Pancreatoduodenectomy for suspected malignancy: nonmalignant histology confers increased risk of serious morbidity.

BACKGROUND/AIMS: A tissue diagnosis is not always obtained prior to pancreatoduodenectomy (PD) and a proportion of patients are found to have noncancerous histology postoperatively. It is unknown if these patients have different outcomes when compared with those who have malignancy confirmed. METHODS: A retrospective paired case matched control study was undertaken. Patients who underwent PD for suspected malignancy but ultimately had nonmalignant histology were identified. Each was matched to a confirmed malignant control using the following criteria: age, gender, body mass index, American Society of Anesthesiologists grade, neoadjuvant treatment, preoperative serum bilirubin, preoperative biliary stenting and type of pancreatic anastomosis. Matching was blinded to the measured outcomes, which included perioperative morbidity and mortality. RESULTS: Forty-five cases were compared with 45 well-matched controls. There was no difference in 30- or 90-day mortality, or length of stay. While overall morbidity rates were the same, patients with nonmalignant disease were more likely to experience major (Clavien-Dindo grade III-IV) morbidity (40.0% versus 17.8%, p = 0.0352). Independently, rates of clinically relevant pancreatic fistula (CR-POPF) were higher in the nonmalignant group (22.2% versus 4.44%, p = 0.0131). CONCLUSIONS: In our study, PD patients with nonmalignant histology had significantly higher incidence of major morbidity and CR-POPF when compared with those who had malignancy confirmed. This should be considered when planning the management of patients with known or presumed benign/premalignant disease.

Complete Genome Sequence of a Novel WU Polyomavirus Isolate from Arkansas, USA, Associated with Acute Respiratory Infection.

We report here the complete genome sequence of a WU polyomavirus (WUPyV) isolate, also known as human polyomavirus 4, collected in 2016 from a patient in Arkansas with an acute respiratory infection. Isolate hPyV4/USA/AR001/2016 has a double-stranded DNA genome of 5,229 bp in length.

Complete Genome Sequences of Two Novel Isolates of Human Parainfluenza Virus 1 Associated with Acute Respiratory Infection.

Using target capture of viral nucleic acid and next-generation sequencing, we generated the complete genomes of two novel human parainfluenza virus 1 isolates. Isolates AR001 (accession no. KX570602) and NM001 (accession no. KX639498) were collected 3 months apart from pediatric patients with acute respiratory infection from Arkansas and New Mexico, respectively.

Nicotine stimulates expression of proteins implicated in peripheral and central sensitization.

Pain patients who are nicotine dependent report a significantly increased incidence and severity of pain intensity. The goal of this study was to determine the effects of prolonged nicotine administration on inflammatory proteins implicated in the development of peripheral and central sensitization of the trigeminal system. Behavioral, immunohistochemical, and microarray studies were utilized to investigate the effects of nicotine administered daily for 14 days via an Alzet® osmotic pump in Sprague Dawley rats. Systemic nicotine administration caused a significant increase in nocifensive withdrawals to mechanical stimulation of trigeminal neurons. Nicotine stimulated expression of the pro-inflammatory signal transduction proteins phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-c-Jun N-terminal kinase (p-JNK), and protein kinase A (PKA) in the spinal trigeminal nucleus. Nicotine also promoted elevations in the expression of glial fibrillary acidic protein (GFAP), a biomarker of activated astrocytes, and the microglia biomarker ionized calcium-binding adapter molecule 1 (Iba1). Similarly, levels of eleven cytokines were significantly elevated with the largest increase in expression of TNF-α. Levels of PKA, p-ERK, and p-JNK in trigeminal ganglion neurons were increased by nicotine. Our findings demonstrate that prolonged systemic administration of nicotine promotes sustained behavioral and cellular changes in the expression of key proteins in the spinal trigeminal nucleus and trigeminal ganglion implicated in the development and maintenance of peripheral and central sensitization.

Dual orexin receptor antagonist 12 inhibits expression of proteins in neurons and glia implicated in peripheral and central sensitization.

