Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13.

Hallervorden-Spatz syndrome (HSS) (OMIM #234200) is a rare, autosomal recessive neurode-generative disorder with brain iron accumulation as a prominent finding. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals massive iron deposits in the basal ganglia. Systemic and cerebrospinal fluid iron levels are normal, as are plasma levels of ferritin, transferrin and ceruloplasmin. Conversely, in disorders of systemic iron overload, such as haemochromatosis, brain iron is not increased, which suggests that fundamental differences exist between brain and systemic iron metabolism and transport. In normal brain, non-haem iron accumulates regionally and is highest in basal ganglia. Pathologic brain iron accumulation is seen in common disorders, including Parkinson's disease, Alzheimer's disease and Huntington disease. In order to gain insight into normal and abnormal brain iron transport, metabolism and function, our approach was to map the gene for HSS. A primary genome scan was performed using samples from a large, consanguineous family (HS1) (see Fig. 1). While this family was immensely powerful for mapping, the region demonstrating homozygosity in all affected members spans only 4 cM, requiring very close markers in order to detect linkage. The HSS gene maps to an interval flanked by D20S906 and D20S116 on chromosome 20p12.3-p13. Linkage was confirmed in nine additional families of diverse ethnic backgrounds.

DNA sequence and comparative analysis of chimpanzee chromosome 22.

Human-chimpanzee comparative genome research is essential for narrowing down genetic changes involved in the acquisition of unique human features, such as highly developed cognitive functions, bipedalism or the use of complex language. Here, we report the high-quality DNA sequence of 33.3 megabases of chimpanzee chromosome 22. By comparing the whole sequence with the human counterpart, chromosome 21, we found that 1.44% of the chromosome consists of single-base substitutions in addition to nearly 68,000 insertions or deletions. These differences are sufficient to generate changes in most of the proteins. Indeed, 83% of the 231 coding sequences, including functionally important genes, show differences at the amino acid sequence level. Furthermore, we demonstrate different expansion of particular subfamilies of retrotransposons between the lineages, suggesting different impacts of retrotranspositions on human and chimpanzee evolution. The genomic changes after speciation and their biological consequences seem more complex than originally hypothesized.

Confirmation of linkage of Clouston syndrome (hidrotic ectodermal dysplasia) to 13q11-q12.1 with evidence for multiple independent mutations.

Clouston syndrome (hidrotic ectodermal dysplasia) is an autosomal dominant disorder characterized by the triad of nail dystrophy, alopecia, and palmoplantar hyperkeratosis. Recently, linkage of a Clouston syndrome locus to chromosome 13q11-q12.1 was reported in eight families of French-Canadian descent. We have confirmed linkage to this region in four additional families: two of French-Canadian descent, one of Scottish-Irish descent, and one French family. Multipoint linkage analysis gave a lod score of 5.09 at marker D13S175. The two families of French-Canadian descent share haplotypes with those reported by Kibar et al (1996), indicating a common founder. The French and Scottish-Irish families do not demonstrate the common haplotype, indicating that the mutations in these populations are most likely of different origin.

A novel gene, DSCR5, from the distal Down syndrome critical region on chromosome 21q22.2.

Based on a detailed sequence of the distal Down syndrome critical region (DSCR), we predicted and molecularly cloned a novel gene, designated DSCR5. We determined the sequences of expressed sequence tags (ESTs) that almost matched the predicted cDNA sequence of DSCR5. Northern blot analysis showed that DSCR5 is expressed in several tissues including the liver, skeletal muscle, heart, pancreas and testis. To determine the 5'-end of DSCR5, the oligo-capping method was employed. Combining the EST sequence data and that from the oligo-capping experiments, we obtained the full-length cDNA sequence of DSCR5. DSCR5 had at least four types of alternatively spliced variants. According to the number of exons, they could be classified into two subtypes: DSCR5alpha and DSCR5beta. DSCR5alpha includes three splice variant subtypes, DSCR5alpha1, alpha2 and alpha3, which each has different first non-coding exon. In addition, the most abundantly isolated form, DSCR5alpha1, shows microheterogeneity of the mRNA start site. Comparison of the sequences between the predicted cDNA and the molecularly cloned cDNA revealed that the computer programs had limited validity to correctly predict the terminal exons. Thus, molecular cloning should always be required to complement the inadequacy of the computer predictions.

