Testing immediate dosage compensation in Drosophila miranda via irradiation with heavy-ion beams.

Many organisms with heteromorphic sex chromosomes possess a mechanism of dosage compensation (DC) in which X-linked genes are upregulated in males to mitigate the dosage imbalance between sexes and between chromosomes. However, how quickly the DC is established during evolution remains unknown. In this study, by irradiating Drosophila miranda male flies, which carry young sex chromosomes (the so-called neo-sex chromosomes), with heavy-ion beams, we induced deletions in the neo-Y chromosome to mimic the condition of Y-chromosome degeneration, in which functional neo-Y-linked genes are nonfunctionalized; furthermore, we tested whether their neo-X-linked gametologs were immediately upregulated. Because the males that received 2-Gy iron-ion beam irradiation exhibited lower fertility, we sequenced the genomes and transcriptomes of six F1 males derived from these males. Our pipeline identified 82 neo-Y-linked genes in which deletions were predicted in the F1 males. Only three of them showed a one-to-one gametologous relationship with the neo-X-linked genes. The candidate deletions in these three genes occurred in UTRs and did not seriously affect their expression levels. These observations indirectly suggest that DC was unlikely to have operated on the neo-X-linked genes immediately after the pseudogenization of their neo-Y-linked gametologs in D. miranda. Therefore, the dosage imbalance caused by deletions in the neo-Y-linked genes without paralogs may not have effectively been compensated, and individuals with such deletions could have exhibited lethality. Future studies on sex chromosomes at different ages will further reveal the relationship between the age of sex chromosomes and the stringency of DC.

[A Case of Neuroendocrine Carcinoma Originating from the Papilla of Vater].

A woman in her late 70s with fatigue, nausea, and epigastric discomfort was found to have a tumor at the papilla of Vater through endoscopy. We performed subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection. The immunohistological analysis showed positive staining for chromogranin A, synaptophysin, and CD56. The definitive diagnosis was neuroendocrine carcinoma of the papilla of Vater. Although the patient declined adjuvant chemotherapy, she had to start chemotherapy with carboplatin and etoposide because multiple liver metastases, lymph node metastasis, and peritoneal dissemination occurred 6 months after surgery. We performed 6 courses of chemotherapy. However, progressive disease(PD)was assessed, and she died of cancer 13 months after the surgery. The prognosis of the disease is poor when surgery alone is performed. Adjuvant chemotherapy, in addition to surgery, may be necessary.

[Successful Experience of Negative Pressure Wound Therapy with Instillation and Dwelling(NPW Ti-d)for Patient with Wound Dehiscence Developed by Infection after Right-Hemicolectomy for Ascending Colon Cancer].

We report a case of infected and incised wound cured by negative pressure wound therapy with instillation and dwelling (NPWTi-d)after right hemicolectomy for ascending colon cancer. The patient was a 72-year-old male. An ascending colon cancer with abdominal wall invasion and enterocutaneous fistula was found. We performed the right hemicolectomy and debridement of abdominal wall for the patients. However, the leakage of ileum-transverse colon anastomosis was found on postoperative day 3. We performed the resection of anastomosis and ileostomy. Nevertheless, 2 days after second operation, the abdominal wall of debridement became open by infection, and the small intestine was exposed. As the surgical treatment and NPWT was thought to be difficult because of infection, we started NPWTi-d on day 4 after second operation. 25 day after starting NPWTi-d, benign granulation covered the small intestine. NPWTi-d may be useful for wound dehiscence after surgery in infectious conditions.

Intrathecal baclofen therapy for Lesch-Nyhan disease: illustrative case.

BACKGROUND: Lesch-Nyhan disease (LND) is a very rare metabolic disorder involving the purine salvage pathway. LND manifests hyperuricemia, self-mutilation, cognitive impairment, and movement disorders such as spasticity and dystonia, whose control is difficult pharmaceutically. OBSERVATIONS: Intrathecal baclofen (ITB) therapy was received by a 22-year-old male for generalized dystonia. His paroxysmal abnormal dystonic posturing reduced after surgery, making the task of caregivers easier despite the unchanged assignment on the dystonia scale during a follow-up period of 4 years. LESSONS: ITB may be a safe and feasible option for dystonic symptoms and difficulty with nursing care in patients with LND.

Premorbid instrumental activities of daily living predicts discharge home following stroke.