Sensitization and activation of trigeminal nociceptors is implicated in prevalent and debilitating orofacial pain conditions including temporomandibular joint (TMJ) disorders. Orexins are excitatory neuropeptides that function to regulate many physiological processes and are reported to modulate nociception. To determine the role of orexins in an inflammatory model of trigeminal activation, the effects of a dual orexin receptor antagonist (DORA-12) on levels of proteins that promote peripheral and central sensitization and changes in nocifensive responses were investigated. In adult male Sprague-Dawley rats, mRNA for orexin receptor 1 (OX1R) and receptor 2 (OX2R) were detected in trigeminal ganglia and spinal trigeminal nucleus (STN). OX1R immunoreactivity was localized primarily in neuronal cell bodies in the V3 region of the ganglion and in laminas I-II of the STN. Animals injected bilaterally with complete Freund's adjuvant (CFA) in the TMJ capsule exhibited increased expression of P-p38, P-ERK, and lba1 in trigeminal ganglia and P-ERK and lba1 in the STN at 2 days post injection. However, levels of each of these proteins in rats receiving daily oral DORA-12 were inhibited to near basal levels. Similarly, administration of DORA-12 on days 3 and 4 post CFA injection in the TMJ effectively inhibited the prolonged stimulated expression of protein kinase A, NFkB, and Iba1 in the STN on day 5 post injection. While injection of CFA mediated a nocifensive response to mechanical stimulation of the orofacial region at 2h and 3 and 5 days post injection, treatment with DORA-12 suppressed the nocifensive response on day 5. Somewhat surprisingly, nocifensive responses were again observed on day 10 post CFA stimulation in the absence of daily DORA-12 administration. Our results provide evidence that DORA-12 can inhibit CFA-induced stimulation of trigeminal sensory neurons by inhibiting expression of proteins associated with sensitization of peripheral and central neurons and nociception.

Adiaspiromycosis mimicking widespread malignancy in a patient with pulmonary adenocarcinoma.

Adiaspiromycosis, a mycotic disease of small animals, has rarely been reported in humans. The principle causative organism in Europe is Emmonsia crescens. Inhaled, dust-borne spores of E crescens fail to germinate in host tissue, instead increasing in size dramatically to become thick-walled, round adiapsores, which induce a granulomatous response. The pathological effects depend on the spore burden and host immunocompetence, and range from asymptomatic infection through to necrogranulomatous pneumonia, respiratory failure and, rarely, death. Diagnosis is principally made through histological examination. This report describes a case of a patient with low-grade, localised pulmonary adenocarcinoma with occult adiaspiromycosis that radiologically mimicked widespread malignancy. It is believed to be the first reported human case of adiaspiromycosis in the UK.

Effectiveness of a simulator in training anesthesiology residents. 1969.

The educational potential of a computer-controlled patient simulator was tested by the University of Southern California School of Medicine. The results of the experiment suggest unequivocally that there is a twofold advantage to the use of such a simulator in training anesthesiology residents in the skill of endotracheal intubation: (a) residents achieve proficiency levels in a smaller number of elapsed days of training, thus effecting a saving of time in the training of personnel, and (b) residents achieve a proficiency level in a smaller number of trials in the operating room, thus posing significantly less threat to patient safety. The small number of subjects in the study and the large within-group variability were responsible for a lack of statistical significance in 4 of 6 of the analyses performed; however, all differences were substantial and in the hypothesized direction. Thus, despite the narrowly circumscribed tasks to be learned by the experimental subjects, the findings suggest that the use of simulation devices should be considered in planning for future education and training not only in medicine but in other health care professions as well.

Cyclopropane. 1963.

Special precautions are stressed for cyclopropane, not because they are uniquely required for this drug, but because failure to observe them is apt to result in the more rapid occurrence of disaster for the patient. Strict attention to every minute detail is absolutely essential for good, safe cyclopropane anesthesia. Most important of all is adequate ventilation. Practically, this means assisting or controlling the ventilation at all times. Constant monitoring of the precordial heart tones is also mandatory. The blood pressure must be checked frequently, especially when the level of anesthesia is being deepened. In addition to all the required antiexplosion precautions required in operating rooms, we also recommend the use of a wet towel grounding as an added precaution. The anesthesiologist should further protect himself and the patient by keeping everything around the head of the table at the same electrical potential by frequently touching the various items. He should maintain constant contact with the patient whenever possible. The anesthesiologist should train himself to take these precautions automatically, so that they will not be omitted during trying circumstances. Our experience has been that residents trained to administer good, safe cyclopropane anesthesia according to the principles enunciated usually are much more attentive to details with other techniques. Constant observation of the patient and the progress of the surgery is also necessary, if good cyclopropane anesthesia is to result. Finally, there are some guiding principles that I believe are essential for the conduct of good, safe cyclopropane anesthesia. 1. Be thoroughly familiar with the pharmacological actions of the drug. 2. Maintain a healthy respect for the potency of the drug, but no fear. 3. Be especially sure to maintain adequate ventilation through a patent airway. 4. Remember the drug is explosive. 5. Be eternally vigilant to the minute details of the conduct of the anesthesia. 6. This drug is for the real "pro," not the amateur. It is to be handled with the finesse of the violinist, not with the banging of the cymbal player. 7. Answer for yourself the question, "If this drug is so frequently selected for the very poor risk patient, wouldn't it be equally good or better for the healthy patient?".

Overexpression and characterization of a prolyl endopeptidase from the hyperthermophilic archaeon Pyrococcus furiosus.

