The impact of a fasting mimicking diet on the metabolic health of a prospective cohort of patients with prostate cancer: a pilot implementation study.

BACKGROUND: This pilot prospective study investigated the effect of a periodic fasting mimicking diet (FMD) on metabolic health factors in patients with Prostate Cancer (PC). There is a well-documented association between PC and metabolic health. Impaired metabolic health is a significant risk factor for the development of PC, and a metabolic syndrome can be induced by hormonal therapies commonly required for its management. (ClinicalTrials.gov Identifier: NCT04292041). METHODS: We introduced a periodic 4-day FMD -low in calories, sugars, and proteins but high in unsaturated fats -to a cohort of PC patients and features of metabolic syndrome. 29/35 patients completed 3-monthly cycles of the 4-consecutive day packaged FMD. We compared the subjects' baseline weight, abdominal circumference (AC), blood pressure (BP) and selected laboratory results to the same measurements 3-months after completing the FMD cycles. RESULTS: Several important metabolic factors showed improvements post-intervention. On average patients' weights dropped by 3.79 kg (95% CI: -5.61, -1.97, p = 0.0002). AC was reduced on average by 4.57 cm, (95% CI: -2.27, -6.87, p = 0.0003). There was also a decrease in systolic and diastolic BP by 9.52 mmHg (95% CI: -16.16, -2.88, p = 0.0066) and 4.48 mmHg (95% CI: -8.85, -0.43, p = 0.0316) respectively. A sub-analysis indicates that FMD had more relevant effects in 'at-risk' patients than those with normal values of risk factors for metabolic syndrome. For example, subjects with baseline levels of systolic BP > 130 mmHg experienced a greater reduction in BP(-16.04 mmHg, p = 0.0001) than those with baseline systolic BP < 130 mmHg (-0.78 mmHg, p = 0.89). CONCLUSIONS: The FMD cycles were safely introduced to this small cohort of PC patients with little or no observed toxicity, and a high overall compliance of 83%. Analysis of the metabolic variables showed an overall decrease in weight, AC, and BP. Larger clinical trials focused on metabolic risk factors, PC quality of life and progression free survival are needed to assess the effect of the FMD on prostate cancer patients.

Effect of lower limb massage on electromyography and force production of the knee extensors.

OBJECTIVE: To evaluate the effect of massage on force production and neuromuscular recruitment. METHODS: Ten healthy male subjects performed isokinetic concentric contractions on the knee extensors at speeds of 60, 120, 180, and 240 degrees /s. These contractions were performed before and after a 30 minute intervention of either rest in the supine position or lower limb massage. Electromyography (EMG) and force data were captured during the contractions. RESULTS: The change in isokinetic mean force due to the intervention showed a significant decrease (p<0.05) at 60 degrees /s and a trend for a decrease (p = 0.08) at 120 degrees /s as a result of massage compared with passive rest. However, there were no corresponding differences in any of the EMG data. A reduction in force production was shown at 60 degrees /s with no corresponding alteration in neuromuscular activity. CONCLUSIONS: The results suggests that motor unit recruitment and muscle fibre conduction velocity are not responsible for the observed reductions in force. Although experimental confirmation is necessary, a possible explanation is that massage induced force loss by influencing "muscle architecture". However, it is possible that the differences were only found at 60 degrees /s because it was the first contraction after massage. Therefore muscle tension and architecture after massage and the duration of any massage effect need to be examined.

Paradoxical embolism with a patent foramen ovale and atrial septal aneurysm.

Patent foramen ovale (PFO) and atrial septal aneurysm have been cited as potential risk factors for cryptogenic stroke. We present two cases which we propose to directly illustrate paradoxical embolisation as a mechanism of cerebrovascular accident. The diagnosis of PFO is discussed and the literature reviewed.

Nephrotic syndrome following allogeneic stem cell transplantation associated with increased production of TNF-alpha and interferon-gamma by donor T cells.