BACKGROUND AND PURPOSE: Stroke survivors who remain dependent require multiple healthcare resources, including rehabilitation and nursing care. The effect of premorbid instrumental ADL (IADL) on the discharge destination, which has not been studied previously in detail, is analyzed. MATERIALS AND METHODS: Between April and September 2015, 40 stroke patients admitted to hospital were enrolled prospectively in the present study. The ADL (Barthel index) and IADL (Frenchay activities index: FAI) scores in their premorbid status were recorded. Baseline demographic data, stroke severity (NIHSS) and type of stroke, and whether they lived with family were also recorded. Simple univariate regression was performed between the two discharge destination groups (Home or Not Home). Significant factors were then included in multivariate logistic regression in order to determine the adjusted odds ratio for the discharge destination. A P value <.05 was taken as significant. RESULTS: 25 patients (64.1%) returned home. According to univariate analysis, NIHSS on admission and premorbid FAI were significantly associated with the discharge destination. Multivariate analysis found that NIHSS (OR, 0.71; 95% CI0.56-0.92; p = .008) and premorbid FAI (OR, 1.17; 95% CI1.03-1.33; p = .01) were independent predictors of the discharge destination. CONCLUSIONS: Severity of stroke upon admission and premorbid IADL are associated with discharge destination following stroke.

[Local Contributions and Regional Alliances by Pharmaceutical Wholesalers].

Recently, we considered the term 'integrated community care system' and aimed to play a role in the process by joining various healthcare occupations as part of this new integrated system. Given our company's ties with people involved in a range of occupations, we are poised to play a liaison role. We called a "face-to-face meeting" with local healthcare practitioners to begin exploring this cooperation. We believe that as meetings such as these become more widespread across the Kinki Region, they can serve as part of an integrated community care system. Through the formation of a number of alliances by this means, we hope to facilitate the transition to an integrated community care system. The meetings will provide opportunities for a range of healthcare and long-term care professionals, such as physicians, pharmacists, care managers, social workers, and home-visit nurses, to engage in discussions centered on the interests and needs of patients. Another important topic is whether we can derive from these conversations efforts that would assist in the development of "health support pharmacies". In that regard, we have set up some support tools for pharmacies that have held health fairs for local inhabitants. We consider these meetings beneficial in finding a solution to the situation of "polypharmacy"-a recent medical problem. We hope that our meetings will create an opportunity to work cooperatively toward a vision for the future of healthcare and long-term care within a community, through communicating and sharing our proposals for pharmacists based on these experiences.

Phenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report.

BACKGROUND: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with severe prognosis. Disease-specific therapy is crucial to prevent disease progression; however, diagnosing NPC is quite difficult because of remarkably variable clinical presentations. The NPC Suspicion Index (NPC-SI) was developed to overcome this problem. Identifying preclinical cases is important for prevention and therapy. Here, we report three newly diagnosed NPC cases, one typical juvenile-onset case and the cases of two sisters with symptoms neurologically/psychiatrically indistinguishable from dystonia and schizophrenia, respectively. CASE PRESENTATION: In Case 1, a 25-year-old man presented with a 14-year history of intellectual disability, clumsiness, spastic ataxia, dysphagia, and frequent falls. Neurological examination revealed vertical supranuclear gaze palsy and involuntary movements. Ultrasonography revealed mild splenomegaly, and filipin staining of skin fibroblasts was positive with a variant staining pattern. NPC1 gene analysis showed compound heterozygous mutations, including c.1421C > T (p.P474L), a known causative mutation, and c.3722 T > C (p.L1241S), a new mutation. In Case 2, a 28-year-old woman, the proband, who had marked splenomegaly in her childhood, survived well, contrary to the expected severe prognosis of infantile NPC. She had minor neuropsychiatric symptoms including auditory hallucinations, nocturnal urination, and sleep paralysis. At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient's 35-year-old sister (Case 3) was diagnosed with schizophrenia. In both cases, filipin staining of skin fibroblasts was positive with variant staining patterns, as well as elevated levels of urinary bile acids. NPC1 gene analysis showed compound heterozygous mutations including c.3011C > T (p.S1004 L), a known causative mutation, and c.160_161insG (p.D54GfsX4), a new mutation. Their mother, who was under therapy with modafinil for narcolepsy, shared the latter mutation. CONCLUSIONS: Marked clinical variability was observed in our three cases. NPC could masquerade as a pure neuropsychiatric disorder such as dystonia or schizophrenia. Abdominal ultrasonography, history evaluation, and neurological examination were quite important in the diagnostic process.