Architecture and anatomy of the genomic locus encoding the human leukemia-associated transcription factor RUNX1/AML1.

The RUNX1 gene on human chromosome 21q22.12 belongs to the 'runt domain' gene family of transcription factors (also known as AML/CBFA/PEBP2alpha). RUNX1 is a key regulator of hematopoiesis and a frequent target of leukemia associated chromosomal translocations. Here we present a detailed analysis of the RUNX1 locus based on its complete genomic sequence. RUNX1 spans 260 kb and its expression is regulated through two distinct promoter regions, that are 160 kb apart. A very large CpG island complex marks the proximal promoter (promoter-2), and an additional CpG island is located at the 3' end of the gene. Hitherto, 12 different alternatively spliced RUNX1 cDNAs have been identified. Genomic sequence analysis of intron/exon boundaries of these cDNAs has shown that all consist of properly spliced authentic coding regions. This indicates that the large repertoire of RUNX1 proteins, ranging in size between 20-52 kDa, are generated through usage of alternatively spliced exons some of which contain in frame stop codons. The gene's introns are largely depleted of repetitive sequences, especially of the LINE1 family. The RUNX1 locus marks the transition from a ~1 Mb of gene-poor region containing only pseudogenes, to a gene-rich region containing several functional genes. A search for RUNX1 sequences that may be involved in the high frequency of chromosomal translocations revealed that a 555 bp long segment originating in chromosome 11 FLI1 gene was transposed into RUNX1 intron 4.1. This intron harbors the t(8;21) and t(3;21) chromosomal breakpoints involved in acute myeloid leukemia. Interestingly, the FLI1 homologous sequence contains a breakpoint of the t(11;22) translocation associated with Ewing's tumors, and may have a similar function in RUNX1.

Segregation analysis of Parkinson disease.

Parkinson disease (PD) is a prevalent movement disorder of unknown cause whose incidence rises with increasing age. Nearly 20% of PD is familial, a small subset of which exhibits autosomal dominant transmission. However, in most families, the inheritance is not clear. To determine the most likely mode of inheritance of PD, we performed complex segregation analyses using kindreds of 136 PD patients randomly ascertained from a clinic population. The hypotheses of a nontransmissible environmental factor, no major gene or type (sporadic), and all Mendelian inheritance (dominant, recessive, additive, decreasing) were rejected (P <0.001). Familial clustering of PD in this data set is best explained by a rare familial factor which a) is transmitted in a nonMendelian fashion, and b) influences the age at onset of PD. If confirmed, our results have immediate implications in gene-mapping studies which often search for genes that behave in a Mendelian fashion that affect susceptibility rather than age at onset and long term implications in understanding the pathogenesis of PD.

Alloplastic implants. Their role in reconstruction of the mandible.

This article discusses the use of osseointegrated implants in mandibular reconstruction. Although the article presents the history, indications, and complications of this technique, the primary focus of the article is the technique itself, especially how the technique varies from patients not undergoing reconstruction to those who are. The effect of radiation therapy on the treatment planning of patients undergoing reconstruction also is discussed. Intraoral soft-tissue management also is addressed, as this area often differs significantly in patients undergoing radiation therapy from that in patients not undergoing radiation therapy and reconstruction.

Applications of distraction osteogenesis. Part I.

Distraction osteogenesis (DO) of facial bones is a recent development in the treatment of pediatric patients. The use of DO in current clinical practice of pediatric reconstructive surgery is primarily limited to severe deformities of the lower jaw, most of which are congenital in nature. Clinical experience with DO for early facial deformities remains limited, and no authoritative works are currently available to guide clinicians in the techniques or indications for DO of the facial skeleton.

Algorithms for the treatment of cleft lip and palate.

Developing standardized outcomes and algorithms of treatment is a constantly evolving task. This article examines four variables in this process: cleft type, operative technique, surgical experience, and timing. Input from international cleft lip and palate programs regarding techniques and treatment modalities provide a dynamic tool for assessment and the development of guidelines in the treatment of the cleft lip and palate patient.

Fixed implant rehabilitation for the edentulous maxilla.