SUMMARY: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the immunological complications of stem cell transplantation (SCT) including graft-versus-host disease (GVHD). In this report of a patient undergoing allogeneic SCT for AML, serial cytokine measurements by real-time PCR revealed increased production of interferon-gamma (IFN-gamma) and TNF-alpha, but not interleukin (IL)-4 in purified T cells following withdrawal of immunosuppression. Cytokine changes were contemporaneous with the onset of nephrotic syndrome (NS), a rare manifestation of GVHD. These findings indicate that serial cytokine monitoring may allow for the prediction of GVHD during immunosuppression withdrawal and lend further insight into the pathogenesis of NS. Bone Marrow Transplantation (2003) 32, 447-450. doi:10.1038/sj.bmt.1704151

A comparison of ultrasonic and mechanical stadiometry.

AIM: To compare an ultrasonic height measuring device (Gulliver) with mechanical stadiometry and the classical "book and tape measure" method. METHODS: Blinded duplicate measurements of height were made on each of 14 children by a pair of observers using a stadiometer (H) and Gulliver (G). Height was measured on a further 18 children by parents and an auxologist using Gulliver and the book and tape method (TM), and the results were compared with those obtained with a single stadiometry measurement. Finally, measurement of a rigid metal box was made on 10 occasions by the three methods. RESULTS: In the group of 14 children, the mean difference (range) in height (H minus G) was +2.8 cm (+0.5 to +4.55 cm), with H giving a systematically higher value in 276 of 280 individual measurements. In the group of 18 children, height by H was greater than by G or TM in 47 of 52 individual measurements. The mean (SD) height of the box by H (61.60 (0.07) cm) was greater than by G (60.96 (0.15) cm; p < 0.001) but not TM (61.4 (0.16) cm; p > 0.05). G and TM produced three times less reliable estimations of height than H, but with a large difference in cost, and there was evidence of systematic underrecording of height by 0.5 cm with G. CONCLUSIONS: Stadiometry is precise and reproducible, and can detect true changes in height over one month periods in mid-childhood, and should remain the standard way of observing growth. The book and tape method can produce clinically acceptable quarterly estimations of height that can be performed in the home.

Insulin receptor-related receptor messenger ribonucleic acid: quantitative distribution and localization to subpopulations of epithelial cells in stomach and kidney.

A novel member of the insulin receptor family, the insulin receptor-related receptor (IRR), was initially identified by cloning genomic DNA homologous to the insulin receptor. We have now used Northern blot and polymerase chain reaction analyses of a variety of human tissues to demonstrate that the kidney is a major site of IRR gene expression. IRR transcripts (approximately 6 and approximately 2 kilobases) were detected only in human kidney by Northern blot analyses. Quantitative competitive polymerase chain reaction analysis revealed that IRR messenger RNA levels were distributed more widely. IRR transcripts in human kidney were approximately 3- to 10-fold greater than those in thymus, brain, heart, and stomach and approximately 150-fold higher than those in placenta, skeletal muscle, and liver. In situ hybridization histochemical analysis revealed that IRR transcripts were present in a subpopulation of cells within distal tubules of human kidney, beyond the most proximal segment of the distal convoluted tubule. In rat stomach, IRR messenger RNA was localized to a subset of neuroendocrine cells in gastric glands of the fundic mucosa. This selective distribution of IRR transcripts in human and rat tissues suggests that IRR may mediate the responses of a neuroendocrine factor involved in regulating select aspects of cell function in a highly tissue-specific manner.

A novel guanylyl cyclase-A isoform: rat GC-A1 identification and mRNA localization to renal papilla and adrenal.

Natriuretic peptides modulate systemic blood pressure, diuresis and natriuresis through the stimulation of cGMP production by guanylyl cyclase-coupled natriuretic peptide receptor-A and -B (GC-A and GC-B). A novel isoform of GC-A, GC-A1, has been identified which is the result of differential splicing of a new exon, 5a. This 9 bp sequence is predicted to add proline-cysteine-glutamine to the extracellular juxtamembrane region of the receptor protein. Transcripts for GC-A1 are expressed primarily in the renal papilla and adrenal. In these tissues, its abundance relative to GC-A was 1-2.5% as assessed by quantitative PCR.

