Biomedical subjects

J Schweizer

Publications and source records attributed to J Schweizer.

At least 19 recordsLinked to original sources

PubMed2004

Expression of hair keratins in the adult nail unit: an immunohistochemical analysis of the onychogenesis in the proximal nail fold, matrix and nail bed.

BACKGROUND: Recently, the expression profiles of the members of the complex hair keratin family have been determined in the human anagen hair follicle. In contrast, the details of hair keratin expression in the human nail unit are poorly known. OBJECTIVES: In order to fill this gap, we have performed an immunohistochemical study of the adult human nail unit by means of specific antibodies against nine hair keratins of both types (hHa2, hHb2, hHa5, hHb5, hHa1, hHb1, hHb6, hHa4 and hHa8) as well as three epithelial keratins (K5, K17 and K10). METHODS: Formalin-fixed paraffin sections of adult nails were examined using monoclonal and polyclonal keratin antibodies, respectively. Longitudinal as well as transverse sections were investigated. RESULTS: Our study revealed two types of epithelial tissue compartments in the nail unit. The first comprised the eponychium and hyponychium and the nail bed, which expressed only epithelial keratins. While keratins K5, K17 (basal) and K10 (suprabasal) were found in the orthokeratinizing eponychium and hyponychium, throughout, the nail bed epithelium expressed only K5 and K17. The second type comprised the apical and ventral matrix which exhibited a mixed pattern of epithelial and hair keratin expression. Thus, K5 and K17 were expressed in the entire multilayered basal cell compartment of the apical and ventral matrix; however, in the latter, K5 and K17 also occurred in the lowermost layers of the overlying keratogenous zone. The hair matrix keratin hHb5, but not its type II partner hHa5, was seen in the entire keratogenous zone of the apical and ventral matrix, but was also located in the uppermost cell layers of the basal compartment of the ventral matrix, where it overlapped with K5 and K17. Similar to their sequential expression in the hair follicle cortex, hair keratins hHa1, hHb1, hHb6 and hHa4 were consecutively expressed in the keratogenous zone of both the ventral and, albeit less distinctly, apical matrix, with hHa1 initiating in the lowermost cell layers. The expression of hHa8 in only single cortex cells of the hair follicle was also preserved in cells of the keratogenous zone. In the region of the so-called dorsal matrix, we observed two histologically and histochemically distinct types of epithelia: (i) a dominant type, histologically similar to the eponychium and an associated K5, K17 and K10 keratin pattern which clearly extended into the apical matrix, and (ii) a minor type, histologically resembling the postulated dorsal matrix without a granular layer and a cuticle, and exhibiting extended K5 expression as well as hair keratin expression in superficial cells. CONCLUSIONS: The coexpression of hHb5 with K5 and K17 in the uppermost cell layers of the basal compartment and the lowermost layers of the keratogenous zone of the ventral matrix prompts us to designate this region the prekeratogenous zone of the ventral matrix. The two alternating types of histology and keratin expression in the dorsal matrix identify this region as a transitional zone between the eponychium and the apical matrix. Finally, our data clearly show that the ventral matrix is the main source of the nail plate. In addition, the mixed scenario of hair and epithelial keratins, including demonstrable amounts of K10, in superficial cells of the apical matrix, lends support to the notion that the dorsal portion of the nail is generated by the apical matrix.

Adult↗

PubMed2003

Hair keratin pattern in human hair follicles grown in vitro.

The keratin family includes epithelial (soft) keratins and hair (hard) keratins, and can be divided into acidic type I and basic to neutral type II subfamilies. Recently, nine type I and six type II hair keratin genes have been characterized through the screening of a human PAC library. The expression of these genes in the hair follicle was determined in vivo and a combined catalog of acidic and basic hair keratins was established. In this study, we investigated the expression and localization of most of the human hair keratin members of both types in human hair grown in vitro. We show that in vitro growth of hair follicles for 10 days in complete William's E culture medium did not alter the expression pattern of hair keratins. Similarly to the in vivo situation, each hair keratin was localized in precise and discrete compartments of the follicle, ranging from the matrix to the upper cortex and/or the hair cuticle. This study shows that the increase in length of in vitro grown follicles was accompanied by the proper hair shaft keratinization process. It also shows that hair follicle integrity was maintained in vitro, both in terms of gross morphology and molecular organization despite the complexity of the keratin expression pattern.