The edentulous maxilla presents, perhaps, the greatest challenge to implant therapy. The anatomic, esthetic, and functional demands for fixed reconstruction of the maxillary arch are affected by many variables, some of which are controllable by the surgeon and dentist. This paper describes those variables and offers suggestions for managing the controllable aspects of treatment while avoiding the uncontrollable ones. Suggestions for planning the surgical and prosthodontic phases of treatment are described.

Osteogenesis of the mandible associated with implant reconstruction: a patient report.

A patient report is presented illustrating bone growth of the posterior mandible associated with a fixed implant reconstruction of the Brånemark type. In this instance, the mandible had grown vertically approximately 3 mm and was causing discomfort beneath the cantilever sections of the prosthesis because of gingival impingement between the restoration and the bony mandible. The literature relative to osteogenesis associated with osseointegrated implants is reviewed.

Use of bovine osteogenic protein to promote rapid osseointegration of endosseous dental implants.

An enriched bovine osteogenic protein preparation in combination with bone collagen matrix (osteogenic protein device) was used to effect new bone growth in extraction sites in the presence or absence of titanium dental implants. Incisor and canine teeth were extracted from each of three cynomolgus monkeys, and implants were inserted directly into the sockets without surgical site preparation. The osteogenic protein device induced new bone formation in close apposition to the titanium implants in all trials within 3 weeks. A lesser amount of new bone formation in both sets of control sites was limited to the bony socket walls and not closely apposed to the implant. These data show that the osteogenic protein device is capable of inducing new bone formation in tooth sockets within 3 weeks in the presence or absence of titanium implants. This is the first known demonstration of the therapeutic induction of bone formation in close apposition to metallic implants.

Retentiveness of dental cements used with metallic implant components.

There is limited dental literature evaluating the retentive capabilities of luting agents when used between metal components, such as cast metal restorations cemented onto machined metal implant abutments. This study compared the retentive strengths of 5 different classes of luting agents used to cement cast noble metal alloy crowns to 8-degree machined titanium cementable implant abutments from the Straumann ITI Implant System. Sixty prefabricated 5.5-mm solid titanium implant abutments and implants were used; 30 received the standard surface preparation and the other 30 received an anodized surface preparation. Anodized implant components were used to reflect current implant marketing. Sixty castings were fabricated and randomly paired with an abutment and implant. A total of 12 castings were cemented onto the implant-abutment assemblies for each of the 5 different luting agents (zinc phosphate, resin composite, glass ionomer, resin-reinforced glass ionomer, and zinc oxide-non-eugenol). After cementation, the assemblies were stored in a humidor at room temperature prior to thermocycling for 24 hours. Each casting was pulled from its respective abutment, and the force at which bond failure occurred was recorded as retentive strength. A statistically significant difference was found between the 5 cements at P < or = .001. Of the cements used, resin composite demonstrated the highest mean retentive strength. Zinc phosphate and resin-reinforced glass-ionomer cements were the next most retentive, while glass ionomer and zinc oxide-non-eugenol cements demonstrated minimal retention. In addition, retention was not altered by the use of an anodized abutment surface.

Problems associated with implant rehabilitation of the edentulous maxilla.

Implant rehabilitation of the edentulous maxilla is one of the most challenging endeavors that faces the restorative dentist. Comprehensive diagnosis and precise evaluation of the patient's needs followed by appropriate treatment planning provide the restorative dentist with the necessary tools to satisfy patient expectations and the realization that this patient would greatly benefit from this treatment or that the patient should be referred to a prosthodontist for further evaluation. Not enough emphasis can be placed on adequate placement of the implants by the surgeon. As with any rehabilitation, aesthetics are of prime importance to the patient, and proper occlusion confers longevity to the prosthesis. Whether a removable or fixed implant-supported prosthesis is fabricated, every step is crucial and is reflected in the final product. When all sequences of treatment are properly executed, the successful implant rehabilitation of the maxilla is one of the most gratifying procedures for both the restorative dentist and the patient.

Mandibular restoration in the cancer patient: microvascular surgery and implant prostheses.

This article deals with state of the art reconstruction and rehabilitation of the head and neck cancer patient who requires mandibular resection. The mandible can be reconstructed by microvascular free tissue transfer of bone and soft tissue from distant body sites. The dental units and missing soft tissue contours can be supported by osseointegrated implants placed in the grafted bone. This article discusses the rationale for patient selection and sequencing of this complex and rewarding rehabilitation.