Targeted scan of fifteen regions for nonsyndromic cleft lip and palate in Filipino families.

Cleft lip with or without cleft palate (CL/P) is a congenital anomaly with variable birth prevalence based on geographic origins, with the highest rates commonly found in Asian populations. About 70% of cases are nonsyndromic (NS), in which the affected individual has no other abnormalities. NS CL/P is a complex disorder with genetic and environmental effects and no specific genetic loci yet confirmed. Fifteen candidate regions were examined for linkage to NS CL/P. Regions were chosen based on previous suggestive linkage and/or association in human families, or suggestive animal model data. Polymorphic markers in these regions were genotyped for analysis on 36 Filipino families comprised of 126 affected and 218 unaffected individuals. An additional 70 families with 149 affecteds were used for replication of suggestive results. Parametric (LOD score) and nonparametric (SIMIBD) linkage analyses were performed as well as transmission disequilibrium test (TDT) analysis. Five markers yielded suggestive results from the 36 families. The parametric LOD scores for the MSX1-CA and D4S1629 were >1.0 and the SIMIBD P values for D6S1029 and RFC1 are suggestive (<0.06), while the SIMIBD P value of 0.01 for TGFA was significant. Since the Msx1 mouse knockout has cleft palate and MSX1 mutations have been found in rare cases of syndromic CL/P, this locus is especially plausible for linkage. Previous studies have also found linkage of NS CL/P to 4q31 and 6p23. These regions contain several candidate genes, including AP2 at 6p23 and FGF2, BMPR1B, and MADH1 at 4q31. TGFA has both linkage and linkage disequilibrium data supporting it as a candidate gene for NS CL/P. While no region was definitively confirmed for linkage to NS CL/P, the data do support further investigation using larger sample sizes and candidate gene studies at 2p13.2, 4p16.2, 4q31, 6p23, and 16q22-24.

Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate.

MSX1 has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of MSX1 (two exons, one intron). We compare the completed genomic sequence of MSX1 to the mouse Msx1 sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian, and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known Msx1 orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition, a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of MSX1. MSX1 mutations are found in 2% of cases of clefting and should be considered for genetic counselling implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.

Quantum molecular similarity. 3. QTMS descriptors.

Building on the ideas of a previous paper [part 1, J. Phys. Chem. A 1999, 103, 2883] we present a new molecular similarity method based on the topology of the electron density. This method is directly applicable to QSARs and is called quantum topological molecular similarity (QTMS). It has been tested for five sets of carboxylic systems including para- and meta-benzoic acid, para-phenylacetic acid, 4-X-bicyclo[2.2.2]octane-1-carboxylic acids, and polysubstituted benzoic acids. In combination with the partial least squares (PLS) procedure QTMS is able to produce excellent and statistically valid regressions. It is shown that QTMS avoids certain challenges of traditional Carbó-like similarity indices. Finally, QTMS is able to suggest a molecular fragment that contains the active center or the part of the molecule that is responsible for the QSAR.

Phenotypical features of long Q-T syndrome in transgenic mice expressing human Na-K-ATPase alpha(3)-isoform in hearts.

To understand why the adult human heart expresses three isoforms of the sodium pump, we generated transgenic mice (TGM) with 2.3- to 5. 5-fold overexpression of the human alpha(3)-isoform of Na-K-ATPase in the heart. Hearts from the TGM had increased maximal Na-K-ATPase activity and ouabain affinity compared with control hearts, even though the density of Na-K-ATPase pump sites (of all isoforms) was similar to that of control mice. In perfused hearts, contractility both at baseline and in the presence of ouabain tended to be greater in TGM than in controls. Surface electrocardiograms in anesthetized TGM had a steeper dependence of Q-T on sinus cycle length, and Q-T intervals measured during atrial pacing were significantly longer in TGM. Q-T dispersion during sinus rhythm also tended to be longer in TGM. Thus TGM overexpressing human alpha(3)-isoform have several of the phenotypical features of human long Q-T syndrome, despite the absence of previously described mutations in Na(+) or K(+) channels.

The Janes Surgical Society.

The Janes Surgical Society was formed in 1953 by surgeons who had undertaken their surgical training during the tenure of Dr. Robert M. Janes, Professor of Surgery at the University of Toronto from 1947 to 1957. Over the next 35 years, this unique Canadian surgical society met annually at surgical centres on this continent and abroad as well as at certain resort areas from time to time. Members of the Janes Surgical Society could be found in major clinical and academic positions across the country from St. John's to Victoria. Their annual meetings served a dual purpose: they provided a forum for the exchange of scientific knowledge and ideas by the members; and they provided an opportunity for members and their wives to socialize and renew old friendships dating back to their residency days and to establish new relationships with surgeons and their wives from other countries, including the United States, United Kingdom, France and Sweden. Unfortunately, owing to death and retirements of its members, the Society can no longer hold scientific meetings and travel to distant centres. Its sole activity is now an annual dinner in Toronto, when members and their wives gather to recall the highlights and experiences in their lives that this unique surgical society provided.