Culture Techniques↗

PubMed2002

Fracture toughness of snow in shear under friction.

The fracture toughness of snow in shear is one of the most relevant parameters when studying the mechanics of snow slab avalanche release. Double-cantilever snow beams were loaded asymmetrically to determine K(IIc). If crack surfaces touch under applied pressure, the fracture toughness in shear of snow (rho=247 kg m(-3)) is K(IIc)=680+/-60 Pa m(1/2). Screening of the stress intensity at the crack tip occurs by Newtonian friction with k=1.3+/-0.47 along the crack faces.

Journal Article↗

PubMed2001

The catalog of human hair keratins. II. Expression of the six type II members in the hair follicle and the combined catalog of human type I and II keratins.

The human type II hair keratin subfamily consists of six individual members and can be divided into two groups. The group A members hHb1, hHb3, and hHb6 are structurally related, whereas group C members hHb2, hHb4, and hHb5 are rather distinct. Specific antisera against the individual hair keratins were used to establish the two-dimensional catalog of human type II hair keratins. In this catalog, hHb5 showed up as a series of isoelectric variants, well separated from a lower, more acidic, and complex protein streak containing isoelectric variants of hair keratins hHb1, hHb2, hHb3, and hHb6. Both in situ hybridization and immunohistochemistry on anagen hair follicles showed that hHb5 and hHb2 defined early stages of hair differentiation in the matrix (hHb5) and cuticle (hHb5 and hHb2), respectively. Although cuticular differentiation proceeded without the expression of further type II hair keratins, cortex cells simultaneously expressed hHb1, hHb3, and hHb6 at an advanced stage of differentiation. In contrast, hHb4, which is undetectable in hair follicle extracts and sections, could be identified as the largest and most alkaline member of this subfamily in cytoskeletal extracts of dorsal tongue. This hair keratin was localized in the posterior compartment of the tongue filiform papillae. Comparative analysis of type II with the previously published type I hair keratin expression profiles suggested specific, but more likely, random keratin-pairing principles during trichocyte differentiation. Finally, by combining the previously published type I hair keratin catalog with the type II hair keratin catalog and integrating both into the existing catalog of human epithelial keratins, we present a two-dimensional compilation of the presently known human keratins.

Amino Acid Sequence↗

PubMed2001

Characterization of a cluster of human high/ultrahigh sulfur keratin-associated protein genes embedded in the type I keratin gene domain on chromosome 17q12-21.

Low stringency screening of a human P1 artificial chromosome library using a human hair keratin-associated protein (hKAP1.1A) gene probe resulted in the isolation of six P1 artificial chromosome clones. End sequencing and EMBO/GenBank(TM) data base analysis showed these clones to be contained in four previously sequenced human bacterial artificial chromosome clones present on chromosome 17q12-21 and arrayed into two large contigs of 290 and 225 kilobase pairs (kb) in size. A fifth, partially sequenced human bacterial artificial chromosome clone data base sequence overlapped and closed both of these contigs. One end of this 600-kb cluster harbored six gene loci for previously described human type I hair keratin genes. The other end of this cluster contained the human type I cytokeratin K20 and K12 gene loci. The center of the cluster, starting 35 kb downstream of the hHa3-I hair keratin gene, contained 37 genes for high/ultrahigh sulfur hair keratin-associated proteins (KAPs), which could be divided into a total of 7 KAP multigene families based on amino acid homology comparisons with previously identified sheep, mouse, and rabbit KAPs. To date, 26 human KAP cDNA clones have been isolated through screening of an arrayed human scalp cDNA library by means of specific 3'-noncoding region polymerase chain reaction probes derived from the identified KAP gene sequences. This screening also yielded four additional cDNA sequences whose genes were not present on this gene cluster but belonged to specific KAP gene families present on this contig. Hair follicle in situ hybridization data for single members of five different KAP multigene families all showed localization of the respective mRNAs to the upper cortex of the hair shaft.

Amino Acid Sequence↗

PubMed2001

Human type I hair keratin pseudogene phihHaA has functional orthologs in the chimpanzee and gorilla: evidence for recent inactivation of the human gene after the Pan-Homo divergence.