Widespread co-localization of mRNAs encoding the guanylate cyclase-coupled natriuretic peptide receptors in rat tissues.

Natriuretic peptides modulate vasorelaxation, diuresis, and natriuresis through the stimulation of cGMP production by the guanylate cyclase-coupled natriuretic peptide receptors, GC-A and GC-B. We used reverse transcription-polymerase chain reaction to determine the distribution of mRNA encoding both receptors in rat tissues. GC-A and GC-B transcripts were detected in all peripheral and neural tissues examined. Since the atrial natriuretic peptide gene is expressed in all these tissues, our widespread detection of GC-A and GC-B mRNAs now suggests that natriuretic peptides may act as endocrine and paracrine hormones as well as neurotransmitters via both GC-A and GC-B receptors.

Tissue-specific expression of the rat insulin receptor-related receptor gene.

Characterization of genomic DNA encoding the insulin receptor-related receptor (IRR) previously revealed that the predicted IRR protein is closely related to the insulin and insulin-like growth factor-I receptor protein-tyrosine kinases. Using rat IRR genomic DNA as probe, IRR transcripts were detected by Northern blot analysis in RNA from rat kidney, stomach, and thymus, but not in RNA from other tissues, including skeletal muscle, brain, intestine, and uterus. Primer extension analysis using RNA from stomach revealed a single transcriptional start site 29 basepairs down-stream from a putative TATA box and 544 basepairs up-stream of the initiator methionine codon. Amplification of IRR cDNA by polymerase chain reaction and isolation of partial IRR cDNA clones confirmed that the IRR gene is an expressed gene.

eek and erk, new members of the eph subclass of receptor protein-tyrosine kinases.

We have identified human and rat DNAs encoding two novel members of the eph subclass of putative receptor protein-tyrosine kinases. Rat cDNA clones encoding eek (eph- and elk-related kinase) were isolated from a brain cDNA library probed with DNA encoding the kinase region of the insulin receptor-related receptor. The predicted eek protein contains all the amino acid residues conserved in the catalytic domains of protein-tyrosine kinases and is most similar to two putative receptor protein-tyrosine kinases of the eph subclass, elk (69%) and eph (57%). Human genomic DNAs encoding part of eek (EEK) as well as another putative protein-tyrosine kinase most similar to elk (90%), ERK (elk-related kinase), were isolated and partially characterized. The novel identity of these two eph-family genes was further supported by Southern blot analyses and localization to human chromosome 1. In Northern blot analysis of rat RNA, DNAs encoding rat eek and human ERK hybridized to transcripts most abundant in brain and lung, respectively. These two new members of the eph subclass of receptor protein-tyrosine kinases, eek and erk, may therefore have tissue-specific functions distinct from those of other eph family members.

The human aminopeptidase N gene: isolation, chromosome localization, and DNA polymorphism analysis.

DNA encoding the human aminopeptidase N (EC 3.4.11.2) gene (PEPN) was first isolated using rat cDNA probes and then used in Southern analysis of DNA from mouse-human somatic cell hybrids to assign this gene to the long-arm region (q11-qter) of human chromosome 15. This human genomic DNA probe detects a frequent DraIII polymorphism that is a useful marker for human chromosome 15.

Localization of the insulin receptor-related receptor gene to human chromosome 1.

DNA encoding the insulin receptor-related receptor (IRR), a novel receptor whose predicted primary structure is similar to those of the insulin and insulin-like growth factor I receptors, has been used in Southern blot analysis of DNA from human x mouse somatic cell hybrids to assign the IRR gene (INSRR) to human chromosome 1.

HeLa cells contain the atrial natriuretic peptide receptor with guanylate cyclase activity.