Surgical management of early stage invasive breast cancer (stage I and II). Provincial Breast Disease Site Group.

GUIDELINE QUESTION: What is the optimal surgical management of early stage invasive breast cancer (stage I and II)? More specifically, what is the relative efficacy (and safety) of breast conservation therapy (lumpectomy with axillary dissection) compared with modified radical mastectomy? OBJECTIVE: To make recommendations about surgical management and techniques in the treatment of early stage invasive breast disease (stage I and II). OUTCOMES: Survival, local recurrence (for lumpectomy patients) and quality of life are the primary outcomes of interest. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 6 members of the Ontario Cancer Treatment Practice Guidelines Initiative, Disease Site Group for Breast Cancer (Breast DSG). Earlier drafts of this evidence-based recommendation have been reviewed, discussed and approved by the Breast DSG, which comprises surgeons, medical oncologists, radiation oncologists, epidemiologists, a pathologist and a medical sociologist. There was no consumer participation in the development of this guideline. QUALITY OF EVIDENCE: There are 7 randomized controlled trials (RCTs) comparing breast conservation therapy with mastectomy in women with early stage breast cancer. BENEFITS: In 6 RCTs, no statistically significant differences were detected in survival rate between the mastectomy and conservative therapy (lumpectomy) groups. In 1 RCT, a statistically significant differences was detected in favour of the mastectomy arm; however, this was an early trial with substantial methodologic weaknesses. HARMS: None. PRACTICE GUIDELINE: Women with early stage invasive breast cancer (stage I and II) who are candidates for breast conservation therapy (see discussion of technical factors) should be offered the choice of either breast conservation therapy (excision of tumour with clear margins and axillary dissection) or modified radical mastectomy. The choice is an individual one for the patient, and thus she should be fully informed of the options, including the risks and benefits of each procedure. She should be informed that breast irradiation is part of the procedure for breast conservation therapy. In addition, she should be aware of the potential need for further surgery if the margins are positive. For further information about the use of radiotherapy in the management of early stage breast cancer, please refer to the Ontario Cancer Treatment Practice Guidelines Initiative's practice guideline Breast Irradiation in Women with Early Stage Invasive Breast Cancer Following Breast Conserving Surgery.

Serologic response of pups to the low-passage, modified-live canine parvovirus-2 component in a combination vaccine.

Thirty pups from a general pet population were vaccinated for canine parvovirus-2 (CPV-2), using a low-passage, modified-live CPV-2 in a combination vaccine, every 3 weeks until the pups were between 11 and 18 weeks old. Canine parvovirus-2 antibody titers were measured by means of serum neutralization (SN) immediately before each vaccination and > or = 2 weeks after final vaccination. Thirteen pups that were initially seronegative (SN titer < 2 for CPV-2) developed protective titers (SN titer > or = 16) after 1 to 3 doses of the vaccine, administered when the pups were between 8 and 17 weeks old; 11 of the 13 developed protective titers after the first dose. Seventeen pups were initially seropositive for CPV-2 (SN titer > or = 2). Of these, 8 initially had titers < 16 and 3 others had titers that fell to < 16 during the study. Nine (82%) of these 11 pups developed protective titers. Results indicated that pups at high risk for CPV-2 disease should be vaccinated until 18 to 20 weeks old, even when the low-passage vaccine is used. Pups at lower risk of CPV-2 disease should be vaccinated periodically until 16 weeks old.

Ductal adenoma of the breast.

Ductal adenoma is a recently described benign tumour of the breast that can be mistaken for carcinoma in both frozen and paraffin sections. Such a case is presented. Fortunately a mastectomy was not performed, but the patient did undergo axillary node dissection. Surgeons and pathologists should familiarize themselves with this lesion so that patients do not have to undergo unnecessary mastectomies and axillary node dissections.

Perforating duodenal diverticulitis.

Two cases of perforating duodenal diverticulitis are reported, one with enterolith formation, and the other with sonographic evidence of retroperitoneal emphysema. The possible complications of duodenal diverticula, as well as the difficulties encountered in preoperative diagnosis, are discussed.

The murine complement receptor gene family. Analysis of mCRY gene products and their homology to human CR1.

