Oclacitinib (APOQUEL(®)) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy.

Janus kinase (JAK) enzymes are involved in cell signaling pathways activated by various cytokines dysregulated in allergy. The objective of this study was to determine whether the novel JAK inhibitor oclacitinib could reduce the activity of cytokines implicated in canine allergic skin disease. Using isolated enzyme systems and in vitro human or canine cell models, potency and selectivity of oclacitinib was determined against JAK family members and cytokines that trigger JAK activation in cells. Oclacitinib inhibited JAK family members by 50% at concentrations (IC50 's) ranging from 10 to 99 nm and did not inhibit a panel of 38 non-JAK kinases (IC50 's > 1000 nM). Oclacitinib was most potent at inhibiting JAK1 (IC50 = 10 nM). Oclacitinib also inhibited the function of JAK1-dependent cytokines involved in allergy and inflammation (IL-2, IL-4, IL-6, and IL-13) as well as pruritus (IL-31) at IC50 's ranging from 36 to 249 nM. Oclacitinib had minimal effects on cytokines that did not activate the JAK1 enzyme in cells (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50 's > 1000 nM). These results demonstrate that oclacitinib is a targeted therapy that selectively inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus and suggests these are the mechanisms by which oclacitinib effectively controls clinical signs associated with allergic skin disease in dogs.

The virtues in psychiatric practice.

Using as a guide Pellegrino and Thomasma's "end-oriented beneficence model" of the virtues in medical practice, the author derives from the cardinal forms of psychiatric treatment a set of virtues particular to this field. Prior work from Jung, Havens and Menzer-Benaron helps to clarify the analysis.

Theories of the self.

This paper reviews the historical and conceptual development of theories concerning the nature of the self, highlighting both common themes and differences among representative theorists and their systems. The evolution of the concept of the self is traced from its ancient foundations in Vedic thought through its classical period (Socrates) and into the present century, where the work of James, Freud, Klein, Fairbairn, Sullivan, Winnicott, and Kohut illustrate the major modern refinements of the concept. The paper concludes with my own recent work toward a synthesis of these developments.

A mathematical model of the self.

I attempt here briefly to sketch a mathematical structure with properties analogous to key features of the self. This structure, while not easy to envision, is nonetheless as plausible a basis for theory as any science requires. I hope in this way to account for some aspects of the self that have long impeded systematic thinking on the subject.

Ownership: a pathography of the self.

With this essay I intend to base a theory of psychodynamics on the concept of ownership. I begin with the crucial but negative notion, unconsciousness, exploring certain ways in which this notion is necessary to any psychodynamic theory. Following Havens (1986), I take the concept of self as supraordinate to the elements of psychoanalytic structural theory. Building upon a unique relationship between the self and the unconscious, I then show that variations in self-ownership suffice to generate the gamut of psychopathological situations. I critique the economic aspect of Freudian psychodynamic theory, suggesting a way to improve upon it. In light of the theory thus elaborated, I examine the problem of deliberate suffering. Finally, I suggest a place of special importance for the present theory in psychoanalysis and psychiatry.

Some philosophical directions towards a simple theory of the self.

In the act of self-observation, an individual becomes simultaneously observer and observed, subject and object. While some philosophical psychologists have dismissed this reflexivity, the present author proposes that it is the essential feature of the self, making it the basis of a new, conceptually simple, structural and dynamic theory of the self. Drawing from psychopathology, poetry and literature, the author portrays normal and disordered psychological states as disturbances in reflexivity. Qualitative and quantitative variations in this core function are proposed to define discreet spectra of psychological situations. The author briefly examines the theories and practices of psychoanalytic and existential psychology, and proposes clinical applications of the new views here depicted. He attempts to show that inherent limits to our simultaneous knowledge of both aspects of the reflexive duality limit the precision and validity of all psychological theorization.

The question of medical psychotherapy.

Using Freud's "Question of Lay Analysis" as a starting point, the author discusses the role of psychotherapy in contemporary psychiatry. Certain larger concerns are addressed, including psychiatric theorization, training, stigma, and "the problem of doing."

An H-2Ld hybrid molecule with a Qa-2 alpha-3 domain and phosphatidyl-inositol anchor is not recognized by H-2Ld-specific cytotoxic T lymphocytes.