Receptors for atrial natriuretic peptide (ANP) are heterogeneous: an approximately 140-kDa receptor exhibits ANP-stimulated guanylate cyclase activity whereas an approximately 65-kDa receptor is thought to act only as a clearance-storage protein. We have used photoaffinity labeling techniques to show that the human cell line, HeLa, contains predominantly the approximately 140-kDa ANP receptor. In contrast, several other cell lines contain primarily the approximately 65-kDa receptor. In HeLa cells, ANP bound specifically to high affinity binding sites (Kd approximately 2 nM) and stimulated a rapid, dose-dependent accumulation of cGMP. These cell lines can thus provide useful models to study the multiple mechanisms of ANP action.

Primary structure of a putative receptor for a ligand of the insulin family.

Nucleotide sequence analysis of human and guinea pig genomic DNA encoding a new member of the insulin receptor (IR) family revealed that the predicted primary structure of this IR-related protein is as similar to the IR and insulin-like growth factor (IGF) I receptor as the IR and IGF-IR are to each other. The conservation of this IR-related sequence among mammals and with the IR and IGF-IR suggests that this IR-related protein is a novel receptor for insulin, IGF-I, IGF-II, or an as yet unidentified peptide hormone or growth factor belonging to the insulin family.

The post-mastectomy pain syndrome and the effect of topical capsaicin.

Eighteen patients with the post-mastectomy pain syndrome (PMPS) form the basis of this study. PMPS probably occurs in a minority of women after mastectomy. The onset of persistent pain usually occurred immediately or very shortly after the operation. The pain location or sensory findings implied involvement of the territories of other cutaneous branches of the intercostal nerves as well as the intercostobrachial nerve. A variety of treatment approaches were unsatisfactory. Twelve of 14 patients completing treatment with topical 0.025% capsaicin showed improvement after 4 weeks and 8 (57%) were judged to be good or excellent responses. Six months after the trial's completion 50% of those followed continued to have good pain relief. This therapy should now be subjected to a randomized, double-blind, placebo-controlled trial.

Amino acid sequence deduced from a rat kidney cDNA suggests it encodes the Zn-peptidase aminopeptidase N.

We have isolated and characterized rat kidney cDNA clones encoding a 140-kDa glycoprotein that exhibits characteristics of a cell surface Zn-peptidase. Structural features predicted for this putative kidney Zn-peptidase (KZP) are most consistent with properties previously determined for the Zn-peptidase aminopeptidase N. The deduced amino acid sequence of rat KZP is almost identical to the NH2-terminal sequence of aminopeptidase N purified from rabbit. The overall amino acid composition predicted for rat KZP is remarkably similar to that previously determined for rabbit and pig aminopeptidase N. The predicted Mr of rat kidney KZP approximates the Mr of the unglycosylated form of aminopeptidase N. The topology predicted for KZP is identical to that observed for aminopeptidase N: a short cytoplasmic domain at the NH2 terminus immediately precedes an uncleaved signal/anchor domain; a stalk region connects this membrane anchor to the extracellular, hydrophilic bulk of the protein containing catalytic sites required for Zn-peptidase activity. In addition, mRNA encoding KZP is present in tissues known to exhibit aminopeptidase N activity. Taken together with the observation that only a single gene homologous to KZP DNA is present in the rat and human genomes, these results suggest that we have established the primary structure of rat kidney aminopeptidase N.

Investigation of the polymorphic region in the 5' flanking region of the insulin gene in patients with Alzheimer's disease.

A potential relationship between Alzheimer's Disease (AD) and insulin gene expression was suggested by the observation that patients with AD have altered levels of fasting blood sugar and insulin. Since polymorphisms in the region 5' to the insulin gene have been associated with blood glucose levels, we have studied this polymorphism in AD patients. Subjects were 19 nondiabetic AD patients with symptoms of aphasia and apraxia and a family history of AD; and 20 age and sex-matched nondiabetic controls without family history of AD. The 5' polymorphic region of the insulin gene was analyzed by restriction enzyme digestion of DNA extracted from whole venous blood. We did not observe a correlation between the size of the 5' polymorphic region and AD.