 1994, and December 31, 1995. Controlling for holidays, school closings, time of day, day of the week, season of the year, and their interactions, moderator-variable autoregression analyses indicated that assaults were an inverted U-shaped function of temperature. Replicating past research, the curvilinear relationship was dominant during daylight hours and spring months, whereas linear relationships were observed during nighttime hours and other seasons. The results are interpreted in terms of routine activity theory and the negative affect escape model of aggression.

Connexin 26: required for normal auditory function.

A single base deletion mutation, 35delG, in the gene (GJB2/DFNB1)(OMIM 121011/220290) encoding the gap junction protein, connexin 26 is the most important single cause of genetic hearing loss in European and American populations. It is the cause of one of the most common human genetic disorders with a frequency similar to cystic fibrosis. Mutations in this connexin are associated with skin disorders.

Parental hopes for therapy outcomes: children with sensory modulation disorders.

OBJECTIVE: Understanding parents' hopes for therapy outcomes is essential to family-centered care. This qualitative study explored parents' points of view regarding their hopes for the outcomes of occupational therapy using a sensory integration treatment approach. METHOD: Data were collected as part of a larger research project on the effectiveness of rehabilitating children who have sensory modulation disorders. Five interviews were randomly selected from 17 parent interviews conducted in the larger study. Data were analyzed using grounded theory methods. FINDINGS: Three themes pertinent to the occupations of children and two themes related to the occupations of parenting and sustaining family life emerged. Child-focused outcomes include social participation, self-regulation, and perceived competence. Parent-focused outcomes include learning strategies to support children and obtaining personal validation. DISCUSSION: Interventions are proposed that relate to children's participation in contexts in which they live, learn, and play, as well as the support of parents in the occupations of parenting.

The M34T allele variant of connexin 26.

GJB2 encodes the protein Connexin 26, one of the building blocks of gap junctions. Each Connexin 26 molecule can oligomerize with five other connexins to form a connexon; two connexons, in turn, can form a gap junction. Because mutations in GJB2 are the most common cause of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss, the effect of the Connexin 26 allele variants on this dynamic 'construction' process and the function of any gap junctions that do form is particularly germane. One of the more controversial allele variants, M34T, has been hypothesized to cause autosomal dominant nonsyndromic hearing loss. In this paper, we present clinical and genotypic data that refutes this hypothesis and suggests that the effect of the M34T allele variant may be dependent on the mutations segregating in the opposing allele.