Ld/Q7d, a hybrid molecule consisting of alpha-1 and alpha-2 domains from H-2Ld and alpha-3 and carboxy-end components from Q7d, was expressed on the surface of CRL-3A rat liver cells. This molecule retained serologic H-2Ld epitopes. The Ag is attached to the cell membrane through a phosphatidyl-inositol linkage, characteristic of Qa-2 molecules. Both bulk cultured and cloned H-2Ld alloreactive CTL as well as H-2Ld restricted vesicular stomatitis virus-specific CTL lyse CRL-3A cells which express H-2Ld but show little or no lytic activity on cells which express the Ld/Q7d hybrid. These cells also fail to act as cold target competitors for alloreactive anti-H-2Ld CTL. However, cells expressing Ld/Q7d are not resistant to CTL mediated lysis because they can be killed in the presence of lectin. These data indicate that recognition of polymorphic class I CTL epitopes in the alpha-1 and alpha-2 domains are influenced by the structure of the carboxy-end of the molecule.

Inpatient treatment of the mentally ill substance abuser: some medicolegal concerns.

Alcohol and drug abuses complicate medicolegal issues in psychiatry by blurring the boundaries between medicine and law. Furthermore, the usual tests for the applicability of either legal or medical measures often cannot be applied to the dually diagnosed. Specific quandaries arise with involuntary hospitalization and treatment, and with evaluating patients for the courts. The author discusses these problems, introducing the concept of state-dependent competency, using a case vignette to illustrate several points. Legal theories of behavior assume freedom of action; medical theories assume determinism. Phenomena of addiction defy such distinctions and thus may pose difficulties that cannot reliably be assigned either a medical or a legal remedy.

An immunodominant epitope present in multiple class I MHC molecules and recognized by cytotoxic T lymphocytes.

CTL derived from (C3H x B6.K1)F1 animals were sensitized against L cells that express the transfected gene product Q10d/Ld. These CTL were highly crossreactive against three other class I molecules, H-2Kbm1, H-2Ld, and H-2Kd. In an attempt to define this crossreactive epitope it was noted that between 25 and 39% of amino acids in the alpha helices and central beta strands of these three molecules vary from Q10d. These amino acids represent residues that have been proposed to potentially interact with a peptide antigen or TCR (21). However, all four molecules share the amino acid tyrosine at positions 155 and 156. Additionally, Q10d, H-2Kbm1, and H-2Ld share alanine at position 152, while H-2Kd has an aspartic acid. We showed that these residues were important in controlling this epitope by the finding that anti-Q10d CTL did not recognize H-2Kbm1 revertant molecules that had either the position 152 alanine changed back to the wild-type H-2Kb residue (glutamic acid) or position 155 and 156 tyrosines changed back to wild-type residues arginine and leucine. Further evidence that these molecules share a crossreactive epitope was noted by the failure of (C3H x H-2Kbm1)F1 animals to generate CTL that recognized H-2Ld or H-2Kd, and the inability of (C3H x BALB/c)F1 animals to generate CTL reactive against H-2Kbm1. CTL from these mice were still able to recognize Q10d/Ld indicating that other epitopes could be detected if natural tolerance prevented recognition of the crossreactive epitope. To further define the epitope, CTL clones were generated against Q10d/Ld and maintained on either H-2Kbm1 or BALB/c feeder cells. In addition to testing these clones on the target cells described above, mutant molecules derived from H-2Ld, which have amino acid substitutions in their alpha 1 domain, were analyzed. It was noted that some anti-Q10 clones that did not crossreact on H-2Ld did react against H-2Ld mutant antigens that had H-2Dd amino acid substitutions in the alpha 1 domain at positions 63, 65, 66, and 70. Other clones had differential reactivities on these H-2Ld mutants further substantiating that alpha 1 domain amino acids play a role in controlling the expression of the crossreactive epitope. Thus, four class I molecules with multiple amino acid differences in their alpha 1 and alpha 2 domains share a crossreactive epitope readily recognized by alloreactive CTL.(ABSTRACT TRUNCATED AT 250 WORDS)

A third class I major histocompatibility complex antigen encoded by a gene in the D region of the H-2d haplotype recognized by cytotoxic T lymphocytes.

