Cutaneous manifestations of small fibre polyneuropathy.

BACKGROUND: Because typical and atypical features of small fibre polyneuropathy (SFN) in the skin have not been fully elucidated, the diagnosis is often made by the exclusion of alternative conditions rather than by its identification as a primary syndrome. OBJECTIVE: The objective of this study was to characterize dermatologic manifestations in patients with SFN. METHODS: Large retrospective series of biopsy-proven SFN cases seen at the Massachusetts General Hospital and Brigham and Women's Hospital (January 2000 to December 2019). RESULTS: The majority of the 301 participants included presented with at least one cutaneous manifestation [292/301 (97%)]. Pain was most common with 254/301 (84.4%) perceiving this as occurring in the skin. It was frequently described as 'burning' [95/254 (37.4%)] and affected distal [174/254 (68.5%)] slightly more than proximal [111/254 (43.7%)] limbs. Numbness [182/301 (60.5%)], edema [61/301 (20.3%)] and skin colour changes [53/301 (17.6%)], which include redness [23/53 (43%)], also had predominant distal distribution. Characteristic loss of distal hair occurred among 17/29 (59%) those reporting hair loss. Other findings with classic limb involvement, Raynaud's phenomenon [33/301 (11%)] and erythromelalgia [26/301 (8.6%)] were seen. Itch [45/301 (15%)], mostly localized [22/45 (49%)] and localized eczematous dermatitis were also found. CONCLUSION: SFN has a wide range of clinical features in which the skin is affected, with characteristic findings affecting the extremities.

Analysis of the first 5 years of an interdisciplinary Rheumatology-Dermatology clinic.

BACKGROUND: Multispeciality clinics, such as combined psoriasis-psoriatic arthritis clinics, have shown improved outcomes in various diseases. At Massachusetts General Hospital, we are entering our ninth year of having an interdisciplinary Rheumatology-Dermatology (R-D) clinic. AIM: To evaluate the contribution of an R-D clinic by comparing care of patients pre- and post-evaluation in the combined clinic. As proxies of care, rates and comprehensiveness of evaluations (capillaroscopic examination, skin and joint examination) were compared between the combined clinic and standard Rheumatology or Dermatology clinic. METHODS: This was a retrospective chart review of patients at the R-D clinic in Massachusetts General Hospital during the period November 2012 to December 2017. RESULTS: Prior to the patients visiting the R-D only 5% of capillaroscopic examinations were documented, only 5% of rheumatologists specifically described a rash even when present, and pruritus was documented in only 6% of rheumatology notes. By contrast, in the R-D clinic, capillaroscopic, skin and joint examinations were documented in 100% of visits, and 19% of patients were given a different or a refined diagnosis. Although all our patients had cutaneous manifestations of their disease (hair loss, rash, itch, Raynaud phenomenon, ulcerations, calcinosis) only 34% had seen a dermatologist prior to the combined clinic and only 5% of those had had their concerns addressed by the rheumatologist. This suggests that 95% had a more complete evaluation and management of all aspects of their disease by attendance at the R-D clinic. CONCLUSION: Despite this study being limited by its retrospective nature, we found that it is an efficient model to achieve more comprehensive and potentially lower medication costs. Collaboration between dermatologists and rheumatologists in a combined clinic led to more complete skin and joint examinations, consistent tracking of capillaroscopic examination, better description of rash and improved management. Having this clinic helped in reaching a diagnosis and overall better disease control and outcome.

Development of LRRK2 Inhibitors for the Treatment of Parkinson's Disease.

Linkage and genome-wide association studies have identified a genetic risk locus for late-onset Parkinson's disease in chromosome 12, originally identified as PARK6. The causative gene was identified to code for a large multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). The combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment. Although LRRK2 has so far not been crystallised, the use of homology modelling and crystallographic surrogates has allowed the optimisation of chemical structures such that compounds of high selectivity with good brain penetration and appropriate pharmacokinetic properties are now available for understanding the biology of LRRK2 in vitro and in vivo. This chapter reviews LRRK2 biology, the structural biology of LRRK2 and gives an overview of inhibitors of LRRK2.

Evolution of repeated DNA sequences by unequal crossover.