The mouse genome contains two sets of gene sequences which are highly homologous to the gene encoding the human C3b/C4b receptor (CR1). These genes, termed murine CRY (mCRY) and murine CRX (mCRX) reside on murine chromosomes 1 and 8, respectively. Analysis of cDNA isolated by using these sequences as probes indicates that there are two related but distinct mRNA which are expressed in a wide variety of murine tissues including spleen, liver, lung, and brain. Both of these transcripts encode proteins which should contain a signal sequence for membrane insertion, a transmembrane/cytoplasmic tail region for membrane anchoring, and five extracellular domains made up of 60 amino acid consensus repeat sequences. The difference between the two is the presence of an additional exon of 129 bp immediately 3' of the signal sequence. This additional exon does not encode a 60 amino acid repeat. The sizes of the mature proteins predicted from the cDNA sequences are 43,998 Mr and 48,680 Mr; however, antisera raised against carboxy-terminal sequences detects a 70,000 Mr protein from murine fibroblasts suggesting a high degree of post-translational modification of the mature protein. A comparison of these murine gene sequences with a partial human CR1 sequence suggests that the human CR1 gene evolved by direct duplication of the ancestral coding sequences contained within these murine genes including those sequences important for membrane anchoring and cytoplasmic protein attachment.

Right-to-left patent ductus arteriosus with dysplastic left ventricle in a dog.

A 6-week-old Siberian Husky pup had an unusual group of congenital heart anomalies that included a right-to-left patent ductus arteriosus, a small left ventricular chamber and ascending aorta, and a dysplastic mitral valve that may have been stenotic. Anomalies were diagnosed, using cardiac catheterization, angiocardiography, and blood gas determinations. Findings were confirmed by postmortem examination.

Fine-needle aspiration cytology in breast lumps.

The authors reviewed retrospectively 368 breast lumps subjected to fine-needle aspiration cytology alone or to open biopsy as well. Of those lumps for which the results of both studies were available, there were 39 true-positive results, 32 true-negative, 1 false-positive and 7 false-negative results when the definitive findings of fine-needle aspiration biopsy were compared with the histologic features. Also, in the 40 patients in whom the aspirate was suggestive of malignancy or the findings were atypical, 22 had malignant disease on open biopsy and 18 had benign disease. These results are consistent with those reported in the literature and point to the importance of a positive or suggestive report and the current unreliability of a negative report.

Response of pups to modified-live canine parvovirus component in a combination vaccine.

Twenty-eight pups from a general pet population were vaccinated for canine parvovirus (CPV) with a combination vaccine every 3 weeks until the pups were 11 to 16 weeks old. Canine parvovirus antibody titers were measured by serum neutralization before each vaccination and greater than or equal to 2 weeks after the final vaccination. Eighteen pups that initially were seronegative for CPV seroconverted after 1 to 3 doses of modified-live virus CPV vaccine administered when the pups were between 8 and 16 weeks old; 16 of 18 seroconverted after the 1st dose. Of 10 pups that were seropositive for CPV at initial examination, 7 did not develop protective titers after 3 doses of vaccine, with the last dose given when the pups were 14 to 16 weeks old. Maternally derived antibody was the primary cause of vaccination failure.

Unilateral thyroid neoplasm in a cat.

An aged cat with a thyroid neoplasm showed clinical signs and had laboratory data and post mortem findings similar to those observed in human and canine patients afflicted with hyperthyroidism. Because of these similarities hyperthyroidism was suspected in the cat.

Suicide mortality in Greater London: changes during the past 25 years.

Suicide mortality in the area now administered by the Greater London Council was assessed for three five-year periods 1949-1953, 1959-63, and 1969-73. For each of the periods the standard mortality ratio (SMR) for suicide in various boroughs was calculated for men and women separately. The boroughs with high SMRs for men were constant. There was a pronounced change in the geographical distribution of high mortality among women. These findings support the hypothesis that the determinants of suicide differ between the sexes.

Prevention of venous thrombosis with small, subcutaneous doses of heparin.

The effect of low-dose heparin prophylaxis on venous thrombosis and bleeding after major elective surgery was studied in a prospective controlled study of 820 patients. The total incidence of venous thrombosis detected with leg-scanning using fibrinogen labeled with radioactive iodine (125I) was reduced from 16.0% in the control group to 4.2% in treated patients. More important, the incidence of popliteal or femoral vein thrombosis was reduced from 2.9% to 1.0%. Prophylaxis resulted in a slight increase in bleeding-minor wound hematoma, mean volume of blood transfused, and a post-operative hematocrit fall in treated patients. However, increased bleeding was clinically minor, and prophylaxis was well tolerated.