The D region of the H-2d haplotype contains five class I genes: H-2Dd, D2d, D3d, D4d and H-2Ld. Although previous studies have suggested the presence of D-end encoded class I molecules in addition to H-2Dd and H-2Ld, segregation of genes encoding such molecules has not been demonstrated. In this report we have used cytotoxic T lymphocytes (CTL) to examine the D region of the H-2d haplotype for the presence of additional class I molecules. CTL generated in (C3H x B6.K1)F1 (KkDk, KbDb) mice against the hybrid class I gene product Q10d/Ld expressed on L cells cross-react with H-2Ld but not H-2Dd molecules, as determined by lysis of transfected cells expressing H-2Ld but not H-2Dd. Although H-2Ld-specific monoclonal antibodies (mAb) completely inhibit H-2Ld-specific CTL from killing B10.A(3R) (KbDdLd) target cells, only partial inhibition of anti-Q10 CTL-mediated lysis was observed, suggesting the presence of an additional D-end molecule as a target for these latter CTL. To identify the region containing the gene encoding the Q10 cross-reactive molecule, we show that anti-Q10 CTL lyse target cells from a D-region recombinant strain B10.RQDB, which has H-2Dd, D2d, D3d, D4d, and H-2Db but not the H-2Ld H-2d, and H-2Ld (including D2d, D3d, and D4d), lacks this anti-Q10 CTL target molecule. Together, these data demonstrate that a class I gene mapping between H-2Dd and H-2Ld encodes an antigen recognized by anti-Q10 CTL. A likely candidate for this gene is D2d, D3d, or D4d.

The Special Treatment Team: an inpatient approach to the mentally ill alcoholic patient.

We review the problems unique to the diagnosis and treatment of patients who suffer both major mental illness and alcohol/drug abuse. We describe the experience and the approach evolved in the Special Treatment Team, a State Hospital unit that has specialized in this work. We discuss in detail the assessment and stabilization of such patients, including psychosocial and pharmacologic strategies, giving special attention to the problem of the unmotivated patient. Several case vignettes illustrate our approach.

Introduction of H-2Dd determinants into the H-2Ld antigen by site-directed mutagenesis.

We used site-directed mutagenesis to localize serologically defined (s) and CTL (c)-defined alloantigenic determinants to discrete amino acid sequences of a murine MHC class I antigen. Based on the prediction that amino acid position 63-73 of the H-2Dd antigen forms s-allodeterminants, the H-2Ld gene was mutated in a sequential fashion to replace codons for amino acid positions 63, 65, 66, 70, and 73 with those of the H-2Dd amino acids. Epitopes of the mutant antigens expressed in L-cells were examined by the binding of a series of mAbs specific for the H-2Dd antigen. The mutant antigen M66 had substitutions at residues 63, 65, and 66, and resulted in the acquisition of a number of H-2Dd-specific s-epitopes. Mutant M70 had an additional substitution at residue 70, which led to the gain of multiple additional H-2Dd s-epitopes. Together, more than half of all the relevant H-2Dd s-epitopes were mapped into amino acid position 63-70 of the H-2Dd molecule, which was expressed in the mutant H-2Ld gene. The final mutation at residue 73 (M73) caused no new epitope gains, rather, a few Dd s-epitopes acquired by the preceding mutations were lost. All of the H-2Ld-specific s-determinants were retained in the mutant molecules, as were H-2Dd s-determinants specific for the alpha-2 or alpha-3 domains. Changes of these residues affected c-determinants defined by CTL. Anti-H-2Dd CTL cultures and an anti-H-2Dd CTL clone recognized the mutant H-2Ld molecules, M66 and M70. Some CTL clones generated against the Q10d molecule, which has an identical sequence to H-2Dd between residues 61 and 73, failed to recognize native H-2Dd or Ld but did crossreact with mutant Ld. While bulk-cultured anti-H-2Ld CTL cultures reacted strongly against M73, bulk-cultured H-2Ld restricted anti-vesicular stomatitis virus CTL did not. Finally, at the clonal level two of three anti-H-2Ld CTL clones lost reactivity with some or all of these mutant molecules. From these results we conclude that a stretch of amino acids from position 63 to 70 of the alpha-1 domain controls major s- and c-antigenic sites on the H-2Dd antigen and c-sites on H-2Ld antigen.