The maltose-regulated mlr-2 gene from the hyperthermophilic archaeon Pyrococcus furiosus having homology to bacterial and eukaryal prolyl endopeptidase (PEPase) was cloned and overexpressed in Escherichia coli. Extracts from recombinant cells were capable of hydrolyzing the PEPase substrate benzyloxycarbonyl-Gly-Pro-p-nitroanilide (ZGPpNA) with a temperature optimum between 85 and 90 degrees C. Denaturing gel electrophoresis of purified PEPase showed that enzyme activity was associated with a 70-kDa protein, which is consistent with that predicted from the mlr-2 sequence. However, an apparent molecular mass of 59 kDa was obtained from gel permeation studies. In addition to ZGPpNA (K(Mapp) of 53 microM), PEPase was capable of hydrolyzing azocasein, although at a low rate. No activity was detected when ZGPpNA was replaced by substrates for carboxypeptidase A and B, chymotrypsin, subtilisin, and neutral endopeptidase. N-[N-(L-3-trans-Carboxirane-2-carbonyl)-L-Leu]-agmatine (E-64) and tosyl-L-Lys chloromethyl ketone did not inhibit PEPase activity. Both phenylmethylsulfonyl fluoride and diprotin A inhibited ZGPpNA cleavage, the latter doing so competitively (K(lapp) of 343 microM). At 100 degrees C, the enzyme displayed some tolerance to sodium dodecyl sulfate treatment. Stability of PEPase over time was dependent on protein concentration; at temperatures above 65 degrees C, dilute samples retained most of their activity after 24 h while the activity of concentrated preparations diminished significantly. This decrease was found to be due, in part, to autoproteolysis. Partially purified PEPase from P. furiosus exhibited the same temperature optimum, molecular weight, and kinetic characteristics as the enzyme overexpressed in E. coli. Extracts from P. furiosus cultures grown in the presence of maltose were approximately sevenfold greater in PEPase activity than those grown without maltose. Activity could not be detected in clarified medium obtained from maltose-grown cultures. We conclude that mlr-2, now called prpA, encodes PEPase; the physiological role of this protease is presently unknown.

Training residents to care for the mentally ill.

Recent changes in Royal College training requirements have highlighted the need for residency programs to be able to offer challenging and worthwhile experiences to their trainees in caring for the chronically mentally ill. This training should bring them into contact with patients at each stage of their illness and recovery and expose them to the different settings in which treatment or management takes place. Postgraduate programs face many problems in organizing this teaching that arise from the nature and course of long-term psychiatric illnesses, the organization of residency training programs, attitudes and preconceptions of residents and teachers and competing time demands. The authors review these problems, identify specific goals for the training and suggest strategies for achieving these goals. Expectations of postgraduate programs, clinical placements, supervisors and residents themselves are outlined.

Purification from baker's yeast of an activator of DNA photolyase.

The activity of purified DNA photolyase from Baker's yeast is enhanced by a compound (Activator (III)) obtained from yeast by chloroform extraction ion exchange chromatography and gel filtration. Thin layer chromatography and spectral data indicate that the compound is homogeneous. Activator III emits at 350 and 440 nm when excited at 290 nm, and emits at 440 nm when excited at 358 nm. After acid hydrolysis, emission at 440 nm is produced only by excitation at 358 nm, indicating that activator (III) contains two separate chromophoric moieties. The chromophore excited by 358 nm light has a pK of 9-11, while the other chromophore has a pK of 4-5, and possibly of 9-11. The enhancement of photolytic activity by activator (III) at a concentration equimolar with that of the enzyme and the similarity of the fluorescent spectra of the activator with that of heat-denatured photolyase, suggests that the activator may be the chromophore associated with the enzyme.

Yeast DNA photolyase: molecular weight, subunit structure, and reconstruction of active enzyme from its subunits.

Yeast DNA photolyase, purified by affinity chromatography, ran as a single component when analyzed by either electrophoresis on polyacrylamide gradient gels or by sedimentation velocity through 5-20% sucrose gradients containing 0.4 M KCl, and, therefore, was considered homogeneous. The molecular weights of photolyase, determined by these methods, were 130000 and 136000, respectively. When the enzyme was examined by electrophoresis on sodium dodecyl sulfate polyacrylamide gradient gels, it dissociated into two bands whole molecular weights were 60000 and 85000. After the enzyme was sedimented through sucrose gradients in the presence of 1.0 M KCl, two absorbance maxima, which corresponded to polypeptides of 54000 and 82500, were found in the fractions collected. Thus, the enzyme consists of two dissimilar subunits. When the two fractions that exhibited maximal absorbance were mixed together, a time-dependent increase in activity occurred, demonstrating that active enzyme could be reconstituted from these subunits. Analysis of sucrose gradients containing 1.0 M salt for photolyase activity showed that it was present exclusively in the region of the gradient corresponding to 68200 in agreement with a previous report (J. Cook and T. Worthy (1972), Biochemistry 11, 388). These active fractions were found in the overlap region between the two subunits, and their activity was attributed to reconstitution of the enzyme during the assay.