In addition to nine functional genes, the human type I hair keratin gene cluster contains a pseudogene, phihHaA (KRTHAP1), which is thought to have been inactivated by a single base-pair substitution that introduced a premature TGA termination codon into exon 4. Large-scale genotyping of human, chimpanzee, and gorilla DNAs revealed the homozygous presence of the phihHaA nonsense mutation in humans of different ethnic backgrounds, but its absence in the functional orthologous chimpanzee (cHaA) and gorilla (gHaA) genes. Expression analyses of the encoded cHaA and gHaA hair keratins served to highlight dramatic differences between the hair keratin phenotypes of contemporary humans and the great apes. The relative numbers of synonymous and non-synonymous substitutions in the phihHaA and cHaA genes, as inferred by using the gHaA gene as an outgroup, suggest that the human hHaA gene was inactivated only recently, viz., less than 240,000 years ago. This implies that the hair keratin phenotype of hominids prior to this date, and after the Pan-Homo divergence some 5.5 million years ago, could have been identical to that of the great apes. In addition, the homozygous presence of the phihHaA exon 4 nonsense mutation in some of the earliest branching lineages among extant human populations lends strong support to the "single African origin" hypothesis of modern humans.

Amino Acid Sequence↗

PubMed2001

Expression of type I hair keratins in follicular tumours.

BACKGROUND: Hair keratins are specifically expressed in hair and nails. We previously demonstrated the expression of hair keratin basic 1 mRNA in pilomatrixomas. We recently developed a method for immunohistochemical staining of the group of acidic keratins, which have not yet been investigated in human tumours. OBJECTIVES: To study the expression of eight members of the type I hair keratin subfamily in pilomatrixomas and other skin tumours of follicular origin. METHODS: We performed immunohistochemistry on paraffin sections of formalin-fixed pilomatrixomas (40), trichoepitheliomas (10), trichoblastomas (10), desmoplastic trichoepitheliomas (10) and basal cell carcinomas (10), using antibodies against type I hair keratins hHa1, hHa2, hHa3-II, hHa4, hHa5, hHa6, hHa7 and hHa8 as well as cytokeratin CK17. RESULTS: While CK17 was found in almost all tumours investigated, hair keratins were exclusively expressed in pilomatrixomas. Their expression was restricted to areas of transitional cells, located between outer basophilic matricial cells and an inner zone of eosinophilic shadow cells. The most frequently and most strongly expressed hair keratins were hHa1, hHa2, hHa5 and hHa8, whereas hHa4 and hHa6 were only weakly expressed. No positive staining was observed with anti-hHa3-II and anti-hHa7 antibodies. Hair keratin expression in intermediate maturation stage pilomatrixomas resembled that of normal hair follicles, with early matricial and cuticular keratins hHa5 and hHa2 being expressed in lower transitional cells, followed by expression of early cortex keratins hHa1 and hHa8 in intermediate transitional cells and the late cortex keratins hHa4 and hHa6 in upper transitional cells. The latter were, however, seen only in a few intermediate maturation stage pilomatrixomas and were generally absent in late-stage pilomatrixomas. CONCLUSIONS: These changes in hair keratin expression patterns indicate that the maturation of pilomatrixomas towards large areas of shadow cells is associated with a gradual loss of differentiation-specific hair keratins. The complex hair keratin expression in pilomatrixomas is a further argument in favour of a hair matrix origin of this tumour.

Basal Cell Carcinoma↗

PubMed2001

Comparison of angiotensin II receptor antagonists.

Nonpeptide orally active angiotensin II type 1 (AT1) receptor antagonists are the most specific means presently available to block the renin-angiotensin enzymatic cascade. Six of these drugs have already been licensed in Europe and in the United States for the treatment of high blood pressure, and additional candidates are in the pipeline. The World Health Organisation has also recently endorsed their use for this condition. Inasmuch as AT1 receptor antagonists have proven themselves the equals of angiotensin converting enzyme inhibitors with respect to antihypertensive efficacy, but demonstrated better safety profiles, this class of drugs may be considered to be a qualitative improvement in the treatment of essential hypertension. Interestingly, the six agents now on the market diverge considerably with respect to their pharmacokinetic and pharmacodynamic properties, although it is not certain whether such differences are clinically relevant. A considerable number of large, multicentre trials are in progress to ascertain the possible longer-term organoprotective effects of these substances on cardiovascular morbidity and mortality. Because of their noteworthy safety record to date, and simple once-a-day dosage regimen, AT1 receptor antagonists have the potential to improve compliance in patients with chronic hypertension.

