A randomized controlled trial of acupuncture and receptive music therapy for sleep disorders in the elderly-ELAMUS: study protocol.

BACKGROUND: Globally, the demographic shift towards an aging population leads to significant challenges in healthcare systems, specifically due to an increasing incidence of multimorbidity resulting in polypharmacy among the elderly. Simultaneously, sleep disorders are a common complaint for elderly people. A treatment with pharmacological therapies often leads to side effects causing a high potential for dependency. Within this context, there is a high need to explore non-pharmacological therapeutic approaches. The purpose of this study is to evaluate the effectiveness of acupuncture and music therapy, both individually and combined as a multimodal therapy, in the treatment of sleep disorders in individuals aged 70 years and older. METHODS: We conduct a confirmatory randomized controlled trial using a two-factorial study design. A total of n = 100 elderly people receive evidence-based standard care information for age-related sleep disorders. Beyond that, patients are randomly assigned into four groups of n = 25 each to receive acupuncture, receptive music therapy with a monochord, multimodal therapy with both acupuncture and music therapy, or no further therapy. The study's primary outcome measurement is the improvement in sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) (global score), at the end of intervention. Additionally, depression scores (Geriatric Depression Scale), health-related quality of life (Short-Form-Health Survey-12), neurovegetative activity measured via heart rate variability, and safety data are collected as secondary outcomes. Using a mixed-methods approach, a qualitative process evaluation will be conducted to complement the quantitative data. DISCUSSION: The study is ongoing and the last patient in is expected to be enrolled in April 2024. The results can provide valuable insights into the effectiveness of non-pharmacological interventions for sleep disorders among the elderly, contributing to a more personalized and holistic approach in geriatric healthcare. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00031886).

Differential chemokine expression patterns in tonsillar disease.

Expression profiles of CXC- and CC-chemokines in various forms of tonsillar disease were studied to evaluate whether certain chemokines play a predominant role in a specific subset of tonsillar disease. Total RNA was isolated from 89 biopsies (21 hyperplastic palatine tonsils, 25 adenoids, 16 chronic inflammatory palatine tonsils and 27 chronic inflammatory palatine tonsils with histological prove of acute inflammation), reverse transcribed and subjected to PCR amplifying IL-8, Gro-alpha, eotaxin-1, eotaxin-2, MCP-3, MCP-4 and RANTES. 2% agarose gel electrophoresis revealed a predominance of IL-8 in the chronic inflammatory palatine tonsil group compared to tonsillar hyperplasia. Furthermore, eotaxin-2 was strongly overexpressed in adenoid samples compared to chronic inflammatory specimens. Our data suggest that the majority of diseases related to adenoid formation are mediated via an eotaxin-2 expression, whereas chronic inflammatory tonsillitis is associated with IL-8 upregulation. These data imply that adenoids are related to a Th-2, and chronic inflammatory tonsillitis to a Th-1 based immune response.

An isopeptide bond splitting enzyme from Hirudo medicinalis similar to gamma-glutamyl transpeptidase.

A new enzyme from Hirudo medicinalis capable of splitting gamma-glutamyl-p-nitroanilide and Glu--Lys-(N6-gamma-glutamyllysine) (isopeptidic bond between the epsilon-amino group of lysine and the gammacarboxylic group of glutamic acid) isopeptide bonds was purified. The protein was partially sequenced at the amino acid level, and the complete nucleotide and amino acid sequences were determined after cDNA cloning. The new enzyme has more than 60% similarity at the amino acid level to vertebrate gammaglutamyl transpeptidase (gamma-GT). According to the cDNA, the new protein has a molecular mass of 65 521 Da and a length of 600 amino acids.

A phase I/II study of idarubicin, dexamethasone and interferon-alpha (I-Dexa) in patients with relapsed or refractory multiple myeloma.