Cytotoxic T lymphocytes from mice with soluble class I Q10 molecules in their serum are not tolerant to membrane-bound Q10.

Q10 is a class I Qa-2 region-encoded molecule that is secreted by the liver and present in serum at high concentrations (about 10 to 60 micrograms/ml) in most strains of mice. The amino terminal portion of this molecule can also be expressed as an integral membrane protein by splicing the 5' end of the Q10 gene to the 3' end of H-2Ld and transfecting the hybrid gene into murine L cells. Because CTL primarily recognize polymorphic determinants controlled by the alpha 1 and alpha 2 domains of class I molecules and because the Q10d/Ld product expressed by transfected L cells includes the alpha 1 and alpha 2 domains of Q10d, we could address whether mice bearing serum Q10 were tolerant to this molecule at the CTL level. The results of these experiments demonstrate that Q10+ mice are able to generate H-2-unrestricted CTL activity against Q10d expressed on transfected L cells, and this response was not inhibitable by the addition of Q10-containing normal mouse serum. It is unlikely that this CTL activity is due to possible polymorphic differences in Q10 alleles, since semisyngeneic BALB/c (H-2d) mice, from which the Q10d hybrid gene construct was derived, are able to generate anti-Q10d effector cells. The Q10d molecule was shown to cross-react with H-2Ld, lending support to the concept that Qa genes can serve as donors for polymorphic sequences found in H-2K, -D, and -L. That mice can generate anti-Q10 CTL activity suggests that this soluble class I protein does not act as a toleragen for these cells. The implications of these findings for an understanding of self-tolerance are discussed.

Six months in the treatment of two young chronic schizophrenics.

This paper presents the opening 6 months of dynamic psychotherapy with two chronically paranoid schizophrenic young men. It will focus on the use of metaphoric realms in which to meet patients, and on the vital role of identification in the conduct and motivation of therapeutic change.

Pulmonary compartmentalization of interferon and natural killer cell activity.

Studies were performed to determine if natural killer (NK) activity in the mononuclear cells harvested from infected lungs was dependent on local or systemic factors. Mice were inoculated by intratracheal (it), intraperitoneal (ip), or intravenous (iv) routes with (a LD50 dose of) influenza virus A PR/8/34. At various days postinoculation cells from lungs, spleens, and peripheral blood were assayed for NK activity, and lung wash, lung homogenates, and serum were assayed for interferon. After it inoculation there was three- to fourfold increase of NK activity in the lung with little or no increase in NK activity in spleens or peripheral blood. The local augmentation of NK activity in the lung correlated with an increase in interferon (IFN) titer in the lung wash and lung homogenate of PR8 inoculated mice. The virus failed to induce IFN or augment NK activity when it was inoculated systemically. The observed local augmentation of NK activity and local induction of interferon production following it inoculation suggests that the NK population in the lung is capable of responding to locally derived regulatory factors.

Pharmacologic suppression of the fetal adrenal gland in utero. Attempted prevention of abnormal external genital masculinization in suspected congenital adrenal hyperplasia.

21-Hydroxylase deficiency results in congenital adrenal hyperplasia and leads to masculinization of the external genitalia of affected females. This complication could be avoided if fetal adrenal gland function were suppressed. A woman with mild 21-hydroxylase deficiency whose previous female child had classic congenital adrenal hyperplasia with masculinization was given dexamethasone beginning at the tenth week of gestation. Maternal estriol and cortisol values indicated rapid and sustained fetal and maternal adrenal gland suppression. At 39 weeks' gestation, the patient was spontaneously delivered of a female neonate with normal external genitalia. Postnatal tests indicated the infant was a single heterozygote for 21-hydroxylase deficiency. This study demonstrates prolonged suppression of the fetal adrenal gland with dexamethasone and suggests it might prevent abnormal masculinization in fetuses with severe congenital adrenal hyperplasia.

The antidiuretic hormone response to therapy for acute asthma.

The plasma antidiuretic hormone concentrations in eight asthmatic children were measured at the onset of an acute severe attack and were repeated 24 h later. Conventional therapy and maintenance fluid intake resulted in a significant fall in antidiuretic hormone concentrations without abnormal changes in other biochemical indicators of dehydration.