Angiotensin Receptor Antagonists↗

PubMed2001

A novel type II cytokeratin, mK6irs, is expressed in the Huxley and Henle layers of the mouse inner root sheath.

Hair follicle differentiation involves the expression of both epithelial-type keratins or cytokeratins and hair keratins as well as hair keratin-associated proteins. In this study, a cDNA clone encoding a cytokeratin family member was isolated using RNA differential display techniques. The predicted amino acid sequence derived from this clone, revealed a homology with a number of cytokeratins, not only in the central alpha-helical regions but also in the conserved portions of the amino and carboxy terminal domains, indicating that this protein represents a new member of the mouse type II cytokeratin family. Northern blot analysis showed expression in mouse skin, but not in other tissues, including tongue, esophagus, and forestomach. One- and two-dimensional western blot analysis showed that this new cytokeratin was 57 kDa in size and ran slightly below the area of cytokeratin 5, which corresponded to that of the cytokeratin 6 family members. Both RNA in situ hybridization and immunohistochemical studies of mouse anagen hair follicles demonstrated expression of this cytokeratin in the inner root sheath hair cone during anagen III and in the Henle and Huxley layers of the inner root sheath during anagen VI. The expression of the new cytokeratin began in the hair bulb and progressed up to the height of the keratogenous zone. Taken together the sum of the data analyzed, we have termed this novel cytokeratin mK6irs (mouse gene nomenclature k2-6g) to indicate both its similar mobility with K6 in two-dimensional gels and its specific expression in the inner root sheath of the hair follicle.

Amino Acid Sequence↗

PubMed2001

Potential use of a low-molecular-weight heparin to prevent restenosis in patients with extensive wall damage following peripheral angioplasty.

The long-term outcome of primary successful percutaneous transluminal angioplasty (PTA) for patients with peripheral occlusive arterial disease (POAD) is frequently compromised by the development of restenosis, especially when extensive dissections result from the angioplastic procedure. Unfortunately, prevention of the occlusive process by means of drugs such as antithrombotics, anticoagulants, thrombolytics, corticosteroids, lipid reducers, or cytostatics has not been demonstrated convincingly. The authors sought to clarify whether such patients could benefit from the postsurgical administration of low-molecular-weight heparin. A total of 172 POAD patients with extensive dissections after PTA in the pelvic or upper leg regions were randomized for 7-day post-PTA intravenous treatment with either full heparinization or nadroparin calcium followed by adjunctive oral aspirin for 6 months. The primary outcome measure was the degree of stenosis (normal findings; stenosis < 50%, > 50%, > 80%, occlusion) before and after angioplasty, as well as 3 weeks and 3 and 6 months after dilation; secondary efficacy criteria included changes in the Fontaine stage and in the crurobrachial ratio. No significant treatment-related differences were found at the 3 post-PTA follow-up examinations with regard to the degree of stenosis. This was also the case for the subgroup of patients (n = 62) who had undergone angioplasty in the pelvic region. By contrast, when angioplasty was performed in the superficial femoral artery (n = 110), the degree of restenosis was significantly lower (p<0.01) among patients receiving nadroparin calcium compared to those given heparin at week 3, month 3, and month 6. No intergroup differences emerged for secondary outcome measures in the long term or for safety parameters. These preliminary results indicate that patients with extensive dissections after PTA treatment for POAD in the upper leg region might benefit from a reduction in the rate of restenosis by administration of 7-day weight-adjusted nadroparin calcium.

Adolescent↗

PubMed2000

Small evolutionarily conserved RNA, resembling C/D box small nucleolar RNA, is transcribed from PWCR1, a novel imprinted gene in the Prader-Willi deletion region, which Is highly expressed in brain.