Spontaneous Resolution of Cerebral Pial Arteriovenous Fistula After Angiography: Report of Two Cases.

BACKGROUND: Cerebral pial arteriovenous fistula (AVF) is a rare disorder, and its natural course is uncertain. The present article reports 2 rare cases of pial AVF that underwent spontaneous cure after diagnostic cerebral angiogram. CASE DESCRIPTIONS: A 73-year-old man presented with generalized seizure and reported severe but intermittent headache in the right temporo-occipital area. Single-photon emission computed tomography (SPECT) showed hyperperfusion in that area. The main finding of a cerebral angiogram was an arteriovenous shunt at the cortical surface of the right temporal area. Soon after this diagnostic angiogram, the symptoms vanished. A further cerebral angiogram showed the disappearance of this pial AVF, and a SPECT study showed resolution of the hyperperfusion of the affected area. A 69-year-old man, with a history of intracerebral hemorrhage on the left parietal area 3 years earlier, presented with speech disturbance and headache on his left side. SPECT showed hyperperfusion in the left temporoparietal area. A cerebral angiogram showed an arteriovenous shunt at the surface of the left parietal area. During the same cerebral angiogram session, the pial AVF disappeared after the third injection of a contrast medium with magnification. Two days after the cerebral angiogram, the patient's headache disappeared and speech disturbance gradually improved. SPECT also showed disappearance of the hyperperfusion. CONCLUSIONS: It is possible that pial AVF is a cause of headache and neurologic symptoms in association with focal hyperperfusion. Diagnostic cerebral angiography should be performed to make a definite diagnosis; after this, pial AVF sometimes disappears.

Compound heterozygous intermediate MJD alleles cause cerebellar ataxia with sensory neuropathy.

Spinocerebellar degeneration (SCD) is a group of disorders characterized by progressive ataxia caused by dysfunction and atrophy of the cerebellum or its projections. Approximately one-third of SCD cases are familial SCD, the majority of which are attributed to CAG triplet repeat expansions including spinocerebellar ataxia (SCA)1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA6, SCA8, SCA12, SCA17, and dentate-rubro-pallido-luysian atrophy (DRPLA). The triplet repeat number of the alleles representing complete penetrance varies among diseases. Generally, there is a gap between the normal alleles and the complete penetrance alleles. Rarely, intermediate alleles with the repeat numbers between the abnormal and normal ranges are observed, although the implications of these intermediate alleles remain ambiguous.

Differential effects of fingolimod on B-cell populations in multiple sclerosis.

BACKGROUND: Fingolimod is an oral drug approved for multiple sclerosis (MS) with an ability to trap central memory T cells in secondary lymphoid tissues; however, its variable effectiveness in individual patients indicates the need to evaluate its effects on other lymphoid cells. OBJECTIVE: To clarify the effects of fingolimod on B-cell populations in patients with MS. METHODS: We analysed blood samples from 9 fingolimod-treated and 19 control patients with MS by flow cytometry, to determine the frequencies and activation states of naive B cells, memory B cells, and plasmablasts. RESULTS: The frequencies of each B-cell population in peripheral blood mononuclear cells (PBMC) were greatly reduced 2 weeks after starting fingolimod treatment. Detailed analysis revealed a significant reduction in activated memory B cells (CD38(int-high)), particularly those expressing Ki-67, a marker of cell proliferation. Also, we noted an increased proportion of activated plasmablasts (CD138(+)) among whole plasmablasts, in the patients treated with fingolimod. CONCLUSIONS: The marked reduction of Ki-67(+) memory B cells may be directly linked with the effectiveness of fingolimod in treating MS. In contrast, the relative resistance of CD138(+) plasmablasts to fingolimod may be of relevance for understanding the differential effectiveness of fingolimod in individual patients.

Postmortem analyses of drugs in pericardial fluid and bone marrow aspirate.

