Lenticulostriate vasculopathy in twin-to-twin transfusion syndrome.

Intracranial pathology is a common and important complication in extremely low birth weight babies. Lenticulostriate vasculopathy (LSV) is an abnormal finding on cranial ultrasounds of sick babies and has been associated with congenital infection, chromosomal aberration and twin-to-twin transfusion. We describe a previously unreported situation of LSV being detected in both donor and recipient twin. This pair of monochorionic, diamniotic twins was admitted to the Neonatal Intensive Care Unit at 28 weeks of gestation. The mother underwent an emergency caesarean section because ultrasound and Doppler studies showed stage III twin-to-twin transfusion syndrome. The first twin weighed 998 g and second twin weighed 600 g. The first twin had an uneventful stay, whereas the second twin needed prolonged continuous positive airway pressure and indomethacin for patent ductus arteriosus. Both of them developed LSV. The clinical significance of this condition on the neuro-developmental outcome of a neonate has not yet been fully determined.     

Management of fibroadenoma of the breast.

Fibroadenoma is a common cause of discrete breast lumps in young women. There is agreement that fibroadenomas can be diagnosed preoperatively with a high degree of confidence and that some of the lesions thus diagnosed will resolve, possibly obviating the need for excision. There is, however, wide disagreement over the proportion of fibroadenomas that resolve spontaneously and therefore the benefit that accrues from an expectant policy. The aim of this study was to audit the management of fibroadenomas on one unit and clarify their natural history over a 5-year period. A cohort of 70 women with 87 fibroadenomas diagnosed using a triple assessment of clinical examination, cytology and imaging (sonomammography) have been followed for a minimum of 5 years. In all, 53 of the 'fibroadenomas' have been excised. In four cases the histology revealed benign disease other than fibroadenoma; there were no neoplasms. The sensitivity of cytology and sonomammography for the diagnosis of fibroadenoma were 84% and 98% respectively. Thirty-four fibroadenomas have not been excised. Of 25 fibroadenomas that have been reassessed after at least 5 years of follow-up, 13 (52%) have reduced in size, 4 (16%) are unchanged in size and 8 (32%) have grown. No patient has developed a carcinoma at the site of the presumed fibroadenoma. This study confirms that an expectant management policy of fibroadenomas has not resulted in misdiagnosis of carcinomas. Further, since a significant proportion of fibroadenomas remain static or reduce in size over a 5-year period many women can avoid excision.     

Retrohepatic cavoatrial bypass for coarctation of inferior vena cava with a polytetrafluoroethylene graft

Eight patients with chronic Budd-Chiari syndrome resulting from coarctation of the inferior vena cava underwent operation. Transatrial dilatation was of no avail in the first case. The obstructed segment was directly visualized in the subsequent seven cases by a transthoracic, transdiaphragmatic, retroperitoneal approach. In these latter seven cases, severe hourglass constriction of the inferior vena cava was observed just above the right hepatic vein. There was no evidence of inflammation, extrinsic compression, or thrombosis. Retrohepatic cavoatrial bypass with an antibiotic-sterilized aortic homograft was unsuccessful in three patients. Five patients including one with homograft failure underwent successful retrohepatic cavoatrial bypass with a polytetrafluoroethylene graft (20 mm plain in four cases and 16 mm ringed graft in one case). These patients have been followed up for 21 months to 6 years with no recurrence of symptoms. The term coarctation of the inferior vena cava appears more appropriate than membranous obstruction of the inferior vena cava because of the operative findings in the present series.     

Differential PsaA-, PspA-, PspC-, and PdB-specific immune responses in a mouse model of pneumococcal carriage

Larger numbers of pneumococci were detected in the nasal tract compared to the lung, cervical lymph nodes, and spleen 1, 2, 4, 7, 14, and 21 days after nasal challenge with Streptococcus pneumoniae strain EF3030. In this mouse model of pneumococcal carriage, peripheral S. pneumoniae pneumococcal surface adhesin A (PsaA)-specific humoral responses (immunoglobulin G2a [IgG2a] > IgG1 = IgG2b > IgG3) were significantly higher than pneumococcal surface protein A (PspA)-specific, genetic toxoid derivative of pneumolysin (PdB)-specific, or pneumococcal surface protein C (PspC)-specific serum antibody levels. However, PspA-specific mucosal IgA antibody levels were significantly higher than those against PsaA, PdB, and PspC. In general, both PsaA- and PspA-specific lung-, cervical lymph node-, nasal tract-, and spleen-derived CD4(+) T-cell cytokine (interleukin-4, interleukin-6, granulocyte-macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha) and proliferative responses were higher than those for either PspC or PdB. Taken together, these findings suggest that PsaA- and PspA-specific mucosal responses as well as systemic humoral and T helper cell cytokine responses are predominantly yet differentially induced during pneumococcal carriage.     