Prader-Willi syndrome is a complex neurodevelopmental disorder caused by the inactivation or deletion of imprinted, paternally expressed genes in chromosome band 15q11.2. We report the identification and characterization of PWCR1, a novel imprinted gene within that region, and its mouse orthologue, Pwcr1, which was mapped to the conserved syntenic region on mouse chromosome 7. Expressed only from the paternal allele, both genes require the imprinting-center regulatory element for expression and are transcribed from the same strand. They are intronless and do not appear to encode a protein product. High human/mouse sequence similarity (87% identity) is limited to a 99-bp region called "HMCR" (for "human-mouse conserved region"). The HMCR sequence has features of a C/D box small nucleolar RNA (snoRNA) and is represented in an abundant small transcript in both species. Located in nucleoli, snoRNAs serve as methylation guidance RNAs in the modification of ribosomal RNA and other small nuclear RNAs. In addition to the nonpolyadenylated small RNAs, larger polyadenylated PWCR1 transcripts are found in most human tissues, whereas expression of any Pwcr1 RNAs is limited to mouse brain. Genomic sequence analysis reveals the presence of multiple copies of PWCR1 and Pwcr1 that are organized within local tandem-repeat clusters. On a multispecies Southern blot, hybridization to an HMCR probe encoding the putative snoRNA is limited to mammals.

Alleles↗

PubMed2000

A new family of genes and pseudogenes potentially expressing testis- and brain-specific leucine zipper proteins in man and mouse.

We have characterized a new mouse gene highly transcribed in the testis, and a derived intronless gene expressed in the embryo. The latter gene is present in Mus musculus domesticus and in Mus musculus castaneus but is absent in Mus spretus. The sequencing of different clones from a testis cDNA library reveals a complex transcriptional regulation for the intron-containing gene. The use of several promoters, alternative splicing and trans-splicing, and of two different polyadenylation sites account for the diversity. The different cDNAs encode proteins with features of basic helix-loop-helix leucine zipper (bHLH-ZIP) DNA-binding factors with homology to a new brain-specific factor. The presence of multiple CK2 and PKC phosphorylation sites suggests that their activity may be regulated by phosphorylation. In man, a pseudogene, apparently derived from the same transcript as in mouse and showing 90% homology in the coding region, is present within an intron of another gene. Interestingly, although the human pseudogene is highly mutated in human, in the mouse it has only four nucleotide changes compared with the cDNA of origin, and is still capable of encoding a protein.

Alternative Splicing↗

PubMed2000

Short- and long-term results after thrombolytic treatment of deep venous thrombosis.

OBJECTIVES: The goal of this study was to assess the short- and long-term efficacy of different thrombolytic therapy regimens in patients with leg or pelvic deep venous thrombosis (DVT). BACKGROUND: It is unclear whether locoregional or systemic thrombolysis is superior in treating acute leg DVT or even whether lysis is more effective than anticoagulation therapy in preventing postthrombotic syndrome. METHODS: A total of 250 patients averaging 40 years of age with acute DVT were randomized into five groups to receive full heparinization (1,000 IU/h) and compression treatment, with four groups also administered locoregional tissue plasminogen activator (20 mg/day) or urokinase (100,000 IU/day) or systemic streptokinase (3,000,000 IU daily) or urokinase (5,000,000 IU daily). All groups then received anticoagulation and compression treatment for one year. Primary efficacy criteria included the change after one year in the number of closed vein segments and the occurrence of postthrombotic syndrome. RESULTS: Systemic thrombolytic therapy significantly reduced the number of closed vein segments after 12 months in patients with acute DVT compared with conventional treatment (p < 0.05). Postthrombotic syndrome also occurred with less frequency in systemically treated patients versus controls (p < 0.001). High-dose thrombolysis led to better rates of complete recanalization after seven days (p < 0.01) than locoregional lysis. However, 12 patients receiving thrombolysis (9 systemic, 3 local) suffered major bleeding complications; 9 patients on systemic treatment developed pulmonary emboli. CONCLUSIONS: Systemic thrombolytic treatment for acute DVT achieved a significantly better short- and long-term clinical outcome than conventional heparin/anticoagulation therapy but at the expense of a serious increase in major bleeding and pulmonary emboli. Given the inherent risks for such serious complications, systemic thrombolysis, although effective, should be used selectively in limb-threatening thrombotic situations.

Adult↗

PubMed2000

Characterization of a 300 kbp region of human DNA containing the type II hair keratin gene domain.