In forensic toxicology, bone marrow is often used when adequate blood samples are not available; however, pericardial fluid (PCF) has been poorly investigated. The present study comprehensively reviewed the toxicological data of blood, PCF and bone marrow aspirate (BMA) in forensic autopsy cases to investigate drug distribution. Analysis using automated gas chromatography/mass spectrometry (GC-MS) following solid/liquid phase extraction detected 36 drugs in 218 cases (8.0% among 2,724 cases examined). Drug distribution varied by drug as well as partly by case even when taken as a mixture. Most of the drugs showed overall similar distributions in right heart blood, PCF and BMA with some exceptions, however, several drugs, including phenothiazine derivatives and antidepressants, were detected at ∼1.5 times (1.2-2.0) higher levels in BMA than in right heart blood, but PCF levels were mostly equivalent to blood levels. Midazolam, propofol and thiamylal (intravenous anesthetics) were detected at a substantially lower concentration in PCF than in blood or BMA. These observations suggest that PCF and BMA are useful materials to be included in the forensic toxicological routine when blood samples are not available, as well as to investigate pharmaco-/toxicokinetics and postmortem redistribution.

Differential diagnosis tool for parkinsonian syndrome using multiple structural brain measures.

Clinical differentiation of parkinsonian syndromes such as the Parkinson variant of multiple system atrophy (MSA-P) and cerebellar subtype (MSA-C) from Parkinson's disease is difficult in the early stage of the disease. To identify the correlative pattern of brain changes for differentiating parkinsonian syndromes, we applied discriminant analysis techniques by magnetic resonance imaging (MRI). T1-weighted volume data and diffusion tensor images were obtained by MRI in eighteen patients with MSA-C, 12 patients with MSA-P, 21 patients with Parkinson's disease, and 21 healthy controls. They were evaluated using voxel-based morphometry and tract-based spatial statistics, respectively. Discriminant functions derived by step wise methods resulted in correct classification rates of 0.89. When differentiating these diseases with the use of three independent variables together, the correct classification rate was the same as that obtained with step wise methods. These findings support the view that each parkinsonian syndrome has structural deviations in multiple brain areas and that a combination of structural brain measures can help to distinguish parkinsonian syndromes.

Abnormalities of cerebral blood flow in multiple sclerosis: a pseudocontinuous arterial spin labeling MRI study.

Arterial spin labeling (ASL) is a noninvasive technique that can measure cerebral blood flow (CBF). To our knowledge, there is no study that examined regional CBF of multiple sclerosis (MS) patients by using this technique. The present study assessed the relationship between clinical presentations and functional imaging data in MS using pseudocontinuous arterial spin labeling (pCASL). Twenty-seven patients with MS and 24 healthy volunteers underwent magnetic resonance imaging and pCASL to assess CBF. Differences in CBF between the two groups and the relationships of CBF values with the T2-hyperintense volume were evaluated. Compared to the healthy volunteers, reduced CBF was found in the bilateral thalami and right frontal region of the MS patients. The volume of the T2-hyperintense lesion was negatively correlated with regional CBF in some areas, such as both thalami. Our results suggest that demyelinated lesions in MS mainly have a remote effect on the thalamus and that the measurement of CBF using ASL could be an objective marker for monitoring disease activity in MS.

Postmortem analyses of gaseous and volatile substances in pericardial fluid and bone marrow aspirate.

A previous study suggested the usefulness of pericardial fluid (PCF) and bone marrow aspirate (BMA) for the postmortem analysis of ethanol. The present study reviewed forensic autopsy cases (n = 2,983), which included 683 cases with the following positive toxicological findings, to reassess ethanol distribution and to investigate other gaseous and volatile substances in blood, PCF and BMA. Toxicological analyses detected ethanol (>10 mg/dL, n = 345), acetone (>0.01 mg/dL, n = 402), cyanide (n = 282), toluene (n = 47), liquefied petroleum gas (LPG, n = 1), cresol (n = 1), trichloroethylene (TCE, n = 1) and hydrogen sulfide (H2S, n = 5) in 683 cases. Ethanol and acetone levels showed good correlations among right heart/peripheral blood, PCF and BMA with a few exceptions. Inhaled cyanide in a fire fatality and H2S in suicidal inhalation were substantially lower in PCF than in blood and BMA; however, ingested cyanide showed a higher level in PCF. Distribution of inhaled toluene largely varied by case; however, BMA levels were about twice as high as blood levels in abusers (n = 7). Inhaled LPG and TCE were also higher in BMA than in blood, whereas ingested cresol showed similar distributions in blood and PCF. These observations suggest the usefulness of PCF and BMA as alternatives to blood for postmortem toxicological analysis. The inclusion of these materials in routine analysis may be also useful to investigate pharmacokinetics and toxicokinetics in the death process and the influence of postmortem redistribution/diffusion.