It is often supposed that highly repetitious DNA's arise only as a result of unusual mechanisms or in response to selective pressure. My arguments and simulations suggest, by contrast, that a pattern of tandem repeats is the natural state of DNA whose sequence is not maintained by selection. The simulations show that periodicities can develop readily from nonreptitious DNA as a result of the random accumulation of random mutations and random homology-dependent unequal crossovers. The lengths of these periodicities, and the patterns of subrepeats within them, would fluctuate in evolution, with the probability of a given pattern being dependent on the unknown exact nature of the crossover mechanism. Qualitatively, then, unequal crossover provides a reasonable and uncontrived explanation for the prevalence of highly repeated sequences in DNA and for the patterns of periodicity they evince.

Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface.

Foreign DNA fragments can be inserted into filamentous phage gene III to create a fusion protein with the foreign sequence in the middle. The fusion protein is incorporated into the virion, which retains infectivity and displays the foreign amino acids in immunologically accessible form. These "fusion phage" can be enriched more than 1000-fold over ordinary phage by affinity for antibody directed against the foreign sequence. Fusion phage may provide a simple way of cloning a gene when an antibody against the product of that gene is available.

Mouse immunoglobulin kappa chain MPC 11: extra amino-terminal residues.

The kappa chain from the immunoglobulin of myeloma tumor MPC 11 has 12 extra residues at its amino terminus, the first six of which are identical to the residues at positions 1 to 6 of typical mouse kappa chains and at positionss 13 to 18 of MPC 11 itself. Two of the peptide bonds within this extra 12-residue segment are cleaved under very mild conditions.

Endogenous cholecystokinin reduces feeding in young rats.

The hypothesis that endogenous cholecystokinin (CCK) released from the small intestine during feeding causes satiety was tested in rat pups, 9 to 12 days old. Intragastric administration of soybean trypsin inhibitor, a procedure that releases CCK from the small intestine, decreased the subsequent intake of a test meal. This effect was reversed by prior treatment with MK-329, a selective antagonist of CCK at alimentary-type CCK (CCK-A) receptors. Thus, endogenous, small intestinal CCK can cause satiety in the neonatal rat and this effect involves CCK-A receptors.

Searching for peptide ligands with an epitope library.

Tens of millions of short peptides can be easily surveyed for tight binding to an antibody, receptor or other binding protein using an "epitope library." The library is a vast mixture of filamentous phage clones, each displaying one peptide sequence on the virion surface. The survey is accomplished by using the binding protein to affinity-purify phage that display tight-binding peptides and propagating the purified phage in Escherichia coli. The amino acid sequences of the peptides displayed on the phage are then determined by sequencing the corresponding coding region in the viral DNA's. Potential applications of the epitope library include investigation of the specificity of antibodies and discovery of mimetic drug candidates.

Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat.

The site where peripherally administered cholecystokinin-8 elicits satiety was investigated by injecting rats with cholecystokinin-8 (1 to 8 micrograms per kilogram of body weight, intraperitoneally) after they had received bilateral lesions of the ventromedial hypothalamus or after they had undergone bilateral abdominal vagotomy or selective vagotomies. Abdominal vagotomy or gastric vagotomy abolished or reduced the satiety effect of cholecystokinin, but lesions of the ventromedial hypothalamus did not. These results demonstrate that peripherally administered cholecystokinin acts in the abdomen through gastric vagal fibers and not directly on the brain to produce satiety in the rat.

A complex pattern of mantle flow in the Lau backarc.

Shear-wave splitting analysis of local events recorded on land and on the ocean floor in the Tonga arc and Lau backarc indicate a complex pattern of azimuthal anisotropy that cannot be explained by mantle flow coupled to the downgoing plate. These observations suggest that the direction of mantle flow rotates from convergence-parallel in the Fiji plateau to north-south beneath the Lau basin and arc-parallel beneath the Tonga arc. These results correlate with helium isotopes that map mantle flow of the Samoan plume into the Lau basin through an opening tear in the Pacific plate.

Modified sham feeding of sweet solutions in women with and without bulimia nervosa.