Screening of an arrayed human genomic P1 artificial chromosome DNA library by means of the polymerase chain reaction with a specific primer pair from the human type II hair keratin hHb5 yielded two P1 artificial chromosome clones covering approximately 300 kb of genomic DNA. The contig contained six type II hair keratin genes, hHb1-hHb6, and four keratin pseudogenes psihHbA-psihHbD. This hair keratin gene domain was flanked by type II epithelial keratins K6b/K6hf and K7, respectively. The keratin genes/pseudogene are 5-14 kbp in size with intergenic distances of 5-19 kbp of DNA and do not exhibit a single direction of transcription. With one exception, type II hair keratin genes are organized into nine exons and eight introns, with strictly conserved exon-intron boundaries. The functional hair keratin genes are grouped into two distinct subclusters near the extremities of the hair keratin gene domain. One subcluster encodes the highly related hair keratins hHb1, hHb3, and hHb6; The second cluster encodes the structurally less related hair keratins hHb2, hHb4, and hHb5. Reverse transcription-polymerase chain reaction shows that all hair keratin genes are expressed in the hair follicle. Pseudogene psihHbD is also transcriptionally expressed, albeit with alterations in splicing and frameshift mutations, leading to premature stop codons in the splice forms analyzed. Evolutionary tree analysis revealed a divergence of the type II hair keratin genes from the epithelial keratins, followed by their segregation into the members of the two subclusters over time. We assume that the approximately 200 kbp DNA domain contains the entire complement of human type II hair keratin genes.

Amino Acid Sequence↗

PubMed2000

Short- and long-term results of abciximab versus aspirin in conjunction with thrombolysis for patients with peripheral occlusive arterial disease and arterial thrombosis.

Acute peripheral occlusive arterial disease is an important cause of morbidity and mortality, particularly among older persons. Catheter-directed thrombolytic therapy is the treatment of choice but has limitations: long lytic times, occlusions refractory to thrombolysis, and a high rate of restenosis. We conducted a pilot study to evaluate the use of the platelet GP IIb/IIIa receptor antagonist abciximab versus aspirin in conjunction with thrombolysis in patients with acute peripheral occlusive arterial disease associated with arterial thrombosis. A total of 84 patients were randomized into two equal groups to receive 5 mg recombinant tissue plasminogen activator intravenously and 500 IU heparin/hour along with either 500 mg acetylsalicylic acid or a bolus of 0.25 mg/kg abciximab followed by 10 microg/min abciximab over 12 hours (heparin reduced to 250 IU/hour). Primary efficacy criteria included the number of rehospitalizations, reinterventions, and amputations during the following 6 months. Secondary endpoints were the changes in the Fontaine stage, Bollinger index (vessel occlusion), ankle-to-brachial ratios, distance to claudication after 6 months, and the duration of the initial local lysis treatment. Adjunctive use of abciximab reduced the rates of rehospitalization, reinterventions, and amputations versus results with the use of aspirin (10 vs 14 occurrences, respectively; 9 vs 11; 3 vs 5; when summed, intergroup difference p < 0.05). Secondary peripheral occlusive arterial disease variables became highly significant versus aspirin (p < 0.001 or greater) at 3 and 6 months after treatment. The duration of lysis was markedly shorter upon addition of abciximab versus aspirin (75 vs 110 min; p < 0.001). No major bleeding complications or embolisms occurred. These preliminary results indicate that abciximab may have a useful role when used adjunctively with a thrombolytic agent in older persons with acute peripheral occlusive arterial disease and arterial thrombosis.

Abciximab↗

PubMed1999

The catalog of human hair keratins. I. Expression of the nine type I members in the hair follicle.