Tyrosine-derived novel antimicrobial hydantoin polymers: synthesis and evaluation of anti-bacterial activities

A new approach for the design and synthesis of cyclic N-halamine polymers having anti-bacterial activity based on a vinyl derivative of tyrosine-derived hydantoin is reported. The synthesis of N-halamine polymers generally involves the chemical modification of 5,5′-disubstituted hydantoin to introduce polymerizable vinyl moieties thereby restricting the halogen capture only on the amide nitrogen. Here we show the possibility of synthesizing vinyl monomers of N-halamine from α-amino acids wherein both the amide and imide nitrogens are available for halogen capture. Thus, a hydantoin monomer was synthesized from L-tyrosine and copolymerized with methyl methacrylate and 2-(hydroxyethyl)methacrylate, to obtain random co-polymers. The monomer and its co-polymers were characterized using NMR, IR, HRMS, GPC, DSC, EDAX and TGA analysis. Films of the co-polymers cast from 10% acetone solutions were exposed to sodium hypochlorite solution to activate the hydantoin moieties. The oxidative chlorine content of the films ranged from 0.6 to 0.9%. The activated films were exposed to both Gram positive (S. aureus) and Gram negative (E. coli) bacteria using standard protocols. Polymers having chlorine content as little as 0.6% exhibited 6 log reduction in the bacterial growth within 30 min of exposure. The method allows the halogenation of both amide and imide nitrogens and could be applied to the preparation of a number of vinyl hydantoins from many amino acids.     

Genitourinary non-tuberculous mycobacterial (GU-NTM) infections: A single institution experience in South India

IntroductionNon-tuberculous mycobacterial (NTM) infections are rarely reported, and more so with genitourinary infections. This retrospective study was designed to understand the proportion and behaviour of genitourinary non-tuberculous mycobacterial (GU-NTM) infections compared with genitourinary mycobacterial tuberculosis (GU-MTB) treated at a tertiary care hospital in South India.Materials and methodsThe hospital records of every bacteriologically proved GU-MTB and GU-NTM infections treated at this centre from 2010 to 2016 were retrospectively reviewed.ResultsThere were ten patients of GU-NTM and 15 patients of GU-MTB. There was no significant difference in presentation other than lesser frequency of irritative lower urinary tract symptoms (LUTS) among patients with GU-MTB. Urine smear for AFB was positive in 60% and 47% of GU-NTM and GU-MTB patients. 40% of GU-NTM patients had history of urinary tract instrumentation. Mycobacterium abscessus was grown in four patients and one had Mycobacterium fortuitum/chelonae complex; all the rest were rapid growers. No patient had multi-drug resistant tuberculosis. Imaging studies of GU-NTM patients were indistinguishable from GU-MTB with renal, ureteral and bladder involvements, and stone formation. The drug sensitivities varied among the NTM patients but all showed sensitivity to clarithromycin uniformly. Need for varieties of surgeries in the early and late phases were also comparable.ConclusionsGU-MTB and GU-NTM infections are indistinguishable from their clinical presentation and imaging studies. All cases of suspected genitourinary mycobacterial infections must be subjected to nucleic acid testing. Treatments based on clinical and radiological features without culture studies may misdiagnose GU-NTM infections as MDR GU-MTB, thereby delaying the appropriate treatment.     

Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

Mu-opioid receptor (MOR) agonists are the most effective treatments for moderate to severe acute and chronic pain, yet their use is limited by serious side effects, including constipation, respiratory depression, and physical and psychological dependence. These side effects are on-target effects (MOR-mediated) and result from the wide distribution of MORs across the central nervous system (CNS) (1, 2). Safer pain therapies are desperately needed. However, because of the efficacy of MOR agonists in blocking pain, this receptor continues to be a primary target for the discovery of novel pain therapies. Unfortunately, most drug discovery programs involve designing compounds that bind to the orthosteric site on MOR—the site that binds endogenous opioid peptides as well as exogenous opioids. Not surprisingly, these newer drugs tend to exhibit qualitatively similar side effect profiles to traditional opioid analgesics.As an alternative, we have discovered small molecule, positive allosteric modulators of MOR [mu-PAMs (3)], including BMS-986122 (SI Appendix, Fig. S1). Such compounds interact with a site on MOR that is spatially distinct from the orthosteric site (3–7). Across a variety of in vitro assays, mu-PAMs increase the affinity and/or potency of orthosteric agonists at MOR, including exogenous MOR agonists as well as the endogenous opioid peptides Leucine- and Methionine-enkephalin, endomorphin-1, and β-endorphin (3, 8).These in vitro studies have led to development of a so-far untested hypothesis that in vivo, mu-PAMs will promote the activity of endogenous opioid peptides released during pain (9–11). If this hypothesis is correct, mu-PAMs could replace traditional opioids by boosting the body’s own natural response to pain to provide clinically meaningful analgesia. In support of this concept, so called “enkephalinase inhibitors” that prolong the lifetime of endogenous opioid peptides are effective in the management of pain in preclinical and clinical studies (12–14), although such compounds are not selective for opioid peptides. Since mu-PAMs do not alter peptide release or metabolism, they should be more selective than enkephalinase inhibitors and also preserve the natural spatial and temporal release of the peptides in vivo following injury and/or during pain. To test this hypothesis, we examined the antinociceptive effects of BMS-986122 in mouse models of acute and inflammatory pain using measures of pain-evoked and pain-depressed behaviors as well as opioid side effects and the potential role of endogenous opioid peptides in these responses.