Although it is possible that binge eating in humans is due to increased responsiveness of orosensory excitatory controls of eating, there is no direct evidence for this because food ingested during a test meal stimulates both orosensory excitatory and postingestive inhibitory controls. To overcome this problem, we adapted the modified sham feeding technique (MSF) to measure the orosensory excitatory control of intake of a series of sweetened solutions. Previously published data showed the feasibility of a "sip-and-spit" procedure in nine healthy control women using solutions flavored with cherry Kool Aid and sweetened with sucrose (0-20%). The current study extended this technique to measure the intake of artificially sweetened solutions in women with bulimia nervosa (BN) and in women with no history of eating disorders. Ten healthy women and 11 women with BN were randomly presented with cherry Kool Aid solutions sweetened with five concentrations of aspartame (0, 0.01, 0.03, 0.08 and 0.28%) in a closed opaque container fitted with a straw. They were instructed to sip as much as they wanted of the solution during 1-minute trials and to spit the fluid out into another opaque container. Across all subjects, presence of sweetener increased intake (p<0.001). Women with BN sipped 40.5-53.1% more of all solutions than controls (p=0.03 for total intake across all solutions). Self-report ratings of liking, wanting and sweetness of solutions did not differ between groups. These results support the feasibility of a MSF procedure using artificially sweetened solutions, and the hypothesis that the orosensory stimulation of MSF provokes larger intake in women with BN than controls.

Development of an auxotrophic, live-attenuated Brucella suis vaccine strain capable of expressing multimeric GnRH.

Feral swine cost around $1.5 billion each year in agricultural, environmental, and personal property damages. They are also the most widespread carriers of the zoonotic disease brucellosis, which threatens both livestock bio-security and public health. Currently, there is no approved vaccine against brucellosis in pigs. This is a preliminary report on the development of a live-attenuated B. suis vaccine that could be employed to deliver heterologous antigens to control swine populations. An attenuated vaccine strain provided significant protection against B. suis challenge in mice. Leucine auxotrophy in the vaccine strain allowed the over-expression of heterologous antigens without the use of antibiotic resistant markers. Vaccinated mice showed the development of antibodies against expressed antigen. Further evaluation is required to assess its ability to cause infertility using the mouse model prior to further testing for use as a tool for feral swine population and disease control.

Mycobacterium tuberculosis and whole-genome sequencing: how close are we to unleashing its full potential?

BACKGROUND: Nearly two decades after completion of the genome sequence of Mycobacterium tuberculosis (MTB), and with the advent of next generation sequencing technologies (NGS), whole-genome sequencing (WGS) has been applied to a wide range of clinical scenarios. Starting in 2017, England is the first country in the world to pioneer its use on a national scale for the diagnosis of tuberculosis, detection of drug resistance, and typing of MTB. AIMS: This narrative review critically analyses the current applications of WGS for MTB and explains how close we are to realizing its full potential as a diagnostic, epidemiologic, and research tool. SOURCES: We searched for reports (both original articles and reviews) published in English up to 31 May 2017, with combinations of the following keywords: whole-genome sequencing, Mycobacterium, and tuberculosis. MEDLINE, Embase, and Scopus were used as search engines. We included articles that covered different aspects of whole-genome sequencing in relation to MTB. CONTENT: This review focuses on three main themes: the role of WGS for the prediction of drug susceptibility, MTB outbreak investigation and genetic diversity, and research applications of NGS. IMPLICATIONS: Many of the original expectations have been accomplished, and we believe that with its unprecedented sensitivity and power, WGS has the potential to address many unanswered questions in the near future. However, caution is still needed when interpreting WGS data as there are some important limitations to be aware of, from correct interpretation of drug susceptibilities to the bioinformatic support needed.

Effects of CCK-8 on independent ingestion and central c-Fos-like immunoreactivity in rats on postnatal days 10 and 11.

Controls of the independent ingestion of food in the preweanling rat emerge in the second postnatal week. We investigated the effects of CCK-8 (0, 1, 5, or 10 microg/kg IP) on intake and c-Fos-like immunoreactive (CFLI) cells in hindbrain and forebrain on postnatal days 10 and 11. Five micrograms per kilogram decreased intake and increased the number of CFLI cells in four subnuclei of the nucleus tractus solitarius (NTS), in arcuate nucleus (ARC), and in central nucleus of the amygdala (CeA). Ten micrograms per kilogram decreased intake and increased CFLI in three NTS subnuclei as much as 5 microg/kg did, but was more potent than 5 microg/kg in the medial NTS subnucleus. Ten micrograms per kilogram increased CFLI in paraventricular (PVN) and supraoptic (SON) nuclei, but 5 microg/kg did not. Thus, reduction of intake by CCK-8 on days 10 and 11 is associated with increased hindbrain and forebrain CFLI.