The human type I hair keratin subfamily comprises nine individual members, which can be subdivided into three groups. Group A (hHa1, hHa3-I, hHa3-II, hHa4) and B (hHa7, hHa8) each contains structurally related hair keratins, whereas group C members hHa2, hHa5, and hHa6 represent structurally rather unrelated hair keratins. Antibodies produced against these individual hair keratins, first analyzed for specificity by one- dimensional Western blots of total hair keratins, were used to establish the two-dimensional catalog of the human type I hair keratin subfamily. The catalog comprises two different series of type I hair keratins: a strongly expressed, Coomassie-stainable series containing hair keratins hHa1, hHa3-I/II, hHa4, and hHa5, and a weakly expressed, immunodetectable series harboring hHa2, hHa6 hHa7, and hHa8. In situ hybridization and immunohistochemical expression studies on scalp follicles show that two hair keratins, hHa2 and hHa5, define the early stage of hair differentiation, i.e. hHa5 expression in hair matrix and hHa5/hHa2 coexpression in the early hair cuticle cells. Whereas cuticular differentiation proceeds without the expression of further type I hair keratins, matrix cells embark on the cortical pathway by sequentially expressing hHa1, hHa3-I/II, and hHa4, which are supplemented by hHa6 at an advanced stage of cortical differentiation, and hHa8, which is expressed heterogeneously in cortex cells. Thus, six type I hair keratins are involved in the terminal differentiation of anagen hairs. The expression of hHa7 is conspicuously different from that of the other hair keratins in that it does not occur in the large anagen follicles of terminal scalp hairs but only in central cortex cells of the rare and small follicle type that gives rise to vellus hairs.

Blotting, Western↗

PubMed1999

Monilethrix: a novel mutation (Glu402Lys) in the helix termination motif and the first causative mutation (Asn114Asp) in the helix initiation motif of the type II hair keratin hHb6.

Monilethrix, a rare human hair disorder with autosomal dominant transmission, can be caused by mutations in hair keratins. Up to now, causative mutations have only been found in two type II cortex keratins, hHb6 and hHb1. In these hair keratins, the helix termination motif, HTM, was the only site in which mutations were located. The most frequent mutation, which has been found in 22 cases, was a Glu413Lys substitution in hHb6, whereas other mutations, i.e., hHb6 Glu413Asp, hHb1 Glu413Lys, and hHb1 Glu402Lys, have been reported in a distinctly lower number of cases. In this study, we describe the equivalent of the hHb1 Glu402Lys mutation in the HTM of cortex keratin hHb6. The mutation occurred in an American family in which it could only be detected in one clinically affected individual. Thus the underlying G-->A transition represents a spontaneous germ-line mutation in the hHb6 gene. This new mutation indicates that both the hHb6/hHb1 Glu413Lys substitution and the hHb6/hHb1 Glu402Lys substitution, represent mutational hotspots in the HTM of type II cortex keratins. However, we also describe a monilethrix-causing mutation in the helix initiation motif, HIM, of the cortex keratin hHb6. The critical Asn114Asp substitution was only found in affected members of a large Swedish three-generation family. Considering that since childhood, half of the affected individuals suffer from complete baldness and follicular keratosis, the new HIM mutation seems to be associated with a rather severe disease phenotype. In conclusion, our data strongly suggest that monilethrix is a disease of the hair cortex, whose etiology is interesting in that causative mutations seem to be restricted to type II hair keratins.

Amino Acid Sequence↗

PubMed1999

Comparison of two dosages of ginkgo biloba extract EGb 761 in patients with peripheral arterial occlusive disease Fontaine's stage IIb. A randomised, double-blind, multicentric clinical trial.

BACKGROUND: Rheologically-active drugs are widely used in the therapy of peripheral arterial occlusive disease (pAOD) Fontaine's stage II. Several clinical trials have demonstrated the efficacy of Ginkgo biloba extract in the treatment of pAOD Fontaine's stage II. A pilot study indicated the superiority of 240 mg Ginkgo biloba extract daily compared with the standard dosage of 120 mg to 160 mg daily. This trial was conducted to confirm the superiority of the higher dosage of Ginkgo biloba extract in patients with pAOD Fontaine's stage IIb statistically. PATIENTS AND METHODS: 74 patients were analysed. Thirty-eight patients received the standard dosage (EGb 761 120 mg/d), and 36 patients received 240 mg EGb 761 daily. The primary efficacy criterion was the difference of the pain-free walking distance between the start of treatment and after 24 weeks measured on a treadmill under standardized conditions. RESULTS: The pain-free walking distance improved in both groups. There was a mean increase of 60.6 m in the group of patients who received 120 mg Ginkgo biloba extract daily and a statistically significant higher (p = 0.0253) mean increase of 107.0 m in the group of patients who were treated with the higher dosage. CONCLUSION: Both dosage regimens investigated in this trial led to a clinically relevant improvement of the pain-free walking distance after 24 weeks of treatment. The superiority of the higher dosage over the standard dosage was statistically significant. Both treatment variations were safe and well tolerated.

Aged↗