Medullary ischemia due to vertebral arteritis associated with Behçet syndrome: a case report.

Here we report an extremely rare case of Behçet syndrome (BS) that showed acute onset of Wallenberg syndrome and was treated successfully by corticosteroids. A 51-year-old woman with BS had a sudden onset of Wallenberg syndrome. Three days after the onset, she was transferred to our institute. In the magnetic resonance imaging (MRI) study on admission, T2-weighted and fluid-attenuated inversion recovery images showed a high intensity area in the left paramedian region of the medulla oblongata. Contrast-enhanced T1-weighted images showed enhancement in the vessel wall of the left vertebral artery. We diagnosed her as having Wallenberg syndrome due to the acute vertebral arteritis associated with BS. After initiation of high-dose steroid therapy, her symptoms gradually improved. Two months after admission, she was discharged from our institute with mild hemihypesthesia. We hypothesized that vertebral arteritis due to BS had caused hypoperfusion of the medullary perforators causing Wallenberg syndrome in our patient.

CCR2(+)CCR5(+) T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4(+) autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2(+)CCR5(+) T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2(+)CCR5(+) T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2(+)CCR5(+) T cells showed a higher invasive potential across an in vitro blood-brain barrier model compared with other T cells. Of note, the CCR2(+)CCR5(+) T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6(-), but not the CCR6(+), population within CCR2(+)CCR5(+) T cells was highly enriched in the cerebrospinal fluid during MS relapse (p < 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2(+)CCR5(+)CCR6(-) Th1 cells play a crucial role in the pathogenesis of MS.

New-onset type 1 diabetes mellitus and anti-aquaporin-4 antibody positive optic neuritis associated with type 1 interferon therapy for chronic hepatitis C.

A 60-year-old woman developed type 1 diabetes mellitus and anti-aquaporin-4 antibody positive optic neuritis during type 1 interferon therapies for chronic hepatitis C. The diabetes mellitus was elicited by interferon-α plus ribavirin therapy, while the optic neuritis was induced after interferon-ß treatment, followed by interferon-α and ribavirin therapy. It is possible that type 1 interferons lead to the onset of the two autoimmune diseases by inducing disease-specific autoantibodies. Autoimmune disease is an infrequent complication of type 1 interferon treatment; however, once it has occurred, it may result in severe impairments. Patients undergoing type 1 interferon therapy should therefore be carefully monitored for any manifestations of autoimmune diseases.

[A case of long survival after resection and treatment with imatinib mesylate against metachronous liver metastases and a lung metastasis of a small intestine gastrointestinal stromal tumor].

A 68-year-old man was admitted to our hospital because of an abdominal tumor. Computed tomography(CT)showed a 6 cm tumor in the abdominal cavity. Surgery was performed. Upon laparotomy, a 6 cm tumor was found at the small intestine (210 cm)on the anal side from the Treitz ligament. A partial resection of the small intestine was performed. Immunohistochemistry showed positive staining for c-kit, and the diagnosis of gastrointestinal stromal tumor was confirmed. Multiple liver metastases and a lung metastasis were observed over the next 2 years. We started chemotherapy with imatinib mesylate at a dose of 400mg/day. The size of the tumors was unchanged, and no new lesion was observed. The patient has been alive and well as of 6 years after the initial operation.

Increase of Ki-67+ natural killer cells in multiple sclerosis patients treated with interferon-ß and interferon-ß combined with low-dose oral steroids.

Interferon-ß (IFN-ß) is known to expand regulatory CD56(bright) natural killer (NK) cells in multiple sclerosis (MS). In this cross-sectional study we show that MS patients treated with IFN-ß alone or in combination with low-dose prednisolone displayed increased proportion of all NK cell subsets in the active phase of the cell cycle (Ki-67+). There was no difference in NK cell apoptosis markers. In vitro experiments showed that both IFN-ß and IFN-ß in combination with corticosteroids increased the proportion of Ki-67(+) NK cells. This study, although limited, shows that treatment with IFN-ß affects NK cell cycle without altering NK cell apoptosis in MS patients.