Orosensory stimulation is sufficient and postingestive negative feedback is not necessary for neuropeptide Y to increase sucrose intake.

Although central administration of neuropeptide Y (NPY) has a potent orexic effect, it is not clear how NPY changes the potency of peripheral feedbacks from the gut to prolong eating and increase meal size. It has been suggested that NPY increases the stimulating effect of orosensory sweet stimuli or that it decreases the inhibitory effect of postingestive stimuli. To clarify this issue, we compared the orexic effect of NPY (2 microg) injected into the third ventricle of the brain on the volume and microstructure of intake of 0.8M sucrose during sham feeding (SF) and real feeding (RF) in male Sprague Dawley rats. The rationale for this comparison is that orosensory stimulation occurs in SF and RF, but postingestive negative feedback is present only in RF. NPY increased the volume ingested and the rate and number of clusters of licking significantly more in SF than in RF. This demonstrates that orosensory sucrose stimulation is sufficient and postingestive negative feedback is not necessary for the orexic effect of NPY under these experimental conditions.

Intake, sweetness and liking during modified sham feeding of sucrose solutions.

Although sweet solids and liquids are palatable to humans and ingested frequently when readily available, the quantitative relationship between sweet taste and intake has not been reported in humans. To investigate the quantitative relationship between sweet taste and intake directly, we adapted the modified sham feeding technique, previously used in humans for the study of the orosensory control of autonomic, neuroendocrine, and metabolic mechanisms, to measure the intake of solutions both unsweetened and sweetened with four concentrations of sucrose. By limiting the sucrose stimuli to the mouth, the modified sham feeding technique measures the orosensory stimulation of intake by sucrose in the absence of inhibitory postingestive stimulation. Nine healthy women were randomly presented with two series of five solutions of cherry Kool Aid unsweetened or sweetened with one of four concentrations of sucrose (2.5%, 5%, 10%, or 20%) in a closed opaque container fitted with a straw. They were instructed to sip as much as they wanted of the liquid during 2-min trials and to spit the fluid out into another opaque container. At the end of each trial, they used Visual Analogue Scales to rate the perceived intensities of sweetness and liking of the liquid that they had just sipped and spit. Intake, liking and perceived sweetness were significantly affected by sucrose concentration (p values

Effect of flavone acetic acid on Lewis lung carcinoma: evidence for an indirect effect.

Flavone-8-acetic acid (FAA), a new antitumor agent currently undergoing clinical trial, fails to inhibit the growth of early stage Lewis lung (LL) tumors growing in the lung. However, the growth of advanced subcutaneous tumors, arising from inoculation of either the original in vivo LL line or a tissue culture-adapted cell line (LLTC) derived from the LL line was delayed significantly by FAA treatment. Comparison, by clonogenic survival assays, of the cytotoxic effect of FAA on LLTC cells demonstrated that most cell killing occurred between 2 and 8 hours following in vivo exposure but occurred to a much lesser extent and at later times following in vitro exposure. FAA was inactive against LLTC cells growing in vivo in diffusion chambers, suggesting that a host cellular component was necessary for activity. FAA was found to induce hemorrhagic necrosis in the advanced LL tumors, as well as in a number of human tumor xenografts growing in athymic mice. The human cell lines from which the xenografts were derived, as well as the LL tumor lines and P388 leukemia lines, were inhibited by FAA in vitro. However, the ranking of FAA activity in vivo did not parallel that observed in vitro. Together, these observations strongly suggest that FAA has an indirect mode of antitumor action.

Spontaneous liquid crystal and ferromagnetic ordering of colloidal magnetic nanoplates.

Ferrofluids are familiar as colloidal suspensions of ferromagnetic nanoparticles in aqueous or organic solvents. The dispersed particles are randomly oriented but their moments become aligned if a magnetic field is applied, producing a variety of exotic and useful magnetomechanical effects. A longstanding interest and challenge has been to make such suspensions macroscopically ferromagnetic, that is having uniform magnetic alignment in the absence of a field. Here we report a fluid suspension of magnetic nanoplates that spontaneously aligns into an equilibrium nematic liquid crystal phase that is also macroscopically ferromagnetic. Its zero-field magnetization produces distinctive magnetic self-interaction effects, including liquid crystal textures of fluid block domains arranged in closed flux loops, and makes this phase highly sensitive, with it dramatically changing shape even in the Earth's magnetic field.