To improve the outcome for patients with relapsed or refractory multiple myeloma (MM), we combined idarubicin (Ida), dexamethasone and interferon (IFN) in a new regimen, 'I-Dexa'. Here we report our results of a phase I/II study using the I-Dexa protocol in an outpatient setting. A total of 31 patients were enrolled. Most patients were heavily pretreated with a median of two different chemotherapy regimen (range, 1-4). All but four patients had advanced disease (stage III). The dose of Ida was escalated to define the maximal tolerated dose (MTD) in this regimen. Four patients were treated with 5 mg/m2 and 27 patients with 7.5 mg/m2 Ida (day 1, i.v.). Dexamethasone was given at a fixed dose of 20 mg per os daily on days 2-5 and 11-14. Treatment was repeated at day 21 and consisted of up to six cycles. Patients who achieved a response or stable disease received IFN maintenance. IFN was administered three times weekly at a dose of 3 x 10(6) U/day s.c. until relapse. At the time of evaluation, 125 courses of I-Dexa were analyzed. The MTD of Ida in this regimen was 7.5 mg/m2. Hematological toxicity was mild including 5% leukocytopenia, 3% thrombocytopenia and 1% anemia (WHO grade III) at dose level 2. The MTD was defined by nonhematological toxicities including two WHO grade IV infections and one renal failure. The overall response rate including stable disease was 62.5% (PR: nine patients, 37.5%). So far, nine patients have been treated with IFN maintenance therapy with a median duration of 7 months (range, 1-16). In conclusion, I-Dexa can be given safely in an outpatient setting and is effective for the treatment of relapsed and refractory MM.

Two heads are better than one: crystal structure of the insect derived double domain Kazal inhibitor rhodniin in complex with thrombin.

Rhodniin is a highly specific inhibitor of thrombin isolated from the assassin bug Rhodnius prolixus. The 2.6 Angstrum crystal structure of the non-covalent complex between recombinant rhodniin and bovine alpha-thrombin reveals that the two Kazal-type domains of rhodniin bind to different sites of thrombin. The amino-terminal domain binds in a substrate-like manner to the narrow active-site cleft of thrombin; the imidazole group of the P1 His residue extends into the S1 pocket to form favourable hydrogen/ionic bonds with Asp189 at its bottom, and additionally with Glu192 at its entrance. The carboxy-terminal domain, whose distorted reactive-site loop cannot adopt the canonical conformation, docks to the fibrinogen recognition exosite via extensive electrostatic interactions. The rather acidic polypeptide linking the two domains is displaced from the thrombin surface, with none of its residues involved in direct salt bridges with thrombin. The tight (Ki = 2 x 10(-13) M) binding of rhodniin to thrombin is the result of the sum of steric and charge complementarity of the amino-terminal domain towards the active-site cleft, and of the electrostatic interactions between the carboxy-terminal domain and the exosite.

A Kazal-type inhibitor with thrombin specificity from Rhodnius prolixus.

A thrombin-specific inhibitor with an apparent molecular mass of 11 kDa has been purified from the insect Rhodnius prolixus. Amino-terminal protein sequence analysis allowed the molecular cloning of the corresponding cDNA. The open reading frame codes for a protein of about 103 amino acid residues and displays an internal sequence homology of residues 6-48 with residues 57-101 indicating a two-domain structure. Based on the amino acid sequence the two domains exhibit high homology to protease inhibitors belonging to the Kazal-type family. Model building suggests that the first domain binds to the active site with residue His10 pointing into the specificity pocket. From gel filtration and tight-binding inhibition experiments the inhibitor appears to form 1:1 complexes with thrombin. Periplasma-directed heterologous expression of the rhodniin cDNA in Escherichia coli yields the intact thrombin inhibitor. Natural and recombinant rhodniin both display inhibition constants of about 2 x 10(-13) M.

Isolation, sequence analysis, and cloning of haemadin. An anticoagulant peptide from the Indian leech.

A slow, tight-binding inhibitor of thrombin with an apparent molecular mass of about 5 kDa has been isolated from Haemadipsa sylvestris, an Indian leech of the family of Haemadipsidae. The inhibitory activity, called haemadin, is thrombin specific since it does not inhibit other proteases like trypsin, chymotrypsin, factor Xa, or plasmin. NH2-terminal amino acid sequence analysis (residues 1-45) does not reveal any homology to known serine protease inhibitors, including the thrombin-specific inhibitor hirudin. The haemadin cDNA cloned by polymerase chain reaction techniques codes for a polypeptide of 57 amino acid residues preceded by 20 residues of a signal peptide sequence. A synthetic gene coding for the mature haemadin was expressed in Escherichia coli. Recombinant haemadin displays a similar inhibition constant and specific activity as its natural counterpart. Although there is no obvious sequence identity between haemadin and hirudin, both proteins seem to share common mechanisms for thrombin inhibition.

Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product.

The adenovirus E1A gene product, the simian virus 40 large tumor antigen, and the human papillomavirus E7 protein share a short amino acid sequence that constitutes a domain required for the transforming activity of these proteins. These sequences are also required for these proteins to bind to the retinoblastoma gene product (pRb). Recent experiments have shown that E1A can dissociate complexes containing the transcription factor E2F bound to pRb, dependent on this conserved sequence element. We now show that the E7 protein and the simian virus 40 large tumor antigen can dissociate the E2F-pRb complex, dependent on this conserved sequence element. We also find that the E2F-pRb complex is absent in various human cervical carcinoma cell lines that either express the E7 protein or harbor an RB1 mutation, suggesting that the loss of the E2F-pRb interaction may be an important aspect in human cervical carcinogenesis. We suggest that the ability of E1A, the simian virus 40 large tumor antigen, and E7 to dissociate the E2F-pRb complex may be a common activity of these viral proteins that has evolved to stimulate quiescent cells into a proliferating state so that viral replication can proceed efficiently. In circumstances in which a lytic infection does not proceed, the consequence of this action may be to initiate the oncogenic process in a manner analogous to the mutation of the RB1 gene.

A recombination hotspot in the LTR of a mouse retrotransposon identified in an in vitro system.

The recombinational frequency between two long terminal repeat elements (LTR-IS) of a mouse retrotransposon was about 13 times higher, compared with that of two control DNA sequences in extracts from mouse testes, but not in extracts from ascites cells. Deletion of a 37 bp region from the LTR-IS element strongly suppresses its recombinational activity. This 37 bp region encompasses an area of potentially single-stranded DNA and interacts with at least two nuclear proteins. One of them binds sequence-specifically to single-stranded DNA and is present in both types of extracts. Another protein(s) binds to dsDNA at the motif TGGAAATCCCC and is absent in extracts from testes. Our results suggest that a cis-acting DNA sequence within the 504 bp LTR-IS element is responsible for its high recombinational activity in vitro, and they further support the previous suggestion that the LTR-IS elements are meiotic recombinational hotspots in vivo.

Isolation of novel human retrovirus-related sequences by hybridization to synthetic oligonucleotides complementary to the tRNA(Pro) primer-binding site.

Synthetic oligonucleotides complementary to putative retroviral primer-binding sites were used as hybridization probes to detect novel retroviruslike sequences. An 8.1-kilobase element with structural features of a retroviral provirus was isolated from a human genomic library by this approach. Nucleotide sequence analysis of its 600-base-pair long terminal repeats revealed characteristic motifs known as regulatory signals for RNA polymerase II transcription: CCAAT, TATA, and ATTAAA. In addition, a putative pol gene displays apparent homologies to conserved regions of retroviral reverse transcriptase. The 5' long terminal repeat is flanked at its 3' end by a putative primer-binding site for reverse transcription with homology to tRNA(Pro). This element is therefore termed HuRRS-P (human retrovirus-related sequence-proline). There are 20 to 40 copies of HuRRS-P homologous sequences in DNAs of human and simian origin.

Structure and genomic organization of a new family of murine retrovirus-related DNA sequences (MuRRS).

A new class of murine retrovirus-related sequences (MuRRS) is described. These 5.7 kb long transposon-like DNA-elements start and end with approximately 600 bp long repeats identical to previously identified solitary LTR-like elements (LTR-IS). There are about 50 - 100 5.7 kb elements and about 500 - 1000 solo LTR-IS elements per mouse haploid genome. Sequence analysis of one cloned MuRRS element revealed several possible open reading frames with partial sequence homologies to retroviral gag